Therapeutic combinations and methods for 5-HT3 receptor modulators in treating various disorders

Abstract

In alternative embodiments, provided are compositions, including products of manufacture and kits, and methods, for 5-hydroxytryptamine (5-HT3) receptor modulation using a 5-HT3 receptor partial agonist, a 5-HT3 receptor antagonist or a Glucagon-like peptide-1 (GLP-1) receptor agonist, wherein optionally the GLP-1 receptor agonist is liraglutide, for the treatment of intestinal and other diseases. In alternative embodiments, provided are therapeutic combinations and methods of use of a 5-HT3 receptor modulator, a 5-HT3 receptor partial agonist, a 5-HT3 receptor antagonist, or a Glucagon-like peptide-1 (GLP-1) receptor agonist, wherein optionally the GLP-1 receptor agonist is liraglutide, for treating irritable bowel syndrome (IBS), carcinoid syndrome, Low anterior resection syndrome (LARS), Bile Acid Diarrhea (BAD), ileal resection diarrhea, diarrhea associated with ileoanal anastomosis, adverse reactions related to Glucagon-Like Peptide-1(GLP-1) or dual GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) modulator therapy, and gastrointestinal infections, and other diseases.

Description

[0001]PATENT 7279.154670PCT THERAPEUTIC COMBINATIONS AND METHODS FOR 5- HT3 RECEPTOR MODULATORS IN TREATING VARIOUS DISORDERS TECHNICAL FIELD This invention generally relates to pharmacology and pharmacokinetics, with an emphasis on therapeutic combinations and methods of use involving the modulation of use of 5-HT3 receptor activity, a key signaling modality in the gastrointestinal tract and dermis. In alternative embodiments, provided are therapeutic combinations or formulations of drugs comprising the 5-HT3 receptor modulator (S)-7-(quinuclidine-3-yl)-8,9-dihydro-2H-azepino [5,4,3-cd]indazol-6(7H)- one (Compound I) and analogues and its associated salts, co-crystals, and polymorphs, in combination with other drugs or active agents. In alternative embodiments, provided is a cloud-based digital health system designed to enhance adherence and add the Clinical Trial Effect to therapeutic drug treatments. Specifically, the invention integrates a digitally-enabled therapeutic kit comprising advanced algorithms, models, processors, and physical memories to provide personalized intervention regimens. The platform is designed to facilitate future developments and enhancements through the integration of new algorithms, models, and processors based on clinical data, with a specific focus on the use of Compound I and liraglutide for managing functional gastrointestinal disorders (FGIDs). BACKGROUND Burden of Functional Gastrointestinal Disorders (FGIDs): Functional Gastrointestinal Disorders (FGIDs) represent a significant global unmet medical need, affecting hundreds of millions worldwide, including approximately 70 million individuals in the United States. Unlike organic gastrointestinal disorders, FGIDs are characterized by dysfunction in the brain-gut axis without identifiable structural, imaging, or laboratory abnormalities. Symptoms such as dysmotility, abdominal pain, bloating, urgency, nausea, constipation, diarrhea, and incomplete evacuation severely impair patients' quality of life and daily functioning. FGIDs are among the most common conditions seen in clinical practice, accounting for approximately 35% of office visits to gastroenterology specialists in PATENT 7279.154670PCT the U.S. Despite this prevalence, treatment outcomes remain suboptimal, contributing to a significant burden on healthcare systems. Challenges in FGID Treatment: Existing treatment options—including drug therapies, dietary modifications, psychotherapy, behavioral interventions, and digital therapeutics—fail to provide sustained therapeutic benefit for millions of patients. For hundreds of thousands with rare FGIDs, no approved therapies exist. Several interrelated challenges hinder progress in FGID treatment: 1. Complex Brain-Gut Axis Dysfunction: FGIDs result from bidirectional dysfunction between the brain and gut, complicating the development of targeted monotherapies. 2. Challenging Pharmacology: Therapies require near-perfect safety profiles to avoid exacerbating symptoms or introducing adverse effects, but often have narrow therapeutic windows, requiring careful titration and monitoring for safe use. 3. High Placebo Effect: The placebo effect often accounts for 65% to 80% of the total treatment effect in clinical trials. However, the supportive structure that drives this effect is lost in real-world practice, reducing overall therapeutic efficacy. 4. Poor Real-World Adherence: While adherence exceeds 80% in clinical trials, it drops below 60% in community settings, significantly diminishing treatment effectiveness. 5. Fragmented Care Models: Limited reimbursement for digital and supportive care services prevents the adoption of integrated, multimodal therapies that address FGIDs' multifaceted needs. In addition, irritable bowel syndrome (IBS) is a defined functional bowel disorder that is often debilitating and sometimes presents severe abdominal pain with colonic distension. Prevalence is around 10% to 11%, with a female:male ratio of 2:1. With comorbidities, including anxiety and depression, IBS contributes a considerable burden upon the healthcare system and loss of societal productivity (annual societal costs above $21 billion in the United States). IBS is subcategorized into four forms based on presenting clinical symptoms: diarrhea-predominant (IBS-d), constipation- predominant (IBS-c), alternating symptoms from between diarrhea and constipation PATENT 7279.154670PCT (IBS-mixed), and unsubtyped IBS. IBS-d represents approximately one-third of the IBS patient population. Despite the substantial clinical need, the market for effective therapies for IBS is considered naïve and underpenetrated. There are no pharmaceuticals specifically indicated for IBS-mixed and just two products with IBS-c as an indication that often deliver insufficient benefit and / or are prone to side effects and are hence considered second-line treatments subsequent to failure of laxatives / diet adjustments, which themselves have very limited success. There is no established well-tolerated treatment of IBS-d, and common remedies (diet adjustments and fiber regimens) have very limited success. Within the United States, Allergan’s opiate receptor agonist, eluxadoline (or VIBERZITM), was introduced, recently facilitated by Food and Drug Administration (FDA) “Fast Track” status, yet displays limited efficacy and is associated with common side effects, such as constipation and nausea as well as a report of ischemic colitis. It has been known for over two decades that 5-HT3 receptor antagonists, such as alosetron or ramosetron, deliver strong clinical efficacy to patients with IBS-d, presumably by blocking elevated 5-HT function in these patients that may arise fromlower expression of the 5-HT3 transporter to decrease gut motility and visceralsensation. Furthermore, increased expression of gut 5-HT3 receptor by patients with IBS-d and associated 5-HT3 receptor subunit polymorphisms support therapeutic targeting of this receptor. However, patients with IBS-d receiving 5-HT3 receptor antagonists often report (potentially severe) constipation, and rare instances of ischemic colitis are evident (around 1:750 patients), which led to the withdrawal of the marketing authorization for alosetron by the FDA and may have contributed to the decision to stop clinical development of cilansetron (issues of severe constipation and ischemic colitis were also evident). Unusually, the FDA subsequently reinstated the marketing authorization for alosetron, albeit initially with a “black box” warning. Upon reflection, it would appear that high levels of 5-HT3 receptor inhibition are likely responsible for the severe constipation and possibly ischemic colitis. In addition, a partial agonist may also benefit IBS-C (constipation) and IBS-M (mixed) because of the “dual” agonist and antagonist actions depending on the local serotonin levels. However, the latter side effect is likely a consequence of a multifactorial mechanism PATENT 7279.154670PCT that includes the presence of IBS-d itself, since unmedicated patients can present this symptom and non–IBS-d patients receiving 5-HT3 receptor antagonists for other indications (e.g., emesis), including at relatively high dosage, do not present ischemic colitis. Other conditions that can benefit from a 5-HT3 modulator, in particular, a 5- HT3 partial agonist, or a GLP-1 agonist, or a dopamine D₂ antagonist, or a combination of a 5-HT3 partial agonist and a GLP-1 agonist, include Low anterior resection syndrome (LARS), Bile Acid Diarrhea (BAD), ileal resection diarrhea, diarrhea associated with ileoanal anastomosis, IBS-like symptoms of patients with IBD (inflammable bowel disease) in clinical remission (called “IBD-IBS”), among other similar conditions. In the invention, IBD encompass both ulcerative colitis and Crohn’s disease. Medication non-adherence is a significant issue in therapeutic drug treatment, leading to suboptimal health outcomes and increased healthcare costs. Traditional methods of monitoring adherence, such as patient self-reporting and periodic clinical visits, are often unreliable and inefficient. Current solutions lack the ability to provide real-time monitoring and personalized interventions, necessitating a robust, integrated system that can offer comprehensive data management and dynamically adjust to patient needs. Additionally, non-pharmacological factors, as evidenced by the clinical trial effect (the placebo effect, the Hawthorne effect, the therapeutic alliance, social and environmental factors) contribute significantly to the overall efficacy of drug treatments, accounting for approximately 65 to 80% of the therapeutic outcome in randomized placebo controlled clinical trials. However, current drug therapies often lose these beneficial effects in routine community practice. This highlights the necessity for a digital health system that can efficiently replicate the clinical trial effect at scale in a community setting. SUMMARY This invention provides a novel drug-digital combination product that integrates optimized drug therapies, such as 5-HT3 receptor modulators, GLP-1 agonists, and dopamine D2 antagonists, either individually or in combination, with a Digital Best Supportive Care (DBSC) platform. This integrated solution replicates the PATENT 7279.154670PCT supportive structure of clinical trials, enhancing the efficacy and adherence of proven drug mechanisms in real-world community settings. The invention addresses critical unmet needs in functional gastrointestinal disorders (FGIDs) by bridging the gap between clinical trial efficacy and real-world outcomes. By combining optimized drug therapies with the DBSC platform, it ensures high adherence, sustained therapeutic benefits, and improved quality of life for patients. This integrated approach establishes a new paradigm for FGID treatment, offering a scalable solution for both common and rare FGIDs. It overcomes challenges related to adherence, efficacy, and fragmented care, while its unified regulatory framework and alignment with reimbursement models position it as a transformative innovation in FGID therapy. Scientific Insights and Opportunities for Innovation: Advancements in neuroscience, particularly in predictive processing and active inference frameworks, offer new insights into FGIDs. Predictive processing posits that the brain generates internal models (prior beliefs) to predict sensory inputs and minimize prediction errors. As shown in Figure 18, active inference extends this concept by suggesting that biological systems act to align the external environment with their expectations. In FGIDs, maladaptive prior beliefs—such as heightened visceral sensitivity and expectations of dysfunction—create a self-reinforcing cycle of symptom perception and dysfunction. Proven drug mechanisms, such as 5-HT3 receptor modulation, GLP-1 agonism, and dopamine D2 antagonism, provide symptom relief by dampening noxious gut signaling. Additionally, as shown in Figure 19, research by Ballou et al (Psychosom Med.2022 Jul-Aug 01;84(6):738-746) highlights the potential to replicate the placebo-driven "Clinical Trial Effect" as defined herein, in real-world settings by incorporating the supportive structure and rituals of clinical trials without deception. By integrating these proven drug mechanisms with digital platforms that replicate clinical trial supportive structures, there is a transformative opportunity to revolutionize FGID treatment as illustrated in Figure 20. This invention bridges the gap between clinical trial efficacy and real-world outcomes, ensuring high adherence and sustained therapeutic benefits. PATENT 7279.154670PCT In one embodiment, provided is an integrated drug-digital combination product comprising a pharmaceutical therapy and a digital platform, approved under a single regulatory label. The product includes comprehensive instructions for use within the drug label, designed to guide both physicians and patients in its application. The efficacy of the integrated product is supported by randomized controlled trial (RCT) data demonstrating: (i) the effectiveness of the pharmaceutical therapy versus placebo when paired with consistent Digital Best Supportive Care (DBSC), and (ii) the superiority of the DBSC compared to standard real-world care. In another embodiment, provided are optimized drug formulations and dosing regimens comprising pharmaceutical agents with proven mechanisms of action, including 5-HT3 receptor modulators, GLP-1 receptor agonists, and dopamine D2 antagonists. The formulations are designed with customizable delivery systems and adaptable dosing regimens to maximize therapeutic outcomes for individual patients. In one embodiment, provided is a Digital Best Supportive Care (DBSC) platform, as depicted in Figure 21, designed to enhance patient outcomes through integrated features, including: • Adherence Monitoring: Smart packaging technology, such as RFID or NFC- enabled systems, tracks real-time medication adherence and triggers automated reminders (Figures 22a and 22b). • Behavioral Support: Predictive algorithms identify disengagement risks and escalate interventions via microlessons, care navigators, or telehealth services. • Dietary Guidance: Personalized meal plans and symptom-diet correlations are generated based on patient preferences and real-time data analysis. • Symptom Tracking: Patient-Reported Outcome Measures (PROMs) combined with AI-driven analysis of symptoms and triggers provide actionable insights for targeted interventions. • Telehealth Integration: Secure telehealth consultations with licensed providers and moderated patient groups facilitate engagement and timely, personalized interventions. In one embodiment, provided is a system comprising advanced predictive algorithms designed to enhance patient outcomes by analyzing adherence data, patient-reported outcomes, and behavioral patterns. These algorithms predict risks of disengagement or symptom exacerbation and generate personalized recommendations PATENT 7279.154670PCT to dynamically adjust interventions, thereby optimizing adherence and improving clinical outcomes. In one embodiment, provided is a platform designed for seamless integration across clinical trial and real-world settings to enhance data consistency, accessibility, and reimbursement pathways. The platform includes: • Clinical Trials: Integration with Electronic Data Capture (EDC) and Clinical Trial Management Systems (CTMS) during trials ensures data consistency and facilitates the generation of robust clinical evidence. • Post-Approval Integration: In real-world settings, the platform connects with Electronic Health Records (EHR), enabling seamless access to patient data for physicians and payers to support informed decision-making and monitoring. • Reimbursement Alignment: As an approved drug-led combination product, the platform aligns with the pharmacy benefit of health insurance plans, overcoming barriers to coverage typically associated with standalone digital therapeutics. In alternative embodiments, provided are a therapeutic drug or drugs (or a therapeutic combination of drugs), pharmaceutical dosage forms, drug delivery devices or products of manufacture, comprising one or more of any of the active agents or drugs comprising: a Glucagon-like peptide-1 (GLP-1) receptor agonist, wherein optionally the GLP-1 receptor agonist is liraglutide (or SAXENDATMor VICTOZATM), or a dopamine D₂ antagonist, wherein optionally the dopamine D₂ antagonist comprises Bromopride (or DIGESAN), Domperidone (Motilium), Metoclopramide (Reglan or Maxolon), Metopimazine (Vogalene), or Metopimazine Mesylate, or a 5-HT3 receptor modulator or a 5-HT3 receptor partial agonist or a 5- HT3 antagonist or a 5- HT3 receptor partial agonist combination wherein the 5-HT3 receptor partial agonist or antagonist consists of vortioxetine or Formula I: Formula I PATENT 7279.154670PCT wherein: Q is a saturated, bicyclic, heterocyclic amine, wherein the saturated, bicyclic, heterocyclic amine comprises at least two atoms between the amide nitrogen of the compound of Formula I and any amine nitrogen of Q and wherein the saturated, bicyclic, heterocyclic amine is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from the group consisting of C1-C3 alkyl, halogen, —CN, —OR7, and —NR7R8; X is CH, CR3, or N; J is selected from the group consisting of a direct bond, C==O, and SO2; each R1is independently selected from the group consisting of H, halogen, —OR4, —NR4R5,—NR4C(O)R5, —NR4C(O)2R5, —NR5C(O)NR5R6, —S(O)qR5, —CN, —C(O)R5, —C(O)NR4R5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, aryl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C1-C3 alkyl, halogen, —CN, —OR7, —NR7R8, and phenyl which is optionally substituted 1-3 times with halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, —CN, —OR7, or —NR7R8; R2is selected from the group consisting of H, halogen, —OR7, —NR4R5, — NR4C(O)R5, —NR4C(O)2R5, —NR5C(O)NR5R6, —S(O)qR5, —CN, —C(O)R5, —C(O)NR4R5, C1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, aryl, and heteroaryl, with the proviso that when J=SO2, R is not H, and wherein each of C1- C6 alkyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, aryl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C1-C3 alkyl, halogen, —CN, —OR7, PATENT 7279.154670PCT —NR7R8, and phenyl which is optionally substituted 1-3 times with halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, —CN, —OR7, or —NR7R8; R3is selected from the group consisting of H, halogen, —OR4, —NR4R5, — NR4C(O)R5, —NR4C(O)2R5, —NR5C(O)NR5R6, —S(O)qR5, —CN, —C(O)R5, —C(O)NR4R5, C1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, aryl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C1-C3 alkyl, halogen, —CN, —OR7, — NR7R8, and phenyl which is optionally substituted 1-3 times with halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, —CN, —OR7, or —NR7R8; R4is H, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxyalkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, —C(O)R6, phenyl, or benzyl, wherein phenyl or benzyl is optionally substituted 1 to 3 times with halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy; R5is H, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxyalkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, phenyl, or benzyl, wherein phenyl or benzyl is optionally substituted 1 to 3 times with halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy;R6 is C1-C4 alkyl, C1-C4 haloalkyl, or phenyl;R7and R8are each independently H, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxyalkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, —C(O)R6, phenyl, or benzyl, wherein phenyl or benzyl is optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy; n is 1, 2, or 3; p is 0, 1, 2, or 3; and q is 0, 1, or 2; or an oxide thereof, a co-crystal thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or prodrug thereof. In alternative embodiments, provided are digital health systems designed to enhance adherence and add the Clinical Trial Effect to therapeutic drug treatment, comprising: o A cloud-based computing platform; PATENT 7279.154670PCT o Digitally-enabled therapeutic kit components including RFID- packaging of drug products and pen needles, and optionally Bluetooth- enabled pen systems, and RFID readers and Bluetooth; o eSource data components including electronic health records (EHRs), electronic patient-reported outcomes (ePROs), electronic clinical outcome assessments (eCOAs), digital consent (for example, ECONSENT™), wearables, and internet of things (IoT) devices; o Customized user interfaces for patients, healthcare professionals, pharmacists, laboratory personnel, investigators, researchers, system management, and sponsors; o Functional blocks for medication management, telemedicine, patient data collection, patient behavior change, patient productivity, and clinical trial management; o An application layer comprising algorithms, models, and processors for transforming collected data and generating personalized intervention regimens; o a data processing and analytics layer that aggregates, processes, and analyzes data using machine learning algorithms and an intervention modification engine; o and optionally means for integrating future algorithms, models, and processors based on clinical data. In alternative embodiments, the customized user interfaces are designed to provide: o Patients and caregivers with access to their health data, adherence reminders, and tools for reporting outcomes; o Healthcare professionals with tools for monitoring patient adherence, reviewing clinical outcomes, and adjusting intervention regimens; o Administrative functions for managing clinical trials, accessing aggregated data, and performing system maintenance. In alternative embodiments of systems as provided herein: the functional blocks include: o A medication management block comprising tools for managing medication schedules and adherence; PATENT 7279.154670PCT o A telemedicine block for providing remote clinical services via telecommunications technology; o Patient data collection blocks including chatbots, digital health diaries, and health questionnaires; o Patient behavior change blocks featuring microlearning sessions, personalized coaching, and community support platforms; o Patient productivity blocks enabling self-scheduling of appointments and automatic reminders; o Clinical trial blocks incorporating randomization and trial supply management (RTSM), electronic data capture (EDC), and clinical trial management system (CTMS) functionalities. In alternative embodiments, the data processing and analytics layer uses machine learning algorithms to: o Predict patient adherence patterns; o Optimize therapeutic drug treatment plans; o Personalize patient interventions and dynamically adjust regimens based on real-time data and feedback. In alternative embodiments, the cloud-based computing platform supports: o Scalable data storage, processing, and application hosting; o Integration of future algorithms, models, and processors for continuous improvement of intervention regimens; o Disaster recovery and backup systems to ensure data integrity and availability. In alternative embodiments, provided are methods for enhancing adherence and add the Clinical Trial Effect to therapeutic drug treatment using the digital health system, comprising: o Enrolling patients and obtaining digital consent through the ECONSENT™ system; o Collecting patient-reported outcomes, clinical outcome assessments, and health data from wearables and IoT devices; o Randomizing patients into study groups and managing trial supplies using the RTSM system; PATENT 7279.154670PCT o Aggregating and processing collected data to generate patient profiles and personalized intervention regimens; o Reviewing and approving intervention regimens by healthcare providers and communicating them to patients; o Monitoring patient adherence and dynamically adjusting interventions based on data collected from the digitally-enabled therapeutic kit, and using algorithms and the intervention modification engine; o Ensuring compliance with HIPAA and FDA regulations for data privacy, security, and system integrity; o Incorporating future algorithms, models, and processors based on clinical data to enhance the system's capabilities. In alternative embodiments, provided are therapeutic combinations or formulations of drugs comprising the 5-HT3 receptor modulator (S)-7-(quinuclidine- 3-yl)-8,9-dihydro-2H-azepino [5,4,3-cd]indazol-6(7H)-one (Compound I) and analogues and its associated salts, co-crystals, and polymorphs, in combination with other drugs or active agents. In alternative embodiments, provided is a cloud-based digital health system designed to enhance adherence and add the Clinical Trial Effect to therapeutic drug treatments. Specifically, the invention integrates a digitally- enabled therapeutic kit comprising advanced algorithms, models, processors, and physical memories to provide personalized intervention regimens. The platform is designed to facilitate future developments and enhancements through the integration of new algorithms, models, and processors based on clinical data, with a specific focus on the use of Compound I and liraglutide for managing functional gastrointestinal disorders (FGIDs). In alternative embodiments, the term “alkyl” means an aliphatic hydrocarbon group which may be straight or branched having about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. Exemplary alkyl groups include methyl, ethyl, n-propyl, i-propyl. n-butyl, t-butyl, n-pentyl, and 3-penty1. In alternative embodiments, the term “alkenyl” means an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be straight or branched having about 2 to about 6 carbon atoms in the chain. Preferred PATENT 7279.154670PCT alkenyl groups have 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl, or propyl are attached to a linear alkenyl chain. Exemplary alkenyl groups include ethenyl, propenyl, n-butenyl, and i- butenyl. In alternative embodiments, the term “alkynyl” means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight or branched having about 2 to about 6 carbon atoms in the chain. Preferred alkynyl groups have 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl, or propyl are attached to a linear alkynyl chain. Exemplary alkynyl groups include ethynyl, propynyl, n-butynyl, 2-butynyl, 3- methylbutynyl, and n-pentynyl. In alternative embodiments, the term “aryl” means an aromatic monocyclic or multi-cyclic ring system of 6 to about 14 carbon atoms, preferably of 6 to about 10 carbon atoms, and includes arylalkyl groups. Representative aryl groups include phenyl and naphthyl. In alternative embodiments, the term "heteroaryl” means an aromatic monocyclic or multi-cyclic ring system of about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is / are element(s) other than carbon, for example, nitrogen, oxygen, or sulfur. In the case of multi-cyclic ring system, only one of the rings needs to be aromatic for the ring system to be defined as “heteroaryl”. Preferred heteroaryls contain about 5 to 6 ring atoms. The prefix aza, oxa, thia, or thio before heteroaryl means that at least a nitrogen, oxygen, or sulfur atom, respectively, is present as a ring atom. A nitrogen atom of a heteroaryl is optionally oxidized to the corresponding N-oxide. Representative heteroaryls include pyridyl, 2-oxo-pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, furanyl, pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indolinyl, 2-oxoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indazolyl, benzimidazolyl, benzooxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, benzotriazolyl, benzo[1,3]dioxolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, pthalazinyl, quinoxalinyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,2,3]triazinyl, benzo[1, 2,4]triazinyl, 4H-chromenyl, indolizinyl, quinolizinyl, 6aH-thieno[2,3-d]imidazolyl, PATENT 7279.154670PCT 1H-pyrrolo[2,3-b]pyridinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, [1,2,4] triazolo[1,5-a]pyridinyl, thieno[2,3-b]furanyl, thieno[2,3-b]pyridinyl, thieno[3,2-b]pyridinyl, furo[2,3-b]pyridinyl, furo[3,2- b]pyridinyl, thieno[3,2-d]pyrimidinyl, furo[3,2-d]pyrimidinyl, thieno[2,3-b]pyrazinyl, imidazo[l,2-a]pyrazinyl, 5,6,7,8-tetrahydroimidazol[1,2-a]pyrazinyl, 6,7-dihydro-4H- pyrazolo[5,1-c][1,4]oxazinyl, 2-oxo-2,3-dihydrobenzo[d]oxazolyl, 3,3-dimethyl-2- oxoindolinyl, 2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl, 3,4-dihydro-2H- benzo[b][1,4]oxazinyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, [1,2,4]triazolo[4,3-a]pyrazinyl, 3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl, and the like. In alternative embodiments, the term “alkoxy” means groups of from 1 to 8 carbon atoms of a straight, branched, or cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy, and the like. Lower- alkoxy refers to groups containing one to four carbons. For the purposes of the present patent application, alkoxy also includes methylenedioxy and ethylenedioxy in which each oxygen atom is bonded to the atom, chain, or ring from which the methylenedioxy or ethylenedioxy group is pendant so as to form a ring. In alternative embodiments, the term “cycloalkyl” means a non-aromatic mono- or multi-cyclic ring system of about 3 to about 7 carbon atoms, preferably of about 5 to about 7 carbon atoms. Exemplary monocyclic cycloalkyls include cyclopentyl, cyclohexyl, cycloheptyl, and the like. In alternative embodiments, the term “cycloalkylalkyl” means a cycloalkyl- alkyl group in which the cycloalkyl and alkyl are as defined herein. Exemplary cycloalkylalkyl groups include cyclopropylmethyl and cyclopentylmethyl. In alternative embodiments, the term “arylalkyl” means an alkyl residue attached to an aryl ring. Examples are benzyl, phenethyl, and the like. In alternative embodiments, the term “haloalkyl” means both branched and straight-chain alkyl substituted with one or more halogen, wherein the alkyl group is as herein described. In alternative embodiments, the term “substituted” or “substitution” of an atom means that one or more hydrogen on the designated atom is replaced with a PATENT 7279.154670PCT selection from the indicated group, provided that the designated atoms normal valency is not exceeded. In alternative embodiments, the “unsubstituted” atoms bear all of the hydrogen atoms dictated by their valency. When a substituent is keto (i.e., = 0), then two hydrogens on the atom are replaced. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds; by “stable compound” or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. In alternative embodiments, the term “halogen” means fluorine, chlorine, bromine, or iodine. In alternative embodiments, the term “compounds of Formula I”, and equivalent expressions, are meant to embrace compounds of general Formula I as hereinbefore described, which expression includes the prodrugs, the pharmaceutically acceptable salts, the oxides, co-crystals and the solvates, e.g. hydrates, where the context so permits. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits. For the sake of clarity, particular instances when the context so permits are sometimes indicated in the text, but these instances are purely illustrative and it is not intended to exclude other instances when the context so permits. In alternative embodiments, the term “method of treating” means amelioration or relief from the symptoms and / or effects associated with the disorders described herein. As used herein, reference to “treatment” of a patient is intended to include prophylaxis. In alternative embodiments, compounds described herein may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms. Each chiral center may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present invention is meant to include all such possible isomers, as well as mixtures thereof, including racemic and optically pure forms. Optically active (R)- and (S)-, (-)- and (+)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended PATENT 7279.154670PCT that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included. In alternative embodiments, and as would be understood by the person of skill in the art, the recitation of “a compound” is intended to include salts, solvates, oxides, co-crystals, and inclusion complexes of that compound as well as any stereoisomeric form, or a mixture of any such forms of that compound in any ratio. Thus, in accordance with some embodiments of the invention, a compound as described herein, including in the contexts of pharmaceutical compositions, methods of treatment, and compounds perse, is provided as the salt form. In alternative embodiments, the term “solvate” refers to a compound of Formula I in the solid state, wherein molecules of a suitable solvent are incorporated in the crystal lattice. A suitable solvent for therapeutic administration is physiologically tolerable at the dosage administered. Examples of suitable solvents for therapeutic administration are ethanol and water. When water is the solvent, the solvate is referred to as a hydrate. In general, solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an anti-solvent. The solvate is typically dried or azeotroped under ambient conditions. In alternative embodiments, the term “co-crystal” refers to a complex consisting of a pharmaceutically active compound and one or more co-formers, which are non-solvent, non-active molecule components that form the crystal lattice with the pharmaceutically active compound. The co-crystal can further comprise a pharmaceutically acceptable carrier or excipient. A co-crystal can exhibit improved or more desired pharmaceutical properties compared to the pharmaceutically active compound in its non-co-crystalline form. In alternative embodiments, the inclusion complexes are as described in Remington, The Science and Practice of Pharmacy, 19th Ed.1:176-177 (1995), which is hereby incorporated by reference in its entirety. The most commonly employed inclusion complexes are those with cyclodextrins, and all cyclodextrin complexes, natural and synthetic, are specifically encompassed within the claims. In alternative embodiments, the term “pharmaceutically acceptable salt” refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases. Since the compounds of Formula I contain a basic nitrogen, salts may be prepared from pharmaceutically PATENT 7279.154670PCT acceptable non-toxic acids including inorganic and organic acids. Suitable pharmaceutically acceptable acid addition salts for the compounds of the present invention include acetic, benzenesulfonic (besylate), benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric acid, p-toluenesulfonic, and the like. When the compounds contain an acidic side chain, suitable pharmaceutically acceptable base addition salts for the compounds of the present invention include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. In alternative embodiments, the configuration of any carbon-carbon double bond appearing herein is selected for convenience only and is not intended to designate a particular configuration; thus a carbon-carbon double bond depicted arbitrarily herein as E may be Z, E, or a mixture of the two in any proportion. In alternative embodiments, the abbreviations Me, Et, and Ph represent methyl, ethyl, and phenyl, respectively. A comprehensive list of abbreviations utilized by organic chemists (i.e. persons of ordinary skill in the art) appears in the first issue of each volume of the Journal of Organic Chemistry. The list, which is typically presented in a table entitled “Standard List of Abbreviations.” is incorporated herein by reference in its entirety. In alternative embodiments, the term “therapeutically effective amount” is meant to describe an amount of compound of the present invention effective in modulating 5-HT3 activity and thus producing the desired therapeutic effect. Such amounts generally vary according to a number of factors well within the purview of ordinarily skilled artisans given the description provided herein to determine and account for. These include, without limitation: the particular subject, as well as its age, weight, height, general physical condition, and medical history, the particular compound used, as well as the carrier in which it is formulated and the route of administration selected for it; and, the nature and severity of the condition being treated. In alternative embodiments, the term “pharmaceutical composition” means a composition comprising a compound of Formula I and at least one component PATENT 7279.154670PCT comprising pharmaceutically acceptable carriers, diluents, adjuvants, excipients, or vehicles, such as preserving agents, fillers, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, antibacterial agents, anti-fungal agents, lubricating agents and dispensing agents, depending on the nature of the mode of administration and dosage forms. As used herein, the term “pharmaceutically acceptable carrier” is used to mean any carrier, diluent, adjuvant, excipient, or vehicle, as described herein. Examples of suspending agents include ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystal line cellulose, aluminum metahydroxide, bentonite, agaragar and tragacanth, or mixtures of these substances. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monosterate and gelatin. Examples of suitable carriers, diluents, solvents, or vehicles include water, ethanol, polyols, suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Examples of excipients include lactose, milk sugar, sodium citrate, calcium carbonate, and dicalcium phosphate. Examples of disintegrating agents include starch, alginic acids, and certain complex silicates. Examples of lubricants include magnesium stearate, sodium lauryl sulphate, talc, as well as high molecular weight polyethylene glycols. In alternative embodiments, the term “pharmaceutically acceptable” means it is, within the scope of sound medical judgment, suitable for use in contact with the cells of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. In alternative embodiments, the term “pharmaceutically acceptable dosage forms” means dosage forms of the compound of the invention, and includes, for example, tablets, dragees, powders, elixirs, syrups, liquid preparations, including suspensions, sprays, inhalants tablets, lozenges, emulsions, solutions, granules, capsules, and suppositories, as well as liquid preparations for injections, including liposome preparations. Techniques and formulations generally may be found in PATENT 7279.154670PCT Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., latest edition, which is hereby incorporated by reference in its entirety. In alternative embodiments, the term “pharmaceutically acceptable prodrugs” as used herein means those prodrugs of the compounds useful according to the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of Formula I. The term “prodrug” means compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood. Functional groups which may be rapidly transformed, by metabolic cleavage, in vivo form a class of groups reactive with the carboxyl group of the compounds of this invention. They include, but are not limited to, such groups as alkanoyl (such as acetyl, propionyl, butyryl, and the like), unsubstituted and substituted aroyl (such as benzoyl and substituted benzoyl), alkoxycarbonyl (such as ethoxycarbonyl), trialkylsilyl (such as trimethyl and triethysilyl), monoesters formed with dicarboxylic acids (such as succinyl), and the like. Because of the ease with which the metabolically cleavable groups of the compounds useful according to this invention are cleaved in vivo, the compounds bearing such groups act as prodrugs. The compounds bearing the metabolically cleavable groups have the advantage that they may exhibit improved bioavailability as a result of enhanced solubility and / or rate of absorption conferred upon the parent compound by virtue of the presence of the metabolically cleavable group. A thorough discussion of prodrugs is provided in the following: Design of Prodrugs, H. Bundgaard, ed., Elsevier (1985); Methods in Enzymology, K. Widder et al. Ed., Academic Press, 42, p.309-396 (1985): A Textbook of Drug Design and Development, Krogsgaard-Larsen and H. Bundgaard, ed., Chapter 5; "Design and Applications of Prodrugs.” p.113-191 (1991); Advanced Drug Delivery Reviews, H. Bundgard, 8, p.1-38 (1992); Journal of Pharmaceutical Sciences, 77:285 (1988); Nakeya et al., Chem. Pharm. Bull., 32:692 (1984); Higuchi et al., “Pro-drugs as Novel Delivery Systems.” Vol.14 of the A.C.S. Symposium Series, and Bioreversible Carriers in Drug Design, Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press (1987), which are incorporated herein by reference in their entirety. Examples of prodrugs include, but are not limited PATENT 7279.154670PCT to, acetate, formate, and benzoate derivatives of alcohol and amine functional groups in the compounds of Formula I. In alternative embodiments, the present invention relates to compounds of Formula I, wherein Q is a substituted or unsubstituted bicyclic, heterocyclic amine. In accordance with the present invention, the bicyclic, heterocyclic amines are saturated and contain at least one nitrogen in the ring. They may contain additional nitrogens, as well as other heteroatoms. In the compounds of Formula I, the bicyclic, heterocyclic amine includes at least 2 atoms, preferably from 2 to 4 and preferably carbon atoms, connecting the amide nitrogen to any nitrogen in the amine group Q. In one embodiment, Q is a substituted or unsubstituted bicyclic amine. In another embodiment of the present invention, Q of Formula I is a bicyclic amine of empirical formula C7-10N1-2. In a more preferred embodiment of the present invention, Q is an azabicycloheptane, azabicyclooctane, or azabicyclononane. Suitable heterocyclic amines include, but are not limited to, quinuclidine, tropane, azabicyclo[3,3,1]nonane, methyl azabicyclo[3,3,1]nonane, 9-azabicyclo[3,3,1]nonan- 3-one, 3,9-dimethyl-3,9-diazabicyclo[3,3,1]nonane, 3,9-diazabicyclo[3,3,1] nonane, 3-oxa-9-azabicyclo[3,3,1]nonane, 3-thia-9-azabicyclo[3,3,1]nonane, 9-methyl 3,9- diazabicyclo[3,3,1]nonane, 3-methyl-3,9-diazabicyclo[3,3,1]nonane, 3-oxa-9- azabicyclo[3,3,1]nonane, 3-thia-9-azabicyclo[3,3,1] nonane, and azabicyclo[3,2,2]nonane. In one embodiment of the present invention, the carbon of the bicyclic, heterocyclic amine attached to the amide nitrogen of the tricyclic core of Formula I is chiral and in the (S) configuration. In another embodiment of the present invention, the carbon of the bicyclic, heterocyclic amine attached to the amide nitrogen of the tricyclic core of Formula I is chiral and in the (R) configuration. Another embodiment of the present invention is a mixture of stereoisomeric compounds of Formula I. In another embodiment of the present invention, Q is a saturated, bicyclic, heterocyclic amine or methyl-substituted saturated, bicyclic, heterocyclic amine, in which the nitrogen is tertiary. In one embodiment, Q is selected from the group consisting of: PATENT 7279.154670PCT wherein r=1, 2, 3 or 4; s=0, 1, 2, 3 or 4; and R9is hydrogen or methyl. In these figures, the Q group is connected to the tricyclic core structure through any carbon ring member (i.e., not a terminal N-methyl). In alternative embodiments of the compound of Formula I: suitable heterocyclic amines include: wherein R10is hydrogen or C1-C3 alkyl and Z is NH, NCH3, O, S, SO, or SO2. In alternative embodiments of the compound of Formula I: R2is H, lower alkyl, phenyl, or substituted phenyl. In one preferred embodiment, R2is substituted phenyl and J is SO2. In another preferred embodiment, R2is 4-fluorophenyl. In alternative embodiments of the compound of Formula I: at least one of R1is H, F, Cl, or Br. In alternative embodiments of the compound of Formula I: suitable aryl groups for the substituents are selected from the group consisting of phenyl, benzyl, naphthyl, indanyl, and indenyl. Suitable heteroaryl groups for the substituents of the present invention are selected from the group consisting of pyridyl, 2-oxo-pyridin 1- yl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, furanyl, pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3- triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indolinyl, oxoindolinyl, dihydrobenzofuranyl, dihydroben zothiophenyl, indazolyl, benzimidazolyl, benzooxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, benzot riazolyl, benzo[1,3]dioxolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, pthalazinyl, quinoxalinyl, 2,3-dihy dro- benzo[1,4]dioxinyl, benzo[1,2,3]triazinyl, benzo [1,2,4]triazinyl, 4H-chromenyl, indolizinyl, quinolizinyl, 6aH-thieno[2,3-d]imidazolyl, 1H-pyrrolo[2,3-b]pyridinyl, imidazo[1,2-c]pyridinyl, pyrazolo[1,5-c]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, [1,2,4] triazolo[1,5-a]pyridinyl, thieno[2,3-b]furanyl, thieno[2,3-b]pyridinyl, PATENT 7279.154670PCT thieno[3,2-b]pyridinyl, furo[2,3-b]pyridinyl, furo[3,2-b]pyridinyl, thieno[3,2- d]pyrimidinyl, furo[3,2-d]pyrimidinyl, thieno[2,3-b] pyrazinyl, furo[2,3-b]pyrazinyl, imidazole[1,2-a]pyrazinyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazinyl, 6,7-dihydro- 4H-pyrazolo[5,1-c][1,4]oxazinyl, 2-oxo-2,3-dihydrobenzo[d]oxazolyl, 2-oxo-2,3- dihydro-1H-benzo[d]imidazole, 3.3-dimethyl-2-oxoindolinyl, 2-oxo-2,3-dihydro-1H- pyrrolo[2, 3-b]pyridinyl, benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl, 3,4- dihydro-2H-benzo[b][1,4]oxazinyl, 5,6,7, 8-tetrahydro-[1,2,4]triazolo[4,3- a]pyrazinyl, [1,2,4]triazolo[4,3-a]pyrazinyl, and 3-oxo[1,2,4]triazolo [4,3-a]pyridinyl. Within these embodiments, the selection of a particular preferred substituent at any one of Q, X, J, R1R2and R3does not affect the selection of a substituent at any of the others of Q, X, J, R1, R2, and R3. That is, preferred compounds provided herein have any of the preferred substituents at any of the positions. In another embodiment, the 5-HT3 receptor modulator is the following formula: wherein: X is CH or N: each R' is independently selected from the group consisting of H, halogen, - OR, or C1-C4 alkyl, wherein C1-C4 alkyl is optionally substituted with from 1 to 3 Substituents independently selected at each occurrence thereof from C1-C4 alkyl, halogen, —CN, -OR7, NR7R8, and phenyl which is optionally substituted 1-3 times with halogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, -CN, -OR7, or – NR7R8; R2is H; R4is H, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxyalkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, -C(O)R6, phenyl, or benzyl, wherein phenyl or benzyl PATENT 7279.154670PCT is optionally substituted 1 to 3 times with halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy; R6is C1-C4 alkyl, C1-C4 haloalkyl, or phenyl: R7and R8are each independently H, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxyalkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, -C(O)R6, phenyl, or benzyl, wherein phenyl or benzyl is optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4, alkoxy; n is 1 or 2; and p is 0, 1, 2, or 3: or an oxide thereof or a pharmaceutically acceptable salt thereof. In one embodiment, the 5-HT3 receptor modulator is Compound I. Compound I In one embodiment, a co-crystal comprising an active pharmaceutical ingredient (API) represented by Compound I, or a pharmaceutically acceptable salt or derivative thereof; and a co-former selected from the group consisting of co-formers, from organic acids, amines, alcohols, amides, and combinations thereof; wherein said co-crystal exhibits improved or desired pharmaceutical properties compared to Compound I in its non-co-crystalline form. In another embodiment, the co-former is selected from one or more of the following compounds or their derivatives: acetic acid, benzoic acid, tartaric acid, fumaric acid, nicotinamide, isoniazid, phenol, resorcinol, urea, saccharin, pyrazine, or caffeine. In alternative embodiments, provided are therapeutic combinations, pharmaceutical dosage forms, drug delivery devices or products of manufacture PATENT 7279.154670PCT comprising a Glucagon-like peptide-1 (GLP-1) receptor agonist, wherein optionally the GLP-1 receptor agonist is liraglutide (or SAXENDATMor VICTOZATM), or a dopamine D₂ antagonist, wherein optionally the dopamine D₂ antagonist comprises Bromopride (DIGESANTM), Domperidone (MOTILIUMTM), Metoclopramide (REGLANTMor MAXOLONTM), Metopimazine (VOGALENETM), or Metopimazine Mesylate, or a 5-HT3 receptor modulator or a 5-HT3 receptor partial agonist or a 5- HT3 antagonist or vortioxetine or Formula I, optionally Compound I , with any one of the following drugs or molecules, or a corresponding salt, hydrate, solvate, oxide, co- crystal thereof if the drug or molecule is a non-peptide small molecule, or a PEGylated, albumin-conjugated, liposome, microsphere, amide, ester, multimer, cyclic form, fusion protein, D-amino acid modified form, or analogue (e.g., sequences with amino acid substitutions, additions, or deletions) if the drug or molecule is a peptide thereof: (1) a tryptophan hydroxylase inhibitor, wherein optionally the tryptophan hydroxylase inhibitor comprises telotristat ethyl (or XERMELOTM); (2) a 5-HT2 receptor antagonist, wherein optionally the 5-HT2 receptor antagonist comprises sarpogrelate orteguride; (3) a somatostatin analog, wherein optionally the somatostatin analog comprises octreotide (or SANDOSTATINTM), octreotide LAR (or SANDOSTATIN LARTM), lanreotide LAR (or SOMATULINETMDepot), or pasireotide LAR (or SIGNIFOR LARTM); (4) a somatostatin type 2 receptor agonist, wherein optionally the somatostatin type 2 receptor agonist comprises paltusotine; (5) smectite dioctadec (or SMECTATM), (6) rifaximin (or XIFAXANTM), (7) an opioid receptor agonist, wherein optionally the opioid receptor agonist comprises eluxadoline (or VIBERZITM), loperamide (or IMODIUMTM), asimadoline, or ORP-101; (8) a guanylate cyclase-C agonist, PATENT 7279.154670PCT wherein optionally the guanylate cyclase-C agonist comprises linaclotide (or LINZESSTM), or plecanatide (or TRULANCETM), (9) a chloride channel activator, wherein optionally the chloride channel activator comprises lubiprostone (or AMITIZATM); (10) a 5-HT4 receptor agonist, wherein optionally the 5-HT4 receptor agonist comprises tegaserod (or ZELNORMTM); (11) a Glucagon-Like Peptide-1(GLP-1) receptor agonist, wherein optionally the GLP-1 receptor agonist comprises dulaglutide (or TRULICITYTM), exenatide (or BYETTATM), exenatide extended-release (or BYDUREONTM), liraglutide (or SAXENDATMor VICTOZATM), lixisenatide (or ADLYXINTM), semaglutide injection (or OZEMPICTMor WEGOVYTM), semaglutide tablets (or RYBELSUSTM), albiglutide (or TANZEUMTMor EPERZANTM), CT-996(Carmot Therapeutics), ECC5004(AstraZeneca), GSBR- 1290 (Structure Therapeutics), LY-307161 (Eli Lilly), danuglipron (or PF- 06882961, Pfizer), LY2189265 (Eli Lilly), ecnoglutide (Sciwind Biosciences), efpeglenatide (or HM11260C), (Hanmi Pharm Co., Ltd), beinaglutide, JY09 (Beijing Dongfang Baitai Biotechnology Co., Ltd), HRS-7535 (Hercules CM NewCo) or orforglipron (or LY-3502970, Eli Lilly), (12) a dual GLP-1 / GIP agonist, wherein optionally the GLP-1 / GIP agonist comprises tirzepatide (or MOUNJAROTMor ZEPBOUNDTM), AZD9550 (AstraZeneca), VK2735 (Viking Therapeutics, Inc.), SCO-094 (Scohia Pharma, Inc.), HRS-9531 (Hercules CM NewCo), CT-388 or CT-868 (Carmot Therapeutic), (13) a GLP-1 / Glucagon (Gcg) receptor co-agonist, wherein optionally the GLP-1 / Gcg receptor co-agonist comprises AZD- 9550 (AstraZeneca), Mazdutide (or IBI362, or LY-3305677) (Eli Lilly and Company), DD01 (D&D Pharmatech), RGT-075 (Regor Therapeutics Group), Efinopegdutide (or MK-6024) (Merck & Co., Inc.), Pemvidutide (Altimmune, Inc.), or Survodutide (or BI-456906) (C.H. Boehringer Sohn AG & Co. KG), (14) a GLP-1 / GIP / Gcg receptor tri-agonist, wherein optionally the GLP-1 / GIP / Gcg receptor tri-agonist is LY3437943 (Eli Lilly), SAR425899 (Sanofi), SAR441255 PATENT 7279.154670PCT (Sanofi), HM15275, Efocipegtrutide (or HM15211), Hanmi Pharm Co., Ltd), or MEDI0382 (AstraZeneca), (15) a live biotherapeutic product (LBP) wherein optionally the LBP is CJRB-205 (or BLAUTIXTM); (16) an amylin analogue, wherein optionally the amylin analogue comprises pramlintide (or SYMLINTM), cagrilintide, or AZD-6234; (17) an amylin / GLP-1 dual agonist, wherein optionally the amylin / GLP-1 dual agonist comprises NNC-0487- 0111; (18) a cannabinoid receptor (CBR1) antagonist, wherein optionally the cannabinoid receptor (CBR1) antagonist comprises INV-202; (19) a cannabinoid receptor (CBR2) agonist, wherein optionally the cannabinoid receptor (CBR2) agonist comprises olorinab; (20) a bitter taste receptor (TAS2R) agonist, wherein optionally the bitter taste receptor (TAS2R) agonist comprises ARD- 101; (21) anti-histamines, wherein optionally the anti-histamine comprises diphenhydramine, (22) A GIP receptor antagonist conjugated to GLP-1 analogues, wherein optionally the GIP receptor antagonist conjugated to GLP-1 analogues is AMG-133; (23) a GLP-1 / GLP-2 receptor co-agonist, Wherein optionally the GLP-1 / GLP-2 receptor co-agonist comprises dapiglutide (or ZP7570) (Zealand Pharma), (24) a GLP-1 agonist / GIP antagonist, wherein optionally the GLP-1 agonist / GIP antagonist comprises AMG-133 (Amgen Inc.), or (25) a dopamine D₂ antagonist, PATENT 7279.154670PCT wherein optionally the dopamine D₂ antagonist comprises Bromopride (or DIGESANTM), Domperidone (or MOTILIUMTM), Metoclopramide (or REGLANTMor MAXOLONTM), Metopimazine (or VOGALENETM), or Metopimazine Mesylate; (26) an aminosalicylate, wherein optionally the aminosalicylate comprises Sulfasalazine (or AZULFIDINETM), or Mesalamine (also known as mesalazine) (or ASACOLTM, PENTASATM, LIALDATM, APRISOTM, DELZICOLTM, ROWASATM, or CANASATM); (27) a corticosteroid, wherein optionally the corticosteroid comprises budesonide (or ENTOCORT ECTMor UCERISTM), Deflazacort (or EMFLAZATM), Prednisone (or DELTASONETMor RAYOSTM), or Methylprednisolone (or MEDROLTMor SOLU- MEDROLTM); (28) an immunomodulator, wherein optionally the immunomodulator comprises Azathioprine (or IMURANTM), Cyclosporine (or NEORALTM, SANDIMMUNETM, or GENGRAFTM), Methotrexate (or TREXALLTMor RHEUMATREXTM),Mercaptopurine (or PURINETHOLTM or PURIXANTM), or Tacrolimus (orPROGRAFTM, ASTAGRAF XLTM, or ENVARSUS XRTM); (29) a sphingosine-1-phosphate modulator, wherein optionally the sphingosine-1-phosphate modulator comprises Ozanimod (or ZEPOSIATM), Siponimod (MayzentTM), Ponesimod (PonvoryTM); or Fingolimod (GilenyaTM), (30) an integrin receptor antagonist, wherein optionally the integrin receptor antagonist comprises vedolizumab (or ENTYVIOTM); (31) a Janus Kinase Inhibitor, wherein optionally the Janus Kinase Inhibitor comprises Tofacitinib (or XELJANZTM); (32) an anti-tumor necrosis factor (anti-TNF) agent, wherein optionally the anti-TNF agent comprises Adalimumab (or HUMIRATM), Golimumab (or SIMPONITM), or Infliximab (or REMICADETM); (33) an interleukin-12 / 23 (IL-12 / 23) inhibitor, PATENT 7279.154670PCT wherein optionally the IL-12 / 23 inhibitor comprises briakinumab or Ustekinumab (or STELARATM), (34) an interleukin-23 (IL-23) inhibitor, wherein optionally the IL-23 inhibitor comprises brazikumab, guselkumab (or TREMFYATM), mirikizumab, and Risankizumab (or SKYRIZITM); or (35) any combination of (1) to (34). Provided, however, that liraglutide (or SAXENDATM or VICTOZATM) is present as the GLP-1 receptor agonist, it shall not be combined with any GLP-1 receptor agonist listed in category (11), or compounds listed in (22) and (23). Also provided, a dopamine D₂ antagonist, wherein optionally the dopamine D₂ antagonist comprises Bromopride (DIGESANTM), Domperidone (MOTILIUMTM), Metoclopramide (REGLANTM or MAXOLONTM), Metopimazine (VOGALENETM), or Metopimazine Mesylate, should not be combined with compounds listed in (25). In alternative embodiments, Formula I is Compound I. In alternative embodiments, a 5-HT3 receptor modulator includes 5-HT3 antagonists, agonists, partial agonists, inverse angonist. Examples of 5-HT3 receptor modulators include Ondansetron, Granisetron, Dolasetron, Palonosetron, Tropisetron, Alosetron, Ramosetron, Renzapride. In alternative embodiments, two or three or more of the drugs or active agents are formulated as separate compositions, or two or three or more of the drugs or active agents are formulated into one composition or drug formulation (two or more drugs or active agents are formulated together). In alternative embodiments, one or two or more or all of the drugs or active agents are packaged individually, or are packaged together, or packaged in any combination, in a single package, a plurality of packages or packettes, or a blister packet, a sachet, a lidded blister or blister card or packets, or a shrink wrap. In alternative embodiments, one or two or more or all of the drugs or active agents are formulated or manufactured as a parenteral formulation, an aqueous solution, a liposome, an injectable solution, a tablet, a pill, a lozenge, a capsule, a caplet, a spray, a sachet, an inhalant, a powder, a freeze-dried powder, an inhalant, a patch, a gel, a geltab, a nanosuspension, a nanoparticle, a nanolipose, a microgel, a PATENT 7279.154670PCT pellet, a suppository, or any combination thereof, and optionally the drug delivery device or product of manufacture is or comprises a pen injector system or an implant. In alternative embodiments, the one or two or more or all of the drugs or active agents are formulated or manufactured together in one parenteral formulation, one aqueous solution, one liposome, one injectable solution, one freeze-dried powder, one feed, one food, one food supplement, one pellet, one lozenge, one liquid, one elixir, one aerosol, one inhalant, one adhesive, one spray, one powder, one freeze- dried powder, one patch, one tablet, one pill, one capsule, one gel, one geltab, one lozenge, one caplet, one nanosuspension, one autoinjectable, one nanoparticle, one nanolipose, one microgel or one suppository. In alternative embodiments, the pen injector systems are designed with pen needle lengths ranging from 3 mm to 6 mm, with preferred lengths of 3.2 mm to 4 mm, and specifically about 3.5 mm. The pen needles have a gauge between 32 and 34, preferably 32 gauge, to facilitate optimal injection into adipose tissue while preventing penetration into the underlying muscle tissue and minimizing cMAX spikes. Additionally, both the pen body and the pen needle are equipped with a custom base to ensure the system utilizes the correct pen needle length and gauge for each application. In alternative embodiments, the one or two or more or all of the drugs or active agents are packaged in dosages that match a chrono-dosing regimen to match an optimal dose for the time of day; and specifically, Compound I is formulated in a unit dosage amount ranging from between about 0.1 mg, 0.2 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.5 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, or 50 mg; and specifically, the tryptophan hydroxylase inhibitor, optimally telotristat ethyl (XERMELOTM), is formulated in a unit dosage amount ranging from between about 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 350 mg, 500 mg, 750 mg, or 1 gram; and specifically, rifaximin (XIFAXANTM) is formulated in a unit dosage amount ranging from between about 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 250 mg, 550 mg, 750 mg, or 1 gram; PATENT 7279.154670PCT and optionally, the one or two or more or all of the drugs or active agents are formulated as immediate-release formulations or controlled-release formulations, including extended and biphasic release formulations. In alternative embodiments, provided are methods for treating, ameliorating, slowing the progress of, reducing the symptoms of, reducing adverse events associated with, or preventing a disease or condition, the method comprising administering an effective amount of a therapeutic agent to a subject in need thereof, wherein the disease or condition is selected from the group consisting of: - abdominal migraine, - aerophagia, - alcohol dependency, - altered central nervous system (CNS) processing, - altered gut microbiota, - altered mucosal and immune function, - anxiety, - Behcet’s disease, - bile acid diarrhea, - bile acid malabsorption, - biliary pain, - binge-eating disorder, - bronchial asthma, - cannabinoid hyperemesis syndrome (CHS), - carbohydrate malabsorption, - Carcinoid syndrome-associated diarrhea, - Carcinoid syndrome-associated fibrosis, - Carcinoid syndrome-induced itch, - cardiovascular disorders mediated by serotonin, - centrally-mediated abdominal pain syndrome (CAPS) - chemotherapy-induced nausea and vomiting (CINV), - chronic nausea vomiting syndrome (CNVS), - Crohn’s disease, - cyclic vomiting syndrome (CVS), - depression, PATENT 7279.154670PCT - diarrhea associated with bacterial overgrowth, - diarrhea associated with bariatric surgery including gastric sleeve surgery, gastric bypass surgery (Roux-en-Y gastric bypass), bariatric resection, - diarrhea associated with bacterial infections, - diarrhea associated with bile acid malabsorption, - diarrhea associated with celiac disease, - diarrhea associated with clostridium difficile infection, - diarrhea associated with ulcerative colitis, - diarrhea associated with Crohn’s disease - diarrhea associated with chemotherapy, - diarrhea associated with cholecystectomy, - diarrhea associated with cholera, - diarrhea associated with cytotoxic therapy, - diarrhea associated with Dumping Syndrome, - diarrhea associated with GLP-1 agonist therapy, - diarrhea associated with GLP-1 / GIP dual agonist therapy, - diarrhea associated with GLP-1 / GIP / Gcg tri-agonist therapy, - diarrhea associated with ileoanal anastomosis, - diarrhea associated with ileal resection, - diarrhea associated with inflammatory bowel disease (IBD), - IBS-like symptoms of patients with IBD in clinical remission, or “IBD-IBS”, - diarrhea associated with metabolite therapy, - diarrhea associated with pancreatic insufficiency, - diarrhea associated with platinum therapy, - diarrhea associated with rotavirus, - diarrhea associated with type 2 diabetes, - diarrhea associated with various causes including bacterial infections, bacterial overgrowth, bile acid malabsorption, bariatric surgery including gastric sleeve surgery, gastric bypass surgery (Roux-en-Y gastric bypass) bariatric resection, celiac disease, ulcerative colitis, Crohn’s disease, chemotherapy, cholecystectomy, cholera, clostridium difficile infection, cytotoxic therapy, Dumping Syndrome, GLP-1 agonist therapy, GLP-1 / GIP dual agonist therapy, GLP-1 / GIP / Gcg tri-agonist therapy, ileoanal anastomosis, ileal resection, inflammatory bowel disease (IBD), metabolite PATENT 7279.154670PCT therapy, pancreatic insufficiency, platinum therapy, rotavirus, vagotomy, and type 2 diabetes, - diarrhea associated with ulcerative colitis, - diarrhea associated with vagotomy, - drug withdrawal effects, - dyssynergic defecation, - epigastric pain syndrome (EPS), - fecal incontinence, - fibromyalgia syndrome, - functional abdominal bloating, - functional abdominal distension, - functional abdominal pain disorders, - functional abdominal pain – NOS, - functional anorectal pain, - functional biliary sphincter of Oddi disorder, - functional constipation, - functional defecation disorders, - functional diarrhea, - functional dyspepsia, - functional gallbladder disorder, - functional nausea, - functional nausea and vomiting disorders, - functional neurological disorders, - functional pancreatic sphincter of Oddi disorders, - functional vomiting, - gastrointestinal disorders, - gastroesophageal reflux disease (GERD), - hepatic encephalopathy, - inadequate defecatory propulsion, - infant colic, - infant dyschezia, - infant regurgitation, - irritable bowel syndrome, PATENT 7279.154670PCT - irritable bowel syndrome-diarrhea (IBS-D), - irritable bowel syndrome-unclassified (IBS-U), - irritable bowel syndrome-constipation (IBS-C), - mixed-irritable bowel syndrome (IBS-M), - levator ani syndrome (LAS), - low anterior resection syndrome (LARS), - Major LARS, - motility disturbance, - narcotic bowel syndrome (NBS), - nausea and vomiting arising from obesity syndrome treatment, - nausea and vomiting disorders, - non-retentive fecal incontinence, - opioid-induced constipation, - opioid-induced gastrointestinal hyperalgesia, - opioid-induced pruritis, - pain and inflammation associated with osteoarthritis, - post-operative-induced nausea and vomiting (RINV), - postprandial distress syndrome (PDS), - post-surgical bowel dysfunctions, - proctalgia fugax, - pruritus, - pruritus secondary to liver disfunction, - psoriasis, - radiation skin injury, - rosacea, - rumination syndrome, - serotonin-induced pruritus, - short bowel syndrome, - small intestine bacterial overgrowth (SIBO), - diversion colitis, - indeterminant colitis, - microscopic colitis, - ulcerative colitis, PATENT 7279.154670PCT - unspecified functional anorectal pain, - unspecified functional bowel disorder, - visceral hypersensitivity, - visceral pain, - Pancreatic Insufficiency, - Diabetic Nephropathy, - Obesity, - Diabetes Mellitus, - Gestational Diabetes Mellitus, - Non-alcoholic Fatty Liver Disease, - NASH, - Hyperlipidemia - gastroparesis, - early dumping Syndrome, - late dumping syndrome, - dumping syndrome post-gastrectomy, - SIBO after gastric bypass, - nutritional deficiencies in gastric bypass, - belching disorders, - supragastric belching, - centrally mediated abdominal pain syndrome (CAPS), - defecation disorders, - functional chest pain of esophageal original, - functional diarrhea of infancy, - functional dysphagia, - functional fecal incontinence, - functional heartburn, - globus, - opioid-induced constipation, - upper gastrointestinal disorders. In alternative embodiments, the diseases or conditions described herein may present with symptoms selected from the group consisting of: - diarrhea, PATENT 7279.154670PCT - constipation, - fecal incontinence (inability to control bowel movements), - abdominal pain, - early satiety, - nausea, - vomiting, - urgency to defecate, - excessive bowel movements, - tenesmus, - clustering, - anorectal pain, - difficulty initiating bowel movements, - prolonged straining, - sensation of anorectal blockage, - sensation of incomplete evacuation, - straining during defecation, - pruritus ani, - anal dermatitis, - post-prandial fullness, - abdominal fullness, - delayed gastric emptying, - bloating, - gastroesophageal reflux, - reduced appetite, - belching (excessive burping), - difficulty swallowing (dysphagia), - painful swallowing, - sensation of a lump in the throat (globus sensation), - chest pain of esophageal origin (non-cardiac chest pain), - rumination (regurgitating food and re-chewing or re-swallowing), - epigastric pain or burning, - unintentional weight loss, - flatulence (excessive gas), PATENT 7279.154670PCT - aerophagia (excessive air swallowing). In alternative embodiments of methods as provided herein: the drug, or therapeutic combination, pharmaceutical dosage form, is administered orally, parenterally, by inhalation spray, nasally, topically, intrathecally, intracerebrally, epidurally, intracranially or rectally, and optionally parenteral administration comprises administration intrathecally, intracerebrally or epidurally (into an intrathecal, intracerebral, or epidural space), subcutaneously, intravenously, intramuscularly and / or intraarterially, the drug, therapeutic combination, or pharmaceutical dosage form, is administered to achieve a therapeutic level range of plasma concentration at a steady state, and wherein: and specifically, Formula I, optionally Compound I, is administered once, twice, three, or four times per day in the amount of between about 0.1 mg to 45 mg, 0.15 mg to 30 mg, 0.25 to 20 mg, 0.4 to 15 mg, 0.5 to 10 mg, 0.6 mg to 5 mg, 0.75 mg to 4 mg, 1 mg to 2.5 mg, or about 1.5 mg; and specifically, the tryptophan hydroxylase inhibitor, optimally telotristat ethyl (XERMELOTM), is administered once, twice, three, or four times per day in the amount of between about 5 mg to 1 gram, 50 mg to 900 mg, 100 mg to 800 mg, 150 mg to 750 mg, 175 mg to 500 mg, 200 mg to 300 mg, or about 250 mg; and specifically, rifaximin (XIFAXANTM) is formulated in a unit dosage amount ranging from between about 50 mg to 1 gram, 75 mg to 900 mg, 100 mg to 850 mg, 150 mg to 750 mg, 200 mg to 600 mg, or about 550 mg. In alternative embodiments for certain therapeutic applications, Formula I, optionally Compound I, is administered one to four times daily. The dosing is determined based on the patient's total body weight or sex and total body weight and rounded to the nearest available dose within the following ranges: between about 1 µg / kg to 1 µg / kg, 2 µg / kg to 400 µg / kg, 4 µg / kg to 20 µg / kg, 6 µg / kg to 200 µg / kg, 8 µg / kg to 120 µg / kg, 10 µg / kg to 80 µg / kg, 12 µg / kg to 60 µg / kg, 5 µg / kg to 35 µg / kg, or approximately 20 µg / kg. In alternative embodiments, the GLP-1 agonist is administered one time daily. The dosing is determined based on the patient's total body weight or sex and total body weight and rounded to the nearest available dose within the following ranges 6 PATENT 7279.154670PCT µg / kg to 30 µg / kg, 8 µg / kg to 25 µg / kg, 10 µg / kg to 20 µg / kg, or approximately 15 µg / kg. In alternative embodiments for certain therapeutic applications of Formula I, optionally Compound I, such that CMAX, defined as the maximum blood day concentration obtained when patients are sampled from a Phase 1 population of healthy male and female volunteers at intervals of 15 minutes, 30 minutes, 60 minutes, 90 minutes, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours, falls between 0.2 ng / mL to 100 ng / mL, 1 ng / mL to 50 ng / mL, about 1.5 ng / mL to 20 ng / mL, about 1.75 ng / mL to 15 ng / mL, or below about 5 ng / mL, or about 0.5ng / mL to 1.5 ng / mL, or about 1.0 ng / mL determined through the application of a mixed- effect modeling software, optionally PHOENIX NLMETMor NONMEMTM. In alternative embodiments for certain therapeutic applications of Formula I, optionally Compound I, such that CMIN, defined as the minimum blood day concentration obtained when patients are sampled from a Phase 1 population of healthy male and female volunteers at intervals of 15 minutes, 30 minutes, 60 minutes, 90 minutes, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours, remains above between 0.1 ng / mL to 10 ng / mL, 0.2 ng / mL to 5 ng / mL, about 0.3 ng / mL to 2 ng / mL, about 0.5ng / mL to 1.0 ng / mL, about 0.7 ng / mL determined through the application of a mixed-effect modeling software, optionally PHOENIX NLMETMor NONMEMTM. In alternative embodiments, to ensure consistent therapeutic efficacy over the dosing interval, the compositions or formulations of Formula I, optionally Compound I as described herein, may be administered such that Ctrough, defined as the blood plasma concentration immediately prior to the administration of the next dose, is between 0.05 ng / mL to 20 ng / mL, 0.2 ng / mL to 10 ng / mL, 0.5 ng / mL to 8 ng / mL; 0.75 ng / mL to 6 ng / mL; 1 ng / mL to 5 ng / mL; 1.5 ng / mL to 4 ng / mL, or above about 2 ng / mL, as determined through the application of a mixed-effect modeling, thereby ensuring the active compound maintains its activity throughout the period. In alternative embodiments for Formula I, optionally Compound I, in order to ensure an optimal therapeutic dose, defined as the quantity of Formula I, optionally Compound I, that achieves the desired pharmacological effect in a patient without causing unacceptable adverse events, is achieved, a titration program should be implemented, wherein, optionally beginning at a No Observed Adverse Effect Level PATENT 7279.154670PCT (NOAEL), with a titration period of between about 3 days to 1 month, about 10 days to 3 weeks, or about 1 week, the therapeutic dose is increased by between about 25% to 150%, 35% to 100%, or about 50% per titration period. In alternative embodiments, the dosing of Formula I, optionally Compound I, shall follow one of four titration protocols: (a) For one to four weeks, or two weeks, a 0.5 mg to 2.5 mg, or 1.5 mg dose of Formula I, optionally Compound I is administered daily in up to four divided doses. Thereafter, the daily dose of Formula I is increased by 0.5 mg to 2.5 mg, or 1.5 mg. (b) In conjunction with GLP-1 agonist therapy, a 1.5 mg daily dose of Formula I is administered in up to four divided doses for one week. For the subsequent two weeks, the daily dose is increased to 3 mg in up to four divided doses. In the fourth week, the daily dose of Formula I is returned to 1.5 mg daily in up to four divided doses; (c) In conjunction with semaglutide therapy, a 0.5 mg to 2.5 mg, or 1.5 mg dose of Formula I, optionally Compound I is administered daily in up to four divided doses. Thereafter, the daily dose of Formula I is increased by .5 mg to 2.5 mg, or 1.5 mg. A 0.25 mg to 2.4 mg, or a 0.25 mg dose of semaglutide is once weekly for 1 to 4 weeks, or 2 weeks. In 1 to 4 week intervals, or 2 week intervals, the weekly dose of semaglutide is increased to 0.5 mg to 2.4 mg or 0.5 mg, 1 mg to 2.4 mg or 1 mg, or 1.7 mg to 2.4 mg or 1.7 mg, to 2.4 mg once weekly. (d) Optionally, a pre-dose regimen involves administering 1 mg of Formula I daily in up to four divided doses for one week prior to initiating GLP-1 agonist therapy. Following the commencement of GLP-1 therapy, the Formula I dosage is escalated to 2 mg daily. In alternative embodiments, the dosing of Formula I, optionally Compound I, shall follow one of four titration protocols: (a) For one to four weeks, or two weeks, a 0.25 mg to 5.0 mg, or 1.5 mg dose of Formula I, optionally Compound I is administered daily in up to four divided doses. Thereafter, the daily dose of Formula I is increased by 0.25 mg to 2.5 mg, or 1.5 mg. PATENT 7279.154670PCT (b) In conjunction with GLP-1 agonist therapy, a 1.5 mg daily dose of Formula I, optionally Compound I is administered in up to four divided doses for one week. For the subsequent two weeks, the daily dose is increased to 3 mg in up to four divided doses. In the fourth week, the daily dose of Formula I is returned to 1.5 mg daily in up to four divided doses. (c) In conjunction with liraglutide therapy, a 0.5 mg to 2.5 mg, or 1.5 mg dose of Formula I, optionally Compound I is administered daily in up to four divided doses. Thereafter, the daily dose of Formula I is increased by 0.5 mg to 2.5 mg, or 1.5 mg. A 0.6 mg to 3.0 mg, or a 0.06 mg dose of liraglutide is once daily for 1 to 4 weeks, or 1 week. In 1-to-4-week intervals, or 1-week intervals, the daily dose of liraglutide is increased to 0.6 mg to 3.0 mg or 1.2 mg, 0.6 mg to 3.0 mg or 1.8 mg, or 0.6 mg to 3.0 mg or 2.4mg mg, to 3.0 mg once daily. (d) Optionally, a pre-dose regimen involves administering 1 mg of Formula I, optionally Compound I daily in up to four divided doses for one week prior to initiating GLP-1 agonist therapy. Following the commencement of GLP-1 therapy, the Formula I dosage is escalated to 2 mg daily. In alternative embodiments, the dosing of Formula I, optionally Compound I, shall follow one of four titration protocols: (dosing based on body weight) (a) For one to four weeks, or two weeks, a 0.25 mg to 5.0 mg, or 1.5 mg dose of Formula I, optionally Compound I is administered daily in up to four divided doses. Thereafter, the daily dose of Formula I is increased by 0.25 mg to 2.5 mg, or 1.5 mg. (b) In conjunction with GLP-1 agonist therapy, a 1.5 mg daily dose of Formula I, optionally Compound I is administered in up to four divided doses for one week. For the subsequent two weeks, the daily dose is increased to 3 mg in up to four divided doses. In the fourth week, the daily dose of Formula I is returned to 1.5 mg daily in up to four divided doses. (c) In conjunction with liraglutide therapy, a 0.5 mg to 2.5 mg, or 1.5 mg dose of Formula I, optionally Compound I is administered daily in PATENT 7279.154670PCT up to four divided doses. Thereafter, the daily dose of Formula I, optionally Compound I is increased by 0.5 mg to 2.5 mg, or 1.5 mg. A 0.6 mg to 3.0 mg, or a 0.06 mg dose of liraglutide is once daily for 1 to 4 weeks, or 1 week. In 1-to-4-week intervals, or 1-week intervals, the daily dose of liraglutide is increased to 0.6 mg to 3.0 mg or 1.2 mg, 0.6 mg to 3.0 mg or 1.8 mg, or 0.6 mg to 3.0 mg or 2.4mg mg, to 3.0 mg once daily. (d) Optionally, a pre-dose regimen involves administering 1 mg of Formula I, optionally Compound I daily in up to four divided doses for one week prior to initiating GLP-1 agonist therapy. Following the commencement of GLP-1 therapy, the Formula I dosage is escalated to 2 mg daily. In alternative embodiments for certain therapeutic applications, Formula I, optionally Compound I, is administered one to four times daily. The dosing is determined based on the patient's total body weight, or total body weight and sex, or trough blood or plasma concentration, and rounded to the nearest available dose within the following ranges: between about 1 µg / kg to 1 mg / kg, 2 µg / kg to 400 µg / kg, 4 µg / kg to 20 µg / kg, 6 µg / kg to 200 µg / kg, 8 µg / kg to 120 µg / kg, 10 µg / kg to 80 µg / kg, 12 µg / kg to 60 µg / kg, 5 µg / kg to 35 µg / kg, or approximately 20 µg / kg. In alternative embodiments, the GLP-1 agonist, optionally liraglutide, is administered one to seven times per week, or once daily. The dosing is determined based on the patient's total body weight, or total body weight and sex, or total body weight, sex and BMI, or total body weight, sex, BMI and trough blood or plasma concentration, and rounded to the nearest available dose within the following ranges: between about 0.5 µg / kg to 500 µg / kg, 4 µg / kg to 50 µg / kg, 5 µg / kg to 40 µg / kg, 6 µg / kg to 30 µg / kg, 8 µg / kg to 25 µg / kg, 10 µg / kg to 20 µg / kg, or approximately 15 µg / kg In alternative embodiments, provided are novel deuterated 5- hydroxytryptamine (5-HT3) receptor modulator, optionally 5-hydroxytryptamine (5- HT3) receptor partial agonists. In alternative embodiments, provided are novel deuterated analogues Formula I, optionally deuterated analogues of Compound I.In an alternative embodiment, provided is a composition comprising Compound I for the treatment of irritable bowel PATENT 7279.154670PCT syndrome, including diarrhea-predominant (IBS-D), constipation-predominant (IBS- C), mixed-type (IBS-M) and unclassified (IBS-U) subtypes. In an alternative embodiment, provided is a composition comprising Compound I and a GLP-1 receptor agonist, as defined herein, for the treatment of irritable bowel syndrome, including diarrhea-predominant (IBS-D), constipation- predominant (IBS-C), mixed-type (IBS-M), and unclassified (IBS-U) subtypes. In an alternative embodiment, provided is a composition comprising Compound I and a GLP-1 receptor agonist selected from the group consisting of liraglutide, semaglutide, and tirzepatide, danuglipron, HRS-7535 for the treatment of irritable bowel syndrome, including diarrhea-predominant (IBS-D), constipation- predominant (IBS-C), mixed-type (IBS-M) and unclassified (IBS-U) subtypes. In an alternative embodiment, provided is a composition comprising Compound I and a GLP-1 receptor agonist, as defined herein, for the treatment of IBS-like symptoms of patients with IBD (inflammable bowel disease) in clinical remission (called “IBD-IBS”), In an alternative embodiment, provided is a composition comprising Compound I and a GLP-1 receptor agonist selected from the group consisting of liraglutide, semaglutide, and tirzepatide, danuglipron, HRS-7535 for the treatment of IBS-like symptoms of patients with IBD (inflammable bowel disease) in clinical remission (called “IBD-IBS”), In an alternative embodiment, provided is a composition comprising Compound I and a GLP-1 receptor agonist selected from the group consisting of liraglutide, semaglutide, and tirzepatide, danuglipron, HRS-7535 for the treatment of IBS-like symptoms of patients with ulcerative colitis or Crohn’s disease in clinical remission, In an alternative embodiment, provided is a composition comprising Compound I and a sphingosine-1-phosphate modulator selected from the group consisting of Ozanimod (or ZEPOSIATM), Siponimod (MayzentTM), Ponesimod (PonvoryTM); or Fingolimod (GilenyaTM), for the treatment of IBS-like symptoms of patients with IBD (inflammable bowel disease) in clinical remission (called “IBD- IBS”), In an alternative embodiment, provided is a composition comprising Compound I and a GLP-1 agonist selected from the group consisting of liraglutide, PATENT 7279.154670PCT semaglutide, and tirzepatide , danuglipron, HRS-7535, for the treatment of low anterior resection syndrome (LARS). In an alternative embodiment, provided is a composition comprising Compound I and a sphingosine-1-phosphate modulator selected from the group consisting of Ozanimod (or ZEPOSIATM), Siponimod (MayzentTM), Ponesimod (PonvoryTM); or Fingolimod (GilenyaTM), for the treatment of IBS-like symptoms of patients with ulcerative colitis or Crohn’s disease in clinical remission, In an alternative embodiment, provided is a composition comprising a dopamine D2 antagonists, selected from the group consisting of Bromopride (DIGESANTM), Domperidone (MOTILIUMTM), Metoclopramide (REGLANTM or MAXOLONTM), Metopimazine (VOGALENETM), or Metopimazine Mesylate, for the treatment of Functional Dyspepsia. In alternative embodiments, provided are therapeutic combinations or formulations of drugs comprising various combinations of 5-hydroxytryptamine (5- HT3) receptor partial agonists. In alternative embodiments, provided are methods for the treatment of various conditions, including, but not limited to, nausea, vomiting, and other gastrointestinal symptoms arising from obesity treatment, chemotherapy- induced nausea and vomiting (CINV), irritable bowel syndrome (IBS), post-operative nausea and vomiting (PONV), and symptoms related to carcinoid syndrome. In alternative embodiments, provided is a comprehensive digital health system that enhances adherence to therapeutic drug treatments through a digitally-enabled therapeutic kit. The system integrates advanced algorithms, models, processors, and physical memories to provide personalized intervention regimens. Key components include a cloud-based computing platform, digitally-enabled therapeutic kit, eSource data components, customized user interfaces, and various functional blocks for data collection, behavior change, and clinical trial management. The platform is designed to enable future integration of new algorithms, models, and processors based on evolving clinical data. In alternative embodiments: Drug-Digital Combination Products: In one embodiment, a drug-digital combination product for the treatment of functional gastrointestinal disorders (FGIDs) is provided. The combination product comprises: • A therapeutically effective amount of a drug selected from: PATENT 7279.154670PCT o 5-HT3 receptor modulators, o GLP-1 agonists, and o Dopamine D2 receptor antagonists, wherein the drug comprises one, a combination of two, or a combination of all three of the listed drugs, with one selected from each category. • In alternative embodiments Smart packaging physically integrated with the drug, is configured to: o Record and transmit time-stamped drug or pen needle dispensing events using RFID or NFC-enabled technology.•In alternative embodiments a digital best supportive care (BSC) platform comprises: o A symptom tracking module for collecting patient-reported outcomes (PROMs) tailored to FGID-specific symptoms, such as pain, stool consistency, and frequency. o A behavioral guidance module delivering cognitive-behavioral therapy (CBT) interventions to address brain-gut interactions in FGIDs, including stress management and maladaptive belief correction. o A dietary recommendation module providing personalized dietary adjustments based on symptom tracking and FGID-specific dietary triggers. o An adherence support system that uses time-stamped drug or pen needle usage data to provide real-time feedback, automated reminders, and escalation protocols for nonadherence. In alternative embodiments: Monitoring by the Digital BSC Platform In another embodiment, the digital BSC platform is configured to: • Monitoring comprises: o Drug adherence using time-stamped data from the smart packaging. o FGID-specific patient-reported symptoms via the symptom tracking module. o Patient engagement with behavioral and dietary guidance modules. • Collect monitored data and transmit it to a centralized database for real-time analysis. PATENT 7279.154670PCT In alternative embodiments: Monitored Data In another embodiment, the monitored data collected by the digital BSC platform comprises: • Adherence metrics derived from time-stamped drug or pen needle dispensing data, analyzed to detect patterns of consistent or missed doses. • Symptom severity scores tracked over time using validated scales such as the IBS Severity Scoring System (IBS-SSS). • Behavioral engagement metrics reflecting patient interactions with the digital BSC platform. In alternative embodiments: Data Analysis and Recommendations In another embodiment, the combination product further comprises: • Analyzing monitored data using predefined algorithms to: o Detect patterns of adherence and nonadherence. o Identify trends in FGID-specific symptom improvement or exacerbation. o Correlate behavioral engagement with changes in symptom severity. • Generating actionable recommendations to modify behavioral, dietary, or adherence interventions based on real-time analysis of the monitored data. In alternative embodiments: Adherence Support Systems In another embodiment, the adherence support system is configured to: • Provide automated reminders for missed doses via the digital BSC platform. • Trigger escalated interventions, including virtual counseling or moderated peer group interactions, when: o Adherence rates fall below 50%-99% or 80%, or o Symptom severity exceeds predefined thresholds. • Offer tailored feedback and support to patients based on analyzed adherence and symptom data. In alternative embodiments: Customized Interventions In another embodiment, the combination product customizes interventions for individual patients using: • Decision-tree or other algorithms that integrate adherence metrics, symptom severity data, and engagement trends to determine appropriate interventions. PATENT 7279.154670PCT • Dynamic adjustments to behavioral guidance or dietary recommendations informed by real-time PROMs and adherence data. In alternative embodiments: Synergistic Therapeutic Effects In another embodiment, the integration of the drug, smart packaging, and digital BSC platform produces synergistic therapeutic effects for treating FGIDs, achieving: • A statistically significant reduction in symptom severity compared to the drug alone during the treatment period, as measured by validated scales such as the IBS Severity Scoring System (IBS-SSS), with statistical significance defined as p < 0.05. • A statistically significant improvement in adherence rates compared to the drug alone, measured as a percentage of prescribed doses taken and recorded via time-stamped data from the smart packaging, with statistical significance defined as p < 0.05. The synergistic effects result from: • Enhanced drug adherence facilitated by real-time monitoring and automated reminders. •Tailored FGID-specific interventions, including CBT modules addressingmaladaptive beliefs and stress. • Dietary adjustments informed by real-time symptom data, improving patient self-management and engagement. In alternative embodiments : Labeling for the Combination Product In another embodiment, the drug label comprises: • A description of the drug, smart packaging, and digital BSC platform. • Instructions for physicians and patients on integrating the digital BSC with drug therapy. • Randomized controlled trial data demonstrating: o The efficacy and safety of the drug. o The adherence and therapeutic benefits achieved through the integration of smart packaging and the digital BSC platform. The details of one or more exemplary embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and PATENT 7279.154670PCT drawings, and from the claims. All publications, patents, patent applications cited herein are hereby expressly incorporated by reference in their entireties for all purposes. DESCRIPTION OF DRAWINGS The drawings set forth herein are illustrative of exemplary embodiments provided herein and are not meant to limit the scope of the invention as encompassed by the claims. Figures are described in detail herein. Gpe FIG.1 graphically illustrates the difference in documented gastrointestinal and dermatological adverse events experienced between subjects who received a placebo dose, a 0.5 mg dose Compound I, a 1 mg dose Compound I, a 2 mg dose Compound I, a 3 mg dose Compound I, and a 4.5 mg dose of Compound I in the SAD study. FIG.2 graphically illustrates Sequential visual representations that elucidate the adverse event profiles observed in the 1.5 mg Compound I dose study cohorts. FIG.3 graphically illustrates Sequential visual representations that elucidate the adverse event profiles observed in the placebo study cohorts. FIG.4 graphically illustrates data showing that the 1.5 mg dose Compound I cohort initially presented with a high incidence of adverse events and demonstrated a significant attenuation as the study progress. FIG.5 graphically illustrates data showing that the 2.75 mg dose Compound I cohort initially presented with a high incidence of adverse events and demonstrated a significant attenuation as the study progress. FIG.6 graphically illustrates Steady State Verification data from Cohort 5 (SAD) and Cohort 1 (MAD), Day 7, showing the predicted steady state concentration for Cohort 1 was a reasonable approximation of the actual data, and shows scaling of the 4.5 mg single dose to 3 mg and 1 mg Compound I was acceptable to allow approximation of PK profiles under different dosage regimes. FIG.7 graphically illustrates Steady State Verification data from Cohort 5 (SAD) and Cohort 1 (MAD), Day 7, showing the predicted steady state concentration for Cohort 1 was a reasonable approximation of the actual data, and shows scaling of the 4.5 mg single dose to 3 mg and 1 mg Compound I was acceptable to allow approximation of PK profiles under different dosage regimes. PATENT 7279.154670PCT FIG.8 graphically illustrates Steady State Prediction data for 1 mg three times a day (TID) Compound I for 7 Days and the data shows the average predicted steady state profile. FIG.9 graphically illustrates data showing 3 mg Daily for 7 Days compound I, indicating the average predicted steady state profile, and that steady state is reached by approximately 40 h post-dose (about 5 x t1 / 2) or the second dose. FIG.10 illustrates Table 1, SAD 0.5 mg Dose Cohort PK. FIG.11 illustrates Table 2, SAD 1 mg Dose Cohort PK. FIG.12 illustrates Table 3, SAD 2 mg Dose Cohort PK. FIG.13 illustrates Table 4, SAD 3 mg Dose Cohort PK. FIG.14 illustrates Table 5, SAD 4.5 mg Dose Cohort PK. FIG.15 illustrates Table 6, MAD 1.5 mg Dose Cohort PK. FIG.16 illustrates Table 7, MAD 2.75 mg Dose Cohort PK. FIG.17 illustrates the instances of flushing, the most commonly reported AE in the study, experienced between subjects who received either a placebo dose, a 0.5 mg dose, a 1 mg dose, a 2 mg dose, a 3 mg dose, and a 4.5 mg dose of Compound I in the SAD study, as discussed in Example 1, below. FIG.18 schematically illustrates that active inference extends this concept by suggesting that biological systems act to align the external environment with their expectations. In FGIDs, maladaptive prior beliefs, such as heightened visceral sensitivity and expectations of dysfunction, create a self-reinforcing cycle of symptom perception and dysfunction. FIG.19 graphically illustrates a Randomized Study Equivalence of Open Label Placebo vs Double-Blind Placebo that proves that drug mechanisms, such as 5- HT3 receptor modulation, GLP-1 agonism, and dopamine D2 antagonism, provide symptom relief by dampening noxious gut signaling, and shows the potential to replicate the placebo-driven "Clinical Trial Effect" as defined herein, in real-world settings by incorporating the supportive structure and rituals of clinical trials without deception. FIG.20 schematically illustrates a Depiction of the Synergy of Drug and Clinical Trial Effect on Pain Perception that shows that by integrating these proven drug mechanisms with digital platforms that replicate clinical trial supportive structures, there is a transformative opportunity to revolutionize FGID treatment. PATENT 7279.154670PCT FIG.21 illustrates a High Level Overview of an exemplary digital Best Supportive Care Platform, showing that an exemplary comprehensive digital health system includes a digital Best Supportive Care (DBSC) Platform. FIG 22A and FIG 22B schematically illustrates an exemplary Smart Blister Card System with Integrated Functional Components: FIG 22A schematically illustrates an exemplary Smart Blister Card System with Integrated Functional Components (Bottom View); an exemplary structural layout of the back of the smart blister card is depicted in Figure 22a, illustrating the arrangement of components 1–4, corresponding to specific areas as detailed in the Figure; and FIG 22B schematically illustrates an exemplary Smart Blister Card System with Integrated Functional Components (Top View), an exemplary front of the smart blister card, which contains the individual pill or pen needle cavities for housing 1 to 70 doses or 7–21 doses or 14 doses of the drug highlighting its conventional blister card design and dose arrangement. FIG.23A schematically illustrates Data Flow in an exemplary Smart Blister Card System (Primary Collection Method), depicting an exemplary Primary Data Collection Method, with the patient recording their data independently using their personal smartphone as an RFID-enabled interrogator. FIG.23B schematically illustrates Data Flow in an exemplary Smart Blister Card System (Secondary Collection Method), depicting an exemplary Secondary Data Collection Method, where the smart blister card’s data is retrieved at the disposal facility. FIG.24 schematically illustrates Data Flow and Escalation Pathways in the Smart Prescription Ecosystem, depicting an exemplary Smart Prescription Ecosystem, a comprehensive workflow integrating data exchange, patient engagement, and algorithmic decision-making to optimize medication use. Like reference symbols in the various drawings indicate like elements. DETAILED DESCRIPTION Definitions In alternative embodiments: Clinical Trial Effect means a measurable difference in therapeutic outcomes achieved through the comparison of the therapeutic outcomes of a control group and a test group: PATENT 7279.154670PCT a) In alternative embodiments: A control group receiving comprises: i. The identical therapeutic drug; ii. Electronically monitored drug administration compliant with FDA 21 CFR Part 11; and iii. Real World Care as defined herein. b) In alternative embodiments: A test group receiving comprises: i. The identical therapeutic drug; ii. Electronically Monitored drug administration compliant with FDA 21 CFR Part 11; and iii. Digital Best Supportive Care (DBSC). In alternative embodiments: Measurable difference quantified by at least one of the following: a) In alternative embodiments: Therapeutic outcomes demonstrating clinically meaningful improvement as defined by: i. Statistically significant improvement in primary endpoints according to: - Applicable FDA or ICH guidelines for the therapeutic area; - Validated peer-reviewed industry standards; or - A minimum clinically important difference (MCID) of 10% versus control. b) In alternative embodiments: Adherence metrics demonstrating clinically significant improvement, comprising: i. Metrics meeting validated therapeutic area standards or regulatory guidelines, such as: - Medication Possession Ratio (MPR) or Proportion of Days Covered (PDC) improvement by ≥10%; or - Improvement thresholds recognized as clinically meaningful within the therapeutic area. In alternative embodiments: Electronic Monitoring systems comprises systems achieving compliance with: a) Current FDA 21 CFR Part 11, GAMP 5, or their equivalent recognized regulatory or industry standards; b) Data accuracy ≥ 95%, completeness ≥ 80%, and system availability ≥90%; or PATENT 7279.154670PCT c) Alternate performance thresholds recognized as valid under applicable therapeutic or regulatory standards. In alternative embodiments: Real World Care refers to routine healthcare delivered in non-clinical trial settings, defined as: a) In alternative embodiments: Standard clinical practices: • Care delivered in primary, secondary, or tertiary care environments, guided by applicable clinical guidelines and standards of care for the therapeutic area. • Care reflective of the geographic region and healthcare system where the patient resides. In alternative embodiments: Evidence-based practices are practices supported by observational studies, claims data, and registries rather than randomized controlled trials (RCTs). In alternative embodiments, provided are compositions, including products of manufacture and kits, and methods, for 5-hydroxytryptamine (5-HT3) receptor modulation using a 5-HT3 receptor modulator or a 5-HT3 receptor partial agonist or a 5-HT3 receptor antagonist or a Glucagon-like peptide-1 (GLP-1) receptor agonist, wherein optionally the GLP-1 receptor agonist is liraglutide (or SAXENDATMorVICTOZATM),for the treatment of intestinal and other diseases. In alternativeembodiments, provided are therapeutic combinations and methods of use of a 5-HT3 receptor modulator or a 5-HT3 receptor partial agonist or a 5-HT3 receptor antagonist or a Glucagon-like peptide-1 (GLP-1) receptor agonist, wherein optionally the GLP-1 receptor agonist is liraglutide (or SAXENDATMor VICTOZATM),for treating irritable bowel syndrome (IBS), carcinoid syndrome, adverse reactions related to Glucagon- Like Peptide-1(GLP-1) or dual GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) modulator therapy, Low anterior resection syndrome (LARS), Bile Acid Diarrhea (BAD), ileal resection diarrhea, diarrhea associated with ileoanal anastomosis, and gastrointestinal infections, and other diseases. In alternative embodiments, provided are therapeutic combinations or formulations of drugs comprising the 5-HT3 receptor modulator (S)-7-(quinuclidine- 3-yl)-8,9-dihydro-2H-azepino [5,4,3-cd]indazol-6(7H)-one (Compound I), and analogues, referred to herein as ‘Formula I’, and its associated salts, co-crystals, and polymorphs, in combination with other drugs or active agents. PATENT 7279.154670PCT In alternative embodiments, provided are methods for administering Formula I and Compound I. In alternative embodiments, provided are methods for the treatment of various conditions and diseases in which the 5-HT3 receptor is implicated, including irritable bowel syndrome (IBS), carcinoid syndrome, adverse reactions related to Glucagon-Like Peptide-1(GLP-1) or dual GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) modulator therapy, Low anterior resection syndrome (LARS), Bile Acid Diarrhea (BAD), ileal resection diarrhea, diarrhea associated with ileoanal anastomosis, and gastrointestinal infections, among other diseases, using therapeutic combinations and formulations of drugs as provided herein. Knowledge of the pathophysiology of IBS-D provides an opportunity of a pharmacological mechanism predicted to deliver clinical efficacy with a reduced side- effect profile. Thus, a selective 5-HT3 receptor partial agonist could reduce receptor activity evoked by endogenous 5-HT3 yet could prevent complete receptor inhibition reducing the likelihood of constipation and perhaps ischemic colitis. In addition, a partial agonist may also benefit IBS-C (constipation) and IBS-M (mixed) because of the “dual” agonist and antagonist actions depending on the local serotonin levels. A similar rationale is relevant to offer symptomatic relief to patients with carcinoid syndrome, which is associated with copious quantities of circulating 5-HT with arising chronic diarrhea that can be controlled by the “off-label” use of 5-HT3 receptor antagonists. In alternative embodiments, provided is a cloud-based digital health system designed to enhance adherence and add the Clinical Trial Effect to therapeutic drug treatments. Specifically, the invention integrates a digitally-enabled therapeutic kit comprising advanced algorithms, models, processors, and physical memories to provide personalized intervention regimens. The platform is designed to facilitate future developments and enhancements through the integration of new algorithms, models, and processors based on clinical data, with a specific focus on the use of Compound I and liraglutide for managing functional gastrointestinal disorders (FGIDs). Pharmaceutical Compositions and Formulations In alternative embodiments, therapeutic combinations of drugs or compounds are provided herein, or therapeutic combinations of drugs or compounds used to practice methods are provided herein, are formulated for administration by any or a PATENT 7279.154670PCT variety of means including orally, parenterally, by inhalation spray, nasally, topically, subcutaneously, intramuscularly, intrathecally, intrathecally, intracerebrally, epidurally, intracranially or rectally. Therapeutic combinations of the drugs or compounds as provided herein, or a composition used to practice methods as provided herein, can further comprise pharmaceutically acceptable carriers, adjuvants and vehicles. In alternative embodiments, the therapeutic combinations of drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, are formulated for pen injector systems or parenteral administration, including administration intrathecally, intracerebrally or epidurally (into a intrathecal, intracerebral, epidural space), subcutaneously, intravenously, intramuscularly and / or intraarterially; for example, by injection routes but also including a variety of infusion techniques. Intraarterial, intrathecal, intracranial, epidural, intravenous and other injections as used in some embodiments can comprise administration pen injector systems or through catheters or pumps, for example, an intrathecal pump, or an implantable medical device (which can be an intrathecal pump or catheter). In alternative embodiments, therapeutic combinations of drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, can be formulated in accordance with a routine procedure(s) adapted for a desired administration route. In alternative embodiments, therapeutic combinations of drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, are formulated or manufactured as lyophilates, powders, lozenges, liposomes, suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and / or dispersing agents. In alternative embodiments, therapeutic combinations of drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, can be formulated as a preparation for implantation or injection. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives (for example, as a sparingly soluble salt). Alternatively, the active ingredient can be in powder form for constitution with a suitable vehicle, for example, sterile pyrogen-free water, before use. Suitable alternative and exemplary formulations for each of these methods of administration can be found, for PATENT 7279.154670PCT example, in Remington: The Science and Practice of Pharmacy, A. Gennaro, ed., 20th edition, Lippincott, Williams & Wilkins, Philadelphia, Pa. In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, can be formulations for parenteral administration comprising any common excipient, for example, sterile water or saline, a polyalkylene glycol such as a polyethylene glycol, an oil of synthetic or vegetable origin, a hydrogenated naphthalene and the like. In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, can be a biocompatible, biodegradable lactide polymer, a lactide / glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers can be useful excipients to control the release of active compounds. In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, are administered using pen injector systems or parenteral delivery systems such as ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, intrathecal catheters, pumps and implants, and / or use of liposomes. Formulations for parenteral administration can also include glycocholate for buccal administration, methoxysalicylate for rectal administration, or citric acid for vaginal administration. Formulations for inhalation administration can contain as excipients, for example, lactose, or can be aqueous solutions containing, for example, polyoxyethylene-9-auryl ether, glycocholate and deoxycholate, or oily solutions for administration in the form of nasal drops, or as a gel to be applied intranasally. In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, are administered intranasally. When given by this route, examples of appropriate dosage forms are a nasal spray or dry powder, as is known to those skilled in the art. For example, a nasal formulation can comprise a conventional surfactant, generally a non-ionic surfactant. When a surfactant is employed in a nasal formulation, the amount present will vary depending on the particular surfactant chosen, the particular mode of administration (for example drop or spray) and the effect desired. In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, are in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous PATENT 7279.154670PCT suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non- toxic parenterally acceptable diluent or solvent such as a solution in 1,3-butane-diol or prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In alternative embodiments, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In alternative embodiments, fatty acids such as oleic acid may likewise be used in the preparation of injectables. Formulations for intravenous administration can comprise solutions in sterile isotonic aqueous buffer. Where necessary, the formulations can also include a solubilizing agent and a local anesthetic to ease pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampule (ampoule) or sachet indicating the quantity of active agent. Where the compound is to be administered by infusion, it can be dispensed in a formulation with an infusion bottle containing sterile pharmaceutical grade water, saline or dextrose / water. Where the compound is administered by injection, an ampule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration. In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, further comprise aqueous and non-aqueous sterile injection solutions that can contain antioxidants, buffers, bacteriostats, bactericidal antibiotics and solutes that render the formulation isotonic with the bodily fluids of the intended recipient: and / or aqueous and non- aqueous sterile suspensions, which can include suspending agents and thickening agents. In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, are formulated for subcutaneous administration, for example, in the form of a liquid for a pen injector system. PATENT 7279.154670PCT In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, are formulated for topical administration, for example, in the form of a liquid, lotion, cream or gel. Topical administration can be accomplished by application directly on the treatment area. For example, such application can be accomplished by rubbing the formulation (such as a lotion or gel) onto the skin of the treatment area, or by a spray application of a liquid formulation onto the application or treatment area. In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, comprise a bioimplant or a bioimplant material, and also can be coated with a compound of the invention or other compounds so as to improve interaction between cells and the implant. In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, comprise minor amounts of wetting or emulsifying agents, or pH buffering agents. In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, are formulated as a suppository, with traditional binders and carriers such as triglycerides. In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, comprise oral formulations such as tablets, pills, troches, lozenges (see, for example, as described in USPN 5,780,055), aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules or geltabs, gels, jellies, syrups and / or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, taste-masking agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Oral formulations can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, polyvinyl pyrrolidone, sodium saccharine, cellulose, magnesium carbonate, etc. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or PATENT 7279.154670PCT alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, or stearic acid. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed. In alternative embodiments, formulations for oral use are hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil. In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, comprise aqueous suspensions comprising the active material in a mixture with excipients suitable for the manufacture of aqueous suspensions. Exemplary excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxy-propyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (for example, lecithin), a condensation product of an alkylene oxide with a fatty acid (for example, polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (for example, heptadecathyle- neoxycetanol), or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitolanhydride (for example, polyoxyethylene sorbitanmonooleate). The aqueous suspension may also contain one or more preservatives such as ethyl or n- propyl p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin. In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, comprise oil suspensions that can be formulated by suspending the active ingredient (for example, a compound of this invention) in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oral suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added PATENT 7279.154670PCT to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid. In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, include an agent which controls release of the compound, thereby providing a timed or sustained release compound. In alternative embodiments, drugs or compounds as provided herein. or a composition used to practice the methods as provided herein, are formulated or made as a multi-particulate and / or a solid dispersion formulation, for example, as described in, for example, U.S. Pat. App. Pub. No.20080118560, for example, comprising a hydrophobic matrix former which is a water-insoluble, non-swelling amphiphilic lipid; and a hydrophilic matrix former which is a meltable, water-soluble excipient. In one embodiment, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, are contained in tablets, pills, capsules, troches, and the like comprising any combination of a binder, for example, as a starch, polyvinyl pyrrolidone, gum tragacanth or gelatin; a filler, such as microcrystalline cellulose or lactose; a disintegrating agent, such as crospovidone, sodium starch glycolate, corn starch, and the like; a lubricant, such as magnesium stearate, stearic acid, glyceryl behenate; a glidant, such as colloidal silicon dioxide and tale; a sweetening agent, such as sucrose or saccharin, aspartame, acesulfame-K; and / or flavoring agent, such as peppermint, methyl salicylate, or orange flavoring. When the dosage unit form is a capsule, it also can comprise a liquid carrier, such as a fatty oil. In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, are formulated or made comprising the active material in a mixture with or coating of a biodegradable synthetic polymers for example Poly(lactic-co-glycolic acid) (PLGA) and Polycaprolactone (PCL), durable synthetic alternatives for example Polyethylene oxide (PEO), or natural polymers such as alginate or chitosan, or combinations herein. The release characteristics of these formulations are governed by mechanisms including diffusion, erosion, or swelling. In alternative embodiments thereof, or comprising the active material in a mixtures thereof, in the delayed (or controlled) release (DR) formulation and / or the immediate release (IR) formulation are contained in or adsorbed to or onto a core, PATENT 7279.154670PCT wherein optionally the core comprises a plurality of sugar spheres, wherein optionally the sugar spheres comprise sugar spheres PF006 or SUGLETS®, and optionally the amount of sugar spheres in the formulation or in each dosage unit is about 30%(w / w), or is between about to 20% to 40%(w / w), or is between about 10% to 50%(w / w). In alternative embodiments, wherein optionally, the coating agent comprises a water soluble cellulose ether and / or OPADRY®, and optionally the water soluble cellulose ether comprises a hypromellose, optionally METHOCEL E5 PREMIUM LV™, wherein optionally the coating agent comprises both the hypromellose and the OPADRY®, and optionally the hypromellose and the OPADRY®are present in approximately equal amounts in the formulation or each dosage unit; and optionally the coating agent further comprises about 5% (w / w), or between about 2% (w / w) to 8% (w / w), or between about 1% (w / w) to 10% (w / w), of the formulation or each dosage unit. In alternative embodiments, the coating agent in the delayed (or controlled) release (DR) formulation further comprises a triethyl citrate, an ammonio methacrylate copolymer dispersion Type A (optionally EUDRAGIT®RL-30D™), an ammonio methacrylate copolymer dispersion Type B (optionally EUDRAGIT®RS- 30D™), or a mixture thereof, and optionally the coating agent comprises: the hypromellose at between about 0.5 %(w / w) and 5.0%(w / w); the OPADRY® at between about 0.5 %(w / w) and 5.0%(w / w); the ammonio methacrylate copolymer dispersion Type A at between about 0.1%(w / w) to 5.0%(w / w); the ammonio methacrylate copolymer dispersion Type B at between about 5%(w / w) to 20%(w / w) or 10%(w / w) to 15%(w / w); and the tri ethyl citrate at between about 0.5%(w / w) to 5%(w / w), of the formulation or each dosage unit, In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, are formulated or made comprising the active material in a mixture with excipients in a mixture with or coating of polymers for targeted release within the gastrointestinal tract, and optionally, within the mouth, the stomach, the small intestine, the colon, or combination herein. Optionally, these formulations comprise pH-sensitive, time- regulated polymers or other polymers that exploit the unique hydration, pH environment, enzymatic activity, and microbial flora of the mouth, stomach, small intestine, colon, or combinations therein for accurate drug targeting. Polymers, such PATENT 7279.154670PCT as EUDRAGIT®S 100™ are used for dissolution in the targeted intestinal pH zones, while EUDRAGIT®NE 30 D™ is incorporated for its tailored swelling and erosion behavior. In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, are formulated or made comprising the active material in a mixture with or coating of polymer and excipients to achieve an extensive range of release profiles, extending from sustained to pulsatile delivery. This is exemplified by the polymer combination of EUDRAGIT®RS PO™ with EUDRAGIT®RL PO™ in variable ratios, which allows for the fine-tuning of release kinetics. Formulations may also utilize pH-sensitive compounds like EUDRAGIT®L 30 D-55™, which are engineered to dissolve at specific pH thresholds, thus facilitating release in the specific regions of the gastrointestinal tract. In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, comprise (or are contained or packaged in) unit dosage formulations having a coating, for example, a coat comprising a sugar, shellac, sustained and or other enteric coating agents, or any pharmaceutically pure and / or nontoxic agents. In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, comprise (or are contained or packaged in) unit dosage formulations, wherein each different compound of the composition or product of manufacture is contained in a different layer of a pill, tablet or capsule, for example, as described in USPN 7,384,653, for example, having an outer base-soluble layer and an inner acid-soluble layer. In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, comprise (or are contained or packaged in) unit dosage formulations, wherein each different compound of the composition or product of manufacture is contained in a liquid or a gel of different viscosity, for example, described in U.S. Pat. App. Pub. No.20050214223. In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, comprise (or are contained or packaged in) unit dosage formulations having reduced abuse potential, for example, as described in U.S. Pat. App. Pub. No.20040228802, for example, comprising a bittering agent, a bright deterrent / indicator dye, or a fine insoluble particulate matter. PATENT 7279.154670PCT Carriers In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, comprise or are formulated with or as aqueous or non-aqueous solutions, suspensions, emulsions and solids. Examples of non-aqueous solvents suitable for use as disclosed herein include, but are not limited to, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyloleate. In alternative embodiments, aqueous carriers can comprise water, ethanol, alcoholic / aqueous solutions, glycerol, emulsions and / or suspensions, including saline and buffered media. Oral carriers can be elixirs, syrups, capsules, tablets and the like. In alternative embodiments, liquid carriers are used to manufacture or formulate drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, including carriers for preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compounds. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid carrier can comprise other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators. In alternative embodiments, liquid carriers used to manufacture or formulate compounds of this invention comprise water (partially containing additives as above, for example cellulose derivatives, preferably sodium carboxy- methyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, for example glycols) and their derivatives, and oils (for example fractionated coconut oil and arachis oil). For parenteral administration, the carrier can also include an oil ester such as ethvl oleate and isopropyl myristate. Sterile liquid carriers are useful in sterile liquid form comprising compounds for parenteral administration. The liquid carrier for pressurized compounds disclosed herein can be halogenated hydrocarbon or other pharmaceutically acceptable propellant. In alternative embodiments, solid carriers are used to manufacture or formulate drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, including solid carriers comprising substances such PATENT 7279.154670PCT as lactose, starch, glucose, methyl-cellulose, magnesium stearate, dicalcium phosphate, mannitol and the like. A solid carrier can further include one or more substances acting as flavor agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating material. In powders, the carrier can be a finely divided solid which is in a mixture with the finely divided active compound. In tablets, the active compound is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins. A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder (for example, povidone, gelatin, hydroxypropy|methyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropyl methylcellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach. In alternative embodiments, parenteral carriers are used to manufacture or formulate drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, including parenteral carriers suitable for use as disclosed herein include, but are not limited to, sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's and fixed oils. Intravenous carriers can comprise fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose and the like. Preservatives and other additives can also comprise, for example, antimicrobials, antioxidants, chelating agents, inert gases and the like. PATENT 7279.154670PCT In alternative embodiments, carriers used to manufacture or formulate drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, can be mixed as needed with disintegrants, diluents, granulating agents, lubricants, binders and the like using conventional techniques known in the art. The carriers can also be sterilized using methods that do not deleteriously react with the compounds, as is generally known in the art. The invention also provides articles of manufacture and kits containing (comprising) drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, including pharmaceutical compositions and formulations. By way of example only a kit or article of manufacture can include a container (such as a bottle) with a desired amount of a compound (or pharmaceutical composition of a compound) described herein. Such a kit or article of manufacture can further include instructions for using the compound (or pharmaceutical composition of a compound) described herein. The instructions can be attached to the container, or can be included in a package (such as a box or a plastic or foil bag) holding the container. The drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, can be delivered to the body or targeted to a specific tissue or organ (for example, a muscle or a brain) by any method or protocol, for example, including ex vivo "loading of cells" with drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, where the "loaded cell" is the administered subcutaneously, or intramuscularly, or intrathecally, intracerebrally, or epidurally into the central nervous system (CNS), for example, as described in U.S. Pat. App. Pub. No.20050048002. In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, are first lyophilized and then suspended in a hydrophobic medium, for example, comprising aliphatic, cyclic or aromatic molecules, for example, as described in U.S. Pat. App. Pub. No. 20080159984. In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, comprise or are formulated as pharmaceutically acceptable salts. Pharmaceutically acceptable salts can include suitable acid addition or base salts thereof. In alternative embodiments, PATENT 7279.154670PCT compounds can be formulated as described in Berge et al, J Pharm Sci, 66, 1- 19(1977). In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, are formulated as salts that are formed, for example, with strong inorganic acids such as mineral acids, for example hydrohalic acids such as hydrochloride, hydrobromide and hydroiodide, sulphuric acid, phosphoric acid sulphate, bisulphate, hemisulphate, thiocyanate, persulphate and sulphonic acids; with strong organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted (for example, by halogen), such as acetic acid; with saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or tetraphthalic; with hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid; with amino acids, for example aspartic or glutamic acid; with benzoic acid; or with organic sulfonic acids, such as (C-C4)-alkyl- or aryl- sulfonic acids which are unsubstituted or substituted (for example, by a halogen) such as methane-or p-toluene sulfonic acid. Compounds of Formula I also encompass salts which are not pharmaceutically acceptable, for example, a salt may still be valuable as an intermediate in a synthetic or analytical process or protocol. In alternative embodiments, compounds, active agents or drugs as provided herein, or as used to practice methods as provided herein, comprise any acceptable salt for example, acetate, trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate, malate, pantothenate, adipate, alginate, aspartate, benzoate, butyrate, digluconate, cyclopentanate, glucoheptanate, glycerophosphate, oxalate, heptanoate, hexanoate, fumarate, nicotinate, palmoate, pectinate, 3-phenylpropionate, picrate, pivalate, proprionate, tartrate, lactobionate, pivolate, camphorate, undecanoate and succinate, organic sulphonic acids such as methanesulphonate, ethanesulphonate, 2- hydroxyethane sulphonate, camphorsulphonate, 2-naphthalenesulphonate, benzenesulphonate, p-chlorobenzenesulphonate and p-toluenesulphonate; and inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, hemisulphate, thiocyanate, persulphate, phosphoric and sulphonic acids. Pharmaceutical compositions as disclosed herein can be prepared in accordance with methods well known and routinely practiced in the art. See, for example, Remington: PATENT 7279.154670PCT The Science and Practice of Pharmacy, Mack Publishing Co., 20th ed., 2000; and Sustained and Controlled Release Drug Delivery Systems, JR. Robinson, ed., Marcel Dekker, Inc., New York, 1978. In some embodiments, compounds, active agents or drugs as provided herein, or as used to practice methods as provided herein, are provided in the form of pharmaceutically acceptable salts comprising an amine that is basic in nature and can react with an inorganic or organic acid to form a pharmaceutically acceptable acid addition salt: for example, such salts comprise inorganic acids such as hydrochloric, hydrobromic, hydriodic, sulfuric and phosphoric acid, as well as organic acids such as para-toluenesulfonic, methanesulfonic, oxalic, parabromophenylsulfonic, carbonic, succinic, citric, benzoic and acetic acid, and related inorganic and organic acids; or optionally such pharmaceutically acceptable salts comprise sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, mono-hydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dio- ate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephathalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, beta-hydroxybutyrate, glycollate, maleate, tartrate, metha- nesulfonate, propanesulfonates, naphthalene-1-sulfonate, naphthalene-2- sulfonate, mandelate, hippurate, gluconate, lactobionate, methylene-bis-b- hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methane- sulphonates, ethanesulphonates, benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates and quinateslaurylsulphonate salts, and the like salts. In alternative embodiments, compounds, active agents or drugs as provided herein, or as used to practice methods as provided herein, comprise compositions manufactured under “Good manufacturing practice” (GMP), or “current good manufacturing practices” (cGMP), conditions. Pen injector systems In alternative embodiments, a pharmaceutical composition or product of manufacture comprises drugs or compounds provided herein, or a composition used to practice the described methods, contained in injectable formulations. Each compound PATENT 7279.154670PCT is contained in a pen injector system or a disposable pen injector system. The pen injector system includes a pen body, a drug reservoir, a dosing mechanism for selecting predetermined amounts of the drug for injection, a needle attachment, an actuation mechanism, and safety features, and is designed for single-use disposal. The pen needle, intended for single-use, includes a protective cap and is of a gauge and length suitable for subcutaneous injection. The needle attachment may feature a custom-configured needle with a unique locking mechanism that ensures compatibility with the specific pen needle designed for this system. Optionally, the system may incorporate an electronic dose counter to record the number and timing of doses administered or include pen needles on a blister card equipped with RFID or other methods for tracking the timing of pen needle usage. Additionally, the pen and pen needle blister card may feature Bluetooth or other connectivity capabilities for adherence tracking. In alternative embodiments, the pen injector systems are designed with pen needle lengths ranging from 3 mm to 6 mm, with preferred lengths of 3.2 mm to 4 mm, and specifically about 3.5 mm. The pen needles have a gauge between 32 and 34, preferably 32 gauge, to facilitate optimal injection into adipose tissue while preventing penetration into the underlying muscle tissue and minimizing cMAX spikes. Additionally, both the pen body and the pen needle are equipped with a custom base to ensure the system utilizes the correct pen needle length and gauge for each application. Methods of Administration In alternative embodiments, drugs or compounds as provided herein, or drugs or compounds used to practice methods as provided herein, are administered by any or a variety of means including orally, parenterally, by inhalation spray, nasally, topically, intrathecally, intrathecally, intracerebrally, epidurally, intracranially or rectally. Drugs or compounds are provided herein, or drugs or compounds used to practice methods are provided herein, are administered with pharmaceutically acceptable carriers, adjuvants and vehicles. In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, are administered intrathecally, intracerebrally or epidurally (into a intrathecal, intracerebral, epidural space), subcutaneously, intravenously, intramuscularly and / or intraarterially; for example, by injection routes but also PATENT 7279.154670PCT including a variety of infusion techniques. Intraarterial, intrathecal, intracranial, epidural, intra- venous and other injections can include administration through catheters or pumps, for example, an intrathecal pump, or an implantable medical device (which can be an intrathecal pump or catheter). In alternative embodiments, the drugs or compounds provided herein, or those used to practice the described methods, are administered via a pen injector system or a disposable pen injector system. The pen injector system comprises a pen body, a drug reservoir, a dosing mechanism for selecting predetermined amounts of the drug for injection, a needle attachment, an actuation mechanism, safety features, and is designed for disposable use. The pen needle is designed for single-use and includes a protective cap. The needle itself is of a gauge and length suitable for subcutaneous injection. The needle attachment may include a custom-configured needle with a unique locking mechanism that only allows the attachment of the specific pen needle designed for this system. The system may also include an electronic dose counter that records the number and timing of doses administered, or pen needles on a blister card with RFID or other methods to track the timing of pen needle usage. Additionally, the pen and pen needle blister card may have Bluetooth or other connectivity features for adherence tracking. In alternative embodiments, therapeutic combinations of drugs, pharmaceutical compositions, preparations and kits, can be administered by any known method or route, including by intranasal, subcutaneous, intramuscular, intravenous, topical or oral, or combinations thereof, routes. One embodiment comprises a product of manufacture comprising a pharmaceutical composition or a formulation, a blister package, a lidded blister or a blister card or packet, a clamshell, a tray or a shrink wrap, or a kit, comprising: therapeutic combinations of drugs, pharmaceutical compositions or preparations as provided herein for oral administration. In alternative embodiments, although all ingredients can be in one blister package, a lidded blister or a blister card or packet, a clamshell, a tray or a shrink wrap, or a kit, separate ingredients can be formulated, for example, for topical application, for oral or for topical application. Each ingredient can be either separately packaged, or can be formulated as one unit dose, for example, as one tube (for example, with gel, lotion etc.), ampoule, blister packette and the like. PATENT 7279.154670PCT In alternative embodiments related to prophylactic applications, Formula I, or its therapeutic combinations as described herein, may be administered at intervals preceding potential exposure to the causative agent or onset of the diseases or conditions mentioned herein. Suitable pre-exposure intervals for the drug include between about 2 weeks, 1 week, 3 days, or as soon as 1 day prior to the anticipated exposure event. Following the initial prophylactic dose, the therapeutic regimen can be continued for durations of between about 1 week, 2 weeks, 3 weeks, or even longer as necessitated by the patient’s condition or risk factors. Continuous therapy may also be considered based on individual patient needs, potential exposure risks, or as determined by a healthcare professional. The aforementioned intervals and durations are illustrative, and adjustments to the prophylactic therapy may be tailored to specific patient profiles and therapeutic outcomes. Dosages In alternative embodiments, drugs or compounds as provided herein, or a composition used to practice the methods as provided herein, are formulated and administered in a variety of different dosages and treatment regimens, depending on the disease or condition to be ameliorated, the condition of the individual to be treated, the goal of the treatment, and the like, as to be routinely determined by the clinician, see for example, the latest edition of Remington: The Science and Practice of Pharmacy, Mack Publishing Co., supra. Packaging and Drug Delivery Systems In alternative embodiments, provided are therapeutic combinations, preparations, formulations and / or kits, comprising combinations of ingredients, as described herein. In one aspect, each member of the combination of ingredients is manufactured in a separate package, kit or container; or all or a subset of the combinations of ingredients are manufactured in a separate package or container. In alternative aspects, the package, kit or container comprises a blister package, a clamshell, a tray, a shrink wrap and the like. In one aspect, the package, kit or container comprises a "blister package" (also called a blister pack, or bubble pack). In alternative embodiments, provided are therapeutic combinations, preparations, formulations and / or kits manufactured as "blister packages" or as a plurality of packettes, including as lidded blister packages, lidded blister or blister card or packets or packettes, or a shrink wrap. PATENT 7279.154670PCT In one aspect, the blister package is made up of two separate elements: a transparent or occlusive plastic cavity shaped to the product and its blister foil backing. These two elements are then sealed together into a blister strip of one or more blister with each blister an environmentally (for example moisture, pathogen, light) protected unit dose. One or more blister strips can be further joined with board material which allows the product to be package, handled, hung, displayed or shipped without damaging the blister seal and provided child resistant features. Exemplary types of "blister packages" include: Face seal blister packages, gang run blister packages, mock blister packages, interactive blister packages, slide blister packages. Blister packs, clamshells or trays are forms of packaging used for goods; thus, provided are blister packs, clamshells or trays comprising a composition (for example, the multi-ingredient combination of drugs as provided herein) combination of active ingredients) as provided herein. Blister packs, clamshells or trays can be designed to be non-reclosable, so consumers can tell if a package has already opened. They are used to package for sale goods where product tampering is a consideration, such as the pharmaceuticals as provided herein. In one aspect, a blister pack as provided herein comprises a molded PVC base, with raised areas (the "blisters") to contain the tablets, pills, etc. comprising the combinations as provided herein, covered by a foil laminate. Tablets, pills, etc. are removed from the pack either by peeling the foil back or by pushing the blister to force the tablet to break the foil. In one aspect, a specialized form of a blister pack is a strip pack. In one aspect, in the United Kingdom, blister packs adhere to British Standard 8404. In alternative embodiments, laminated aluminum foil blister packs are used, for example, for the preparation of drugs designed to dissolve immediately in the mouth of a patient. This exemplary process comprises having the drug combinations, therapeutic combinations and pharmaceutical dosage forms as provided herein prepared as an aqueous solution(s) which are dispensed (for example, by measured dose) into an aluminum (for example, alufoil) laminated tray portion of a blister pack. This tray is then freeze-dried to form tablets which take the shape of the blister pockets. The alufoil laminate of both the tray and lid fully protects any highly hygroscopic and / or sensitive individual doses. In one aspect, the pack incorporates a child-proof peel open security laminate. In one aspect, the system gives tablets an identification mark by embossing a design into the alufoil pocket that is taken up by PATENT 7279.154670PCT the tablets when they change from aqueous to solid state. In one aspect, individual push- through' blister packs / packettes are used, for example, using hard temper aluminum (for example, alufoil) lidding material. In one aspect, hermetically-sealed high barrier aluminum (for example, alufoil) laminates are used. In one aspect, any products of manufacture as provided herein, including kits or blister packs, use foil laminations and strip packs, stick packs, sachets and pouches, peelable and non- peelable laminations combining foil, paper, and film for high barrier packaging. In alternative embodiments, any products of manufacture as provided herein, including kits or blister packs, include memory aids to help remind patients when and how to take the drug. This safeguards the drug's efficacy by protecting each pill until it's taken; gives the product or kit portability, makes it easy to take a dose anytime or anywhere. In alternative embodiments, drug combinations, therapeutic combinations, pharmaceutical dosage forms, drug delivery devices and products of manufacture as provided herein, use child resistant and elderly friendly packaging, for example, packaging compliant to U.S. Government child resistant packaging regulation that requires minimal finger and grip strength. For example, in alternative embodiments foil-only containment of pills is used. In alternative embodiments, drug combinations, therapeutic combinations, pharmaceutical dosage forms, drug delivery devices and products of manufacture as provided herein, use tablets, capsules, pills or equivalents on a blister card or equivalent to track usage. By tracking usage, the blister card monitor can remind the patient and or the primary caregiver to take medication (or that medication has been taken) at the correct time, for example, in AM and / or PM; and can facilitate discussion with health care professionals to identify and overcome barriers to adherence. In alternative embodiments, patient usage is monitored by use of customized blister cards or equivalents using an Electronic Compliance Monitor (ECM) system (Intelligent Devices SEZC Inc. (IDD, Grand Cayman, Cay- man Islands), or equivalents. For example, in alternative embodiments, the blister cards or equivalents comprise an electronic component that detects, records, safeguards and / or transmits medication removal or pen needle from the blister cards or equivalents. For example, a sensor detects medication or pen needle removal from the blister cards or PATENT 7279.154670PCT equivalents, and this information can be transferred to a remote location for review by, for example, the drug provider and / or the primary care institution or individuals. The data transfer can be by hard contact downloading of data to a transmitting and / or storage device, and can be scanned and data downloaded remotely using a radio- frequency identification (RFID) chip, tag or device or equivalent, which can be operatively connected to a computer and / or a mobile phone or other device. Radio- frequency identification uses electromagnetic fields to automatically identify and track tags attached to objects, where the tags contain electronically stored information, which in this embodiment is transmitting whether and / or when medication is removed from each compartment of the blister cards or equivalents, or by Near-Field Communication (NFC) to a NFC-enabled mobile device or mobile phone. The NFC is a set of communication protocols that enable two electronic devices, one of which is usually a portable device such as a smartphone, to establish communication by bringing them within 4 cm (1.6 in) of each other. In alternative embodiments, as described in Figure 22a and Figure 22b, a Smart Blister Card System with Integrated Functional Components is provided. This example in Figure 22a and Figure 22b describes a smart blister card system to improve medication adherence monitoring through the integration of advanced components, including a battery, sensor array, processor, and antenna / receiver. The system incorporates features that optimize functionality, reliability, and operational workflow. The structural layout of the back of the smart blister card is depicted in Figure 22a, illustrating the arrangement of components 1–4, corresponding to specific areas as detailed in the Figure. The front of the smart blister card, which contains the individual pill or pen needle cavities for housing 1 to 70 doses or 7–21 doses or 14 doses of the drug, is depicted in Figure 22b, highlighting its conventional blister card design and dose arrangement. Back Face of Blister Card 1. Battery In alternative embodiments, The system utilizes a compact lithium film battery to power the smart blister card. This battery supports independent operation, eliminating the need for external power sources. Specifically, the battery supplies energy to the sensor array, processor, and integrated memory circuit, enabling semi- passive RFID functionality. Compared to passive RFID systems, this configuration PATENT 7279.154670PCT ensures an extended operational range and enhanced reliability. The battery is further characterized by a long shelf life of up to five years, making it suitable for extended storage and use. 2. Sensory Array In alternative embodiments, The sensor array is embedded within the smart blister card and detects the removal of individual pills or pen needles. It monitors physical changes within the structure of the smart blister card, such as: Pressure Detection: Identifies force application associated with the displacement of pills or pen needles. Electrical Continuity Disruption: Detects circuit breaks caused by foil ruptures during pill removal. Upon detecting a pill or pen needles removal event, the sensor array transmits a signal to the processor for event logging and timestamping. This ensures precise and reliable detection under typical usage conditions. 3. Processor (Including Integrated Memory Circuit and Backscatter Modulator) In alternative embodiments, The processor acts as the operational hub of the system, managing data collection, storage, and transmission. Key functionalities include: Memory Circuit: Stores adherence data, including timestamps of pill removal events. Internal Clock: Provides accurate date and time for event timestamping. Backscatter Modulator: Modulates the antenna’s impedance to encode and transmit adherence data to an external RFID-enabled interrogator. By integrating these functionalities into a single chip, the processor reduces the system’s physical footprint while optimizing power consumption and data processing efficiency. 4. Antenna / Receiver In alternative embodiments, The antenna / receiver is electrically coupled to the processor and facilitates two-way communication with an RFID-enabled interrogator device (e.g., smartphone or disposal facility scanner). The antenna performs the dual function of: Receiving RF Signals: Captures incoming signals from the RFID-enabled interrogator and relays them to the processor for activation and data retrieval. PATENT 7279.154670PCT Transmitting Encoded Signals: Reflects modulated RF signals (via the backscatter modulator) back to the RFID-enabled interrogator, thereby transmitting stored adherence data. The antenna is specifically designed to operate at NFC-compatible frequencies (e.g., 13.56 MHz), ensuring seamless compatibility with standard interrogator devices. Operational Workflow In alternative embodiments, The operation of the smart blister card system is as follows: 1. Event Detection The sensor array detects a pill or pen needles removal event and transmits a signal to the processor. 2. Data Recording The processor timestamps the event using the internal clock and stores the information in the memory circuit. 3. Interrogation and Transmission When activated by an RF signal from an RFID-enabled interrogator, the antenna / receiver initiates the retrieval of adherence data from the processor. The backscatter modulator then encodes the data and transmits it back to the RFID-enabled interrogator via the antenna. 4. Data Access: The RFID-enabled interrogator decodes the adherence data and uploads it to a cloud-based database, where it is accessible through the digital Best Supportive Care (digital BSC) via an application or web interface. Front Face of Blister Card In alternative embodiments, The smart blister card comprises a front face designed to accommodate multiple individual doses of a pharmaceutical drug. The front face comprises a plurality of pill or pen needles cavities, each configured to securely house a single dose. The pill or pen needles cavities are arranged in a uniform grid or sequential layout to facilitate ease of use and dose identification by the user. In alternative embodiments, the card is configured to contain between one (1) and seventy (70), or seven (7) and twenty-one (21), or fourteen (14) doses, depending on the prescribed regimen or treatment duration. Each cavity is sealed with a PATENT 7279.154670PCT transparent or semi-transparent plastic film to enable visual confirmation of the remaining doses. The sealing layer is adhered to the card’s backing material, which comprises tamper-evident properties to ensure product integrity prior to use. Material Construction In alternative embodiments, The front face of the blister card is constructed using standard pharmaceutical-grade materials commonly employed in blister packaging. These materials comprise: 1. Thermoformed Plastic (e.g., PVC or PET): Forms the pill or pen needle cavities to securely house the drug, and / or, 2. Foil Backing: Ensures the protection of individual doses from external contaminants, including moisture, light, and air. In alternative embodiments, The materials and construction conform to regulatory standards for drug packaging, ensuring stability and preservation of the drug product throughout its intended shelf life. Functionality of the Front Face In alternative embodiments, The pill cavities are designed to enable easy removal of the doses by the patient, and in alternative embodiments, comprise: 1. The pill or pen needle is dispensed by applying pressure to the back of the cavity, forcing the pill through the foil backing. 2. The design ensures that each dose is removed individually, preventing accidental removal of adjacent doses. In alternative embodiments, the front face remains consistent with conventional blister card designs, ensuring familiarity and ease of use for patients while incorporating the advanced sensor and data-logging features described in this disclosure. In alternative embodiments, multi-drug delivery systems as used in methods as provided herein can comprise use of a box to house or enclose drug delivery devices or packages, blister packages, clamshells or trays, as provided herein, where in this exemplary delivery system a week of pharmaceutical dosage form (for example, one, two or three or more tablets, pills, capsules, geltabs or equivalents) are stored on four rows, two rows for administration (for opening and self-administering by user, for example, patient) are for morning or breakfast, or AM administration, and two rows are for evening, dinnertime or PM administration; morning or breakfast, or AM PATENT 7279.154670PCT administration rows are clearly separated from the evening, dinnertime or PM administration rows, and each day, and the spare dose, are arranged in column form. In alternative embodiments the blister packages, clamshells or trays are physical linked to a storage box, wherein the blister packages, clamshells or trays slide into and out of the storage box, and in alternative embodiments if needed the PM set of rows can be folded over the AM set of rows for reinsertion of the blister packages, clamshells or trays into the storage box. In alternative embodiments, the storage box comprises sensors to detect medication or pen needle removal from each of the compartments (for example, which compartment is opened and when), and this information can be transferred to a remote location, for example, by Near-Field Communication (NFC) to a NFC-enabled mobile device or mobile phone, for review by for example, the drug provider and / or the primary care institution or individuals. In alternative embodiments: Drug-Digital Combination Product In one embodiment, a drug-digital combination product for the treatment of functional gastrointestinal disorders (FGIDs) is provided. The combination product comprises: • In alternative embodiments, a therapeutically effective amount of a drug selected from: o 5-HT3 receptor modulators, o GLP-1 agonists, and o Dopamine D2 receptor antagonists, wherein the drug comprises one, a combination of two, or a combination of all three of the listed drugs, with one selected from each category. • In alternative embodiments, Smart packaging is physically integrated with the drug, configured to: o Record and transmit time-stamped drug or pen needle dispensing events using RFID or NFC-enabled technology. • In alternative embodiments, a digital best supportive care (BSC) platform, comprising: o A symptom tracking module for collecting patient-reported outcomes (PROMs) tailored to FGID-specific symptoms, such as pain, stool consistency, and frequency. PATENT 7279.154670PCT o A behavioral guidance module delivering cognitive-behavioral therapy (CBT) interventions to address brain-gut interactions in FGIDs, including stress management and maladaptive belief correction. o A dietary recommendation module providing personalized dietary adjustments based on symptom tracking and FGID-specific dietary triggers. o An adherence support system that uses time-stamped drug or pen needle usage data to provide real-time feedback, automated reminders, and escalation protocols for nonadherence. In alternative embodiments: Monitoring by the Digital BSC Platform In another embodiment, the digital BSC platform is configured to: • Monitor: o Drug adherence using time-stamped data from the smart packaging. o FGID-specific patient-reported symptoms via the symptom tracking module. o Patient engagement with behavioral and dietary guidance modules. • Collect monitored data and transmit it to a centralized database for real-time analysis. In alternative embodiments: Monitored Data In another embodiment, the monitored data collected by the digital BSC platform includes: • Adherence metrics derived from time-stamped drug or pen needle dispensing data, analyzed to detect patterns of consistent or missed doses. • Symptom severity scores tracked over time using validated scales such as the IBS Severity Scoring System (IBS-SSS). • Behavioral engagement metrics reflecting patient interactions with the digital BSC platform. In alternative embodiments: Data Analysis and Recommendations In another embodiment, the combination product further comprises: • Analyzing monitored data using predefined algorithms to: o Detect patterns of adherence and nonadherence. o Identify trends in FGID-specific symptom improvement or exacerbation. PATENT 7279.154670PCT o Correlate behavioral engagement with changes in symptom severity. • Generating actionable recommendations to modify behavioral, dietary, or adherence interventions based on real-time analysis of the monitored data. In alternative embodiments: Adherence Support Systems In another embodiment, the adherence support system is configured to: • Provide automated reminders for missed doses via the digital BSC platform. • Trigger escalated interventions, including virtual counseling or moderated peer group interactions, when: o Adherence rates fall below 50%-99% or 80%, or o Symptom severity exceeds predefined thresholds. • Offer tailored feedback and support to patients based on analyzed adherence and symptom data. In alternative embodiments: Customized Interventions In another embodiment, the combination product customizes interventions for individual patients using: • Decision-tree or other algorithms that integrate adherence metrics, symptom severity data, and engagement trends to determine appropriate interventions. •Dynamic adjustments to behavioral guidance or dietary recommendationsinformed by real-time PROMs and adherence data. In alternative embodiments: Synergistic Therapeutic Effects In another embodiment, the integration of the drug, smart packaging, and digital BSC platform produces synergistic therapeutic effects for treating FGIDs, achieving: • A statistically significant reduction in symptom severity compared to the drug alone during the treatment period, as measured by validated scales such as the IBS Severity Scoring System (IBS-SSS), with statistical significance defined as p < 0.05. • A statistically significant improvement in adherence rates compared to the drug alone, measured as a percentage of prescribed doses taken and recorded via time-stamped data from the smart packaging, with statistical significance defined as p < 0.05. The synergistic effects result from: PATENT 7279.154670PCT • Enhanced drug adherence facilitated by real-time monitoring and automated reminders. • Tailored FGID-specific interventions, including CBT modules addressing maladaptive beliefs and stress. • Dietary adjustments informed by real-time symptom data, improving patient self-management and engagement. In alternative embodiments Labeling for the Combination Product In another embodiment, the drug label includes: • A description of the drug, smart packaging, and digital BSC platform. • Instructions for physicians and patients on integrating the digital BSC with drug therapy. • Randomized controlled trial data demonstrating: o The efficacy and safety of the drug. o The adherence and therapeutic benefits achieved through the integration of smart packaging and the digital BSC platform. In alternative embodiments, a comprehensive digital health system includes the following components: 1. Cloud-Based Computing Platform: o The backbone of the system, providing scalable and reliable infrastructure for data storage, processing, and application hosting. The platform supports seamless access and integration of various system components and allows for the future integration of new algorithms and models. 2. Digitally Enabled Therapeutic Kit: o RFID-packaging of drug products and pen needles, and optionally Bluetooth enabled pen systems. o RFID Readers and Bluetooth: Used for automated tracking of drug adherence, ensuring accurate and timely monitoring of medication usage. 3. eSource Data Components: o Electronic Health Records (EHRs): Digital versions of patients' paper charts, used for recording health data. PATENT 7279.154670PCT o ePRO (Electronic Patient-Reported Outcomes): Electronic methods for patients to report outcomes directly. o eCOA (Electronic Clinical Outcome Assessment): Tools for electronically capturing clinical outcomes data. o ECONSENT™: Digital process for obtaining and managing informed consent from trial participants. o Wearables: Electronic devices worn by participants to monitor and collect health data. o IoT (Internet of Things): Network of physical devices connected to the internet, collecting and sharing data. 4. Customized User Interfaces: o Interfaces designed for different stakeholders, including patients, caregivers, healthcare professionals, pharmacists, laboratory personnel, investigators, researchers, system administrators, and sponsors. 5. Functional Blocks: o Medication Management Block: Tools and systems for managing participants' medication schedules and adherence. oTelemedicine Block: Remote clinical services provided throughtelecommunications technology. o Patient Data Collection Blocks: Chatbot, digital health diary, and health questionnaires for collecting patient data. o Patient Behavior Change Blocks: Microlearning, coaching, and community platforms to support behavior change. o Patient Productivity Blocks: Patient self-scheduling and automatic reminders for managing appointments and trial-related activities. o Clinical Trial Blocks: RTSM for randomization and trial supply management, EDC for electronic data capture, and CTMS for clinical trial management. In alternative embodiments, the operation of the comprehensive digital health system comprises the following sequence: 1. Patient Enrollment and ECONSENT™: o Patients enroll in the trial or therapeutic program and complete the ECONSENT™ process via the patient portal. PATENT 7279.154670PCT 2. Data Collection: o Patients report outcomes through ePRO, eCOA, and digital health diaries. The digitally-enabled therapeutic kit, wearables, and IoT devices continuously collect health data. 3. Randomization and Trial Supply Management: o Patients are randomized into study groups, and trial supplies are managed and distributed using the RTSM system. 4. Data Integration and Processing: o Collected data is aggregated, processed, and analyzed to generate patient profiles and intervention regimens. 5. Personalized Intervention: o Healthcare providers review and approve personalized intervention regimens, which are then communicated to patients. 6. Monitoring and Dynamic Adjustment: o The system monitors patient adherence and dynamically adjusts interventions based on real-time data using machine learning algorithms and the intervention modification engine. 7. Regulatory Compliance: o The system ensures compliance with HIPAA and FDA regulations, maintaining data security and integrity throughout the process. In one embodiment, a comprehensive digital health system includes a digital Best Supportive Care (DBSC) Platform as illustrated in Figure 21 with the following descriptions: a) In alternative embodiments of the Application Layer: Purpose: • Acts as the primary interface for end-users, including patients, physicians, care navigators, and telehealth professionals. • Delivers a seamless user experience by presenting actionable insights, personalized recommendations, and adherence tools. Key Features: Patient Dashboard: o Displays adherence metrics, symptom tracking, and personalized recommendations. PATENT 7279.154670PCT o Provides educational resources via multimedia content (e.g., videos, infographics). Physician Dashboard: o Offers summary reports on patient progress and engagement. o Optional web portal access for physicians to review real-time data outside of the EHR. Telehealth Interface: o Secure platform for video consultations and messaging. o Shared visualization of adherence, symptoms, and engagement metrics for care teams. User Engagement Tools: o Push notifications for reminders (e.g., medication adherence, dietary goals). o AI chatbots for instant support or routing to human professionals. b) In alternative embodiments of the Analytics Layer: Purpose: • Processes raw data to generate actionable insights and predictions. •Powers personalized recommendations and risk-based escalation algorithms.Key Features: Risk Escalation Engine: o Predicts patient adherence and engagement risks. o Recommends personalized interventions (e.g., increased frequency of telehealth support). Outcome Prediction Models: o Uses historical and real-time data to forecast patient outcomes. o Identifies correlations between adherence, symptoms, and therapy efficacy. Reporting Tools: o Generates patient-level and aggregate-level reports for clinical trial sponsors and healthcare providers. Behavioral Analytics: o Tracks user behavior to refine patient-centric design and improve engagement. PATENT 7279.154670PCT c). In alternative embodiments of the Data Layer: Purpose: • Stores, retrieves, and organizes all data generated by the platform, including patient-reported outcomes, adherence data, and telehealth interactions. Key Features: Relational Databases: o Houses structured data such as adherence metrics, symptom logs, and user demographics. o Optimized for efficient querying and reporting. Unstructured Data Repositories: o Stores unstructured data like free-text symptom descriptions, patient narratives, or chat logs. Data Integration Pipelines: o Ensures seamless ingestion of data from external systems, such as EHRs and IoT devices (e.g., smart packaging). Data Encryption Module: o Protects sensitive patient information during storage and retrieval. d). In alternative embodiments of the Security Layer: Purpose: • Ensures that all platform interactions comply with data privacy regulations such as HIPAA and GDPR. • Manages role-based access for different stakeholders. Key Features: Role-Based Access Control (RBAC): o Assigns access permissions based on user roles (e.g., patient, physician, telehealth provider). o Prevents unauthorized access to sensitive data. Encryption and Tokenization: o Encrypts all data during transmission and storage. o Tokenizes personally identifiable information (PII) to maintain anonymity. Audit Logs: o Tracks all platform interactions for regulatory compliance. PATENT 7279.154670PCT o Logs access and modification activities for transparency. Security Monitoring: o Detects and mitigates potential breaches or unauthorized access in real- time. e) In alternative embodiments of the Integration Layer: Purpose: • Acts as the intermediary between the Digital BSC Platform and external systems, ensuring seamless interoperability. • Standardizes and synchronizes data flows. Key Features: API Gateway: o Facilitates secure, standardized communication with external systems. o Supports common protocols like REST and FHIR for EHR integration. Data Transformation Engine: o Converts raw data from external systems into standardized formats suitable for the platform (e.g., FHIR for EHR data). Middleware: oConnects with external systems such as:▪ EHR Systems (e.g., Epic, Cerner): Synchronizes patient records and clinical notes. ▪ CTMS / EDC Systems: Integrates trial-specific data such as eConsent and eCOAs. ▪ Smart Packaging / IoT: Tracks medication adherence via RFID / NFC-enabled devices. ▪ Pharmacy Systems: Monitors prescription data and refills. Batch Processing Module: o Handles asynchronous data transfers from EHR systems, which may operate in batch modes. Real-Time Sync Engine: o Supports real-time data updates for critical workflows, such as adherence alerts. f) In alternative embodiments of the External Systems Integrated into the Integration Layer PATENT 7279.154670PCT 1) Smart Packaging System o Specialty pharmacy system updates prescription and refill data to ensure continuity of care o Tracks real-time adherence through smart packaging o Syncs with the Integration Layer for analytics and reporting 2) Clinical Trial Management Systems (CTMS) / Electronic Data Capture (EDC) Systems: o Supplies trial-specific data, including patient-reported outcomes and study metrics. 3) Electronic Health Record (HER) Systems: o Provides patient medical history, prescriptions, and clinical notes. o Data flows asynchronously to the Integration Layer, where it is processed and sent to relevant layers. 4) In alternative embodiments of the Data Flow Description Input: o External systems send data (e.g., EHR medical records, smart packaging adherence logs) to the Integration Layer via the API Gateway. Processing: o The Integration Layer standardizes and transforms data before passing it to the Data Layer for storage. o The Analytics Layer processes stored data to generate actionable insights. Output: o Insights and reports are served to end-users through the Application Layer, either via the web portal or integrated EHR. g) In alternative embodiments, the Digital Supportive Care component of the digital BSC Platform delivers patient-centric features combined with real-time analytics, secure data management, and seamless integration across system layers. Each module is designed to enhance adherence, provide personalized interventions, and optimize patient outcomes. 1) ECONSENT™ (eConsent) for Data Use Module PATENT 7279.154670PCT Overview: In alternative embodiments, the eConsent Module ensures patients can make informed decisions about their data usage, enhancing transparency and compliance while offering user-friendly features. Patient-Facing Features: i) Dynamic Consent Interface: o Simplified forms for reviewing, accepting, or modifying consent preferences. o Multimedia educational content (e.g., videos, infographics) explaining data usage and privacy measures. ii) Interactive Learning: o Micro-lessons provide step-by-step explanations of how patient data supports FGID research and digital tool development. iii) Feedback Mechanism: o In-app surveys allow patients to rate their understanding and ease of use. iv) Integration with System Layers: • Application Layer: Embedded in the patient dashboard with push notifications for completing or updating consent forms. • Analytics Layer: o Outcome Prediction Engine (OPE): Identifies areas in consent materials causing confusion. o Intervention Modification Engine (IME): Personalizes content by adjusting language complexity. • Data Layer: Securely stores consent records and links them to patient profiles. • Security Layer: Implements end-to-end encryption and multi-factor authentication. • Integration Layer: Synchronizes data with external systems to ensure compliance with HIPAA, GDPR, and local regulations. 2) Symptom Tracking Module Overview: PATENT 7279.154670PCT In alternative embodiments, the Symptom Tracking Module enables patients to monitor and analyze symptom trends, correlating them with dietary habits, adherence, and other behaviors for improved management. In alternative embodiments, the Patient-Facing Features comprise: i). Customizable Tracking Options: Patients choose tracking frequency (e.g., daily, weekly) and input formats (text, voice, photo). ii). Real-Time Insights: Graphical trends and correlations enhance patient understanding. iii). Interactive Notifications: Adaptive reminders prompt timely symptom logging based on personal schedules. iv).Integration with System Layers: • Application Layer: Provides real-time visualizations accessible from the patient dashboard. • Analytics Layer: o OPE: Forecasts symptom progression using historical and patient-reported data. o IME: Adjusts tracking schedules for improved compliance. •Data Layer: Stores structured data for analysis and retrospectivereview. • Security Layer: Ensures anonymization and restricted access. • Integration Layer: Syncs data with external health systems for longitudinal analysis. 3). In alternative embodiments, the Dietary Guidance Module comprises: Overview: The Dietary Guidance Module delivers tailored meal plans, tracks dietary habits, and analyzes correlations between symptoms and diet to provide actionable insights. Patient-Facing Features: i). Personalized Meal Plans: AI-driven recommendations respect dietary preferences, cultural factors, and symptom data. ii). Multimedia Logging: Patients log meals using photos, voice notes, or text. iii). Trigger Analysis: AI identifies diet-symptom correlations and recommends adjustments. iv). In alternative embodiments, the Integration with System Layers comprise: PATENT 7279.154670PCT • Application Layer: Integrated dashboard visualizes adherence and provides feedback. • Analytics Layer: o OPE: Identifies patterns in dietary adherence and symptom outcomes. o IME: Dynamically adjusts meal suggestions based on habits. • Data Layer: Securely stores dietary logs for analysis. • Security Layer: Applies data masking to protect identities. • Integration Layer: Links to third-party dietary apps and wearable sensors for enhanced tracking. 4). Cognitive Support Module Overview: In alternative embodiments, the Cognitive Support Module uses CBT and other psychotherapeutic exercises to help patients improve mental health through self- guided learning and interactive feedback. In alternative embodiments, the Patient-Facing Features comprise: i). Self-Guided CBT and other psychotherapeutic Modules: Lessons on cognitive restructuring, emotional regulation, and mindfulness practices. ii). Interactive Feedback: Real-time guidance tracks progress toward mental health goals. iii). Personalized Recommendations: Tailored suggestions based on stress levels, engagement, and symptom history. iv). Integration with System Layers: • Application Layer: Displays progress tracking and bookmarks for preferred exercises. • Analytics Layer: o OPE: Forecasts mental health improvement based on engagement. o IME: Adjusts module complexity to patient behavior. • Data Layer: Stores engagement metrics and anonymized trends. • Security Layer: Restricts access to sensitive data with role-based controls. • Integration Layer: Connects with mental health apps for expanded content options. 5). In alternative embodiments, the Adherence Management Module comprises: PATENT 7279.154670PCT Overview: In alternative embodiments, the Adherence Management Module empowers patients to maintain consistency in medication schedules through real-time alerts and gamified goals. In alternative embodiments, the Patient-Facing Features comprise: i). Real-Time Adherence Metrics: Dashboards track missed doses, upcoming schedules, and streaks. ii). Smart Packaging Alerts: Notifications from RFID / NFC sensors indicate missed or incorrect doses. iii). Gamified Adherence Goals: Rewards motivate patients to meet milestones. iv). In alternative embodiments, the Integration with System Layers comprise: • Application Layer: Adherence scores and improvement tips displayed on dashboards. • Analytics Layer: o OPE: Predicts adherence risks based on historical behavior and environmental factors. o IME: Sends adaptive reminders tailored to patient preferences. •Data Layer: Logs adherence data securely in time-stamped records.• Security Layer: Encrypts medication data and ensures integrity with tamper-proof logs. • Integration Layer: Syncs with pharmacy and EHR systems for medication reconciliation. h). In alternative embodiments, the Supportive Telehealth component of the digital BSC Platform delivers comprehensive support through a Counseling Module, a Moderated Patient Groups Module, and the Physician Web Portal Module. These three modules integrate seamlessly with the platform’s multi-layered system, utilizing advanced analytics, real-time data synchronization, and robust security to provide personalized, data-driven care while ensuring regulatory compliance. 1). In alternative embodiments, the Counseling Module comprise: Overview: In alternative embodiments, the Virtual Counseling Module offers secure, FGID- specific psychological care, combining patient-facing features with tools for therapists to deliver data-driven, compliant, and personalized interventions. PATENT 7279.154670PCT Patient-Facing Features: i). In alternative embodiments, the Virtual Counseling Sessions: Secure video sessions addressing psychological aspects of FGID management comprises: ii). In alternative embodiments, the Pre-and Post-Session Tools comprise: o Pre-session questionnaires identify patient challenges. o Post-session action plans provide personalized guidance. iii). Real-Time Assistance: AI chatbots clarify action items and support follow- ups. iv). In alternative embodiments, the Educational Support comprise: Dynamic resources on cognitive behaviors, stress and other psychological management and the gut-brain axis improve patient understanding and adherence. v). In alternative embodiments, the Non-Patient Facing Features comprise: • Session Monitoring: o AI Analysis: Automatically analyzes session transcripts for adherence to therapeutic guidelines and flags safety concerns or therapeutic gaps. o Supervisor Reviews: Supervisors review flagged sessions, providing feedback to therapists. o Compliance Reports: Generate regulatory adherence reports (e.g., HIPAA, GDPR). • Therapist Training and Development: o Regular updates on FGID-specific strategies. o Role-playing exercises to enhance adherence to therapeutic protocols. o Feedback-driven refresher courses for flagged sessions. vi). In alternative embodiments, the Integration with System Layers comprise: • Application Layer: Therapist dashboards include session reviews, flagged issues, and training materials. • Analytics Layer: o OPE: Predicts therapy success based on patient engagement trends. o IME: Dynamically adjusts therapist recommendations. • Data Layer: Stores encrypted session transcripts and analysis outcomes. PATENT 7279.154670PCT • Security Layer: Implements role-based access controls and secure audit logs. • Integration Layer: Synchronizes therapist updates with patient-facing action plans in real-time. 2). In alternative embodiments, the Moderated Patient Groups Module comprise: Overview: In alternative embodiments, the Moderated Patient Groups Module enhances adherence and emotional support through structured group discussions moderated by FGID-trained healthcare professionals or FGID patients who are supervised by FGID- trained health care professionals. In alternative embodiments, the Patient-Facing Features comprises: i). In alternative embodiments, the Guided Participation comprises: Virtual group sessions foster engagement, adherence, and symptom management. ii). In alternative embodiments, the Interactive Discussions comprise: Topics include therapeutic strategies, emotional resilience, and symptom management. iii). In alternative embodiments, the Real-Time Feedback: Sentiment analysis and session ratings refine group dynamics and content. iv). In alternative embodiments, the Non-Patient Facing Features comprise: • Moderator Tools: o Discussion Analytics: AI monitors interactions to flag misinformation and assess moderation effectiveness. o Performance Feedback: Reports highlight moderator strengths and areas for improvement. o Training Resources: Modules on group dynamics, addressing misinformation, and promoting engagement. • Escalation Protocols: o Real-time alerts for patients requiring individual counseling. o Automated workflows escalate flagged concerns to FGID-trained healthcare professionals. v). In alternative embodiments, the Integration with System Layers comprise: • Application Layer: Moderator dashboards provide real-time sentiment analysis and session summaries. • Analytics Layer: PATENT 7279.154670PCT o OPE: Predicts engagement outcomes and trends. o IME: Dynamically adjusts session content based on participant data. • Data Layer: Logs attendance, interactions, and flagged issues for refinement. • Security Layer: Enforces anonymization and secure access to group data. • Integration Layer: Links group metrics with digital therapeutics for individualized insights. 3). In alternative embodiments Physician Web Portal Module comprise: Overview: In alternative embodiments, the Physician Web Portal supports streamlined care delivery, providing data visualization tools, clinical decision support, and workflow optimization features. i) Patient-Facing Features: • Progress Transparency: Patients can view physician recommendations and treatment updates. • Follow-Up Reminders: Automated notifications ensure adherence and engagement. ii). In alternative embodiments Non-Patient Facing Features comprise: • Data Visualization Tools comprise: o Smart Dashboards: Summarize adherence metrics, symptom trends, and engagement data. o Detailed Records: Provide time-stamped adherence logs and engagement reports. • Clinical Decision Support comprise: o AI-Driven Recommendations: Suggest dosing and treatment adjustments based on adherence and symptom severity. o Real-Time Alerts: Notify physicians of critical thresholds or urgent patient needs. • Workflow Optimization comprises: o Tools for scheduling follow-ups and syncing updates with therapeutic modules. PATENT 7279.154670PCT o Automated reminders enhance adherence and engagement. iii). In alternative embodiments Integration with System Layers comprise: • In alternative embodiments Application Layer comprises: Supports treatment plan updates and communication with patients. • In alternative embodiments Analytics Layer comprises: o OPE: Provides insights for therapy adjustments. o IME: Aligns patient-facing interventions with physician decisions. • In alternative embodiments Data Layer comprises: Securely stores treatment updates and AI-generated insights. • In alternative embodiments Security Layer comprises: Enforces multi-factor authentication and maintains audit logs. • I In alternative embodiments integration Layer comprises: Integrates with EHR systems for continuity of care. In alternative embodiments, provided are methods for data flow in a smart blister system as depicted in Figures 23a and 23b to inform the digital BSC platform to enhance adherence and add the Clinical Trial Effect to therapeutic drug treatment This embodiment describes the process by which adherence data is collected, transmitted, and accessed from the smart blister card system. The system enables secure and reliable data transmission from the smart blister card to the to the digital BSC platform, ensuring patient and physician access through a user-friendly application or web interface. In addition to RFID functionality, the smart blister card system integrates QR-code-enabled workflows for enhanced traceability, adherence monitoring, and data collection throughout the medication lifecycle. Figure 23A depicts the Primary Data Collection Method, with the patient recording their data independently using their personal smartphone as an RFID- enabled interrogator. a). In alternative embodiments, Event Detection and Storage comprises: The sensor array integrated into the smart blister card detects the removal of an individual pill or pen needle. Upon detection, the system timestamps the event and stores the corresponding adherence data in the memory circuit embedded within the card’s processor. Additionally, a QR code affixed to the smart blister card provides metadata linking the packaging to the adherence monitoring system, ensuring that each medication removal is traceable to the de-identified patient within the platform. PATENT 7279.154670PCT b). In alternative embodiments, Interrogation by a Smartphone comprises: When the patient’s smartphone is brought into proximity with the smart blister card, the following process occurs: i) The smartphone sends an RF signal that is captured by the antenna / receiver of the smart blister card. ii) This signal activates the processor, which retrieves the stored adherence data. iii) The backscatter modulator encodes this data and transmits it back to the smartphone via the antenna. Alternatively, patients can scan the QR code on the blister card using their smartphone to register the packaging on the adherence monitoring platform and upload metadata related to the packaging ID. This provides redundancy and ensures data accessibility even in the absence of RFID- enabled devices. c). In alternative embodiments, Automatic Cloud Upload comprises: The adherence data, once received by the smartphone, is automatically transmitted to the cloud-based database via the Integration Layer. This process is seamless and does not require additional input from the patient. QR code scanning facilitates real-time registration of the blister card and its associated metadata, further enhancing the automatic cloud upload process. d). In alternative embodiments, User Access comprises: Physicians and patients access the adherence data on the cloud-based database through the digital BSC platform via an application, web interface, or electronic health record system. This platform displays personalized adherence information, enabling monitoring and review of the patient’s medication regimen. QR code workflows allow patients to view adherence information directly linked to their registered blister card, ensuring a user-friendly experience. Figure 23B illustrates the Secondary Data Collection Method, where the smart blister card’s data is retrieved at the disposal facility. To ensure adherence data is reliably collected, even if the primary method is not utilized, a secondary data collection pathway is provided: a). In alternative embodiments, Electronic Medical Device Disposal comprises: The smart blister card is accompanied by a designated mailing box for disposal. Patients are instructed to mail their used blister cards to a designated disposal facility. PATENT 7279.154670PCT QR codes affixed to the return mailing box link the packaging to the digital BSC platform, initiating the disposal workflow and providing metadata for traceability. b). In alternative embodiments, Data Retrieval at the Facility comprises: Upon receipt of the blister card at the facility, a worker uses a dedicated RFID retrieval device to retrieve adherence data. The retrieval device functions identically to the smartphone interrogator, performing the following actions: o The wand sends an RF signal to the smart blister card, activating the processor. o The processor retrieves adherence data from its memory circuit and transmits it back via the antenna and backscatter modulator. Additionally, the QR code on the return mailing box is scanned to confirm the disposal workflow and link the adherence data to the disposal process. c). In alternative embodiments, Direct Cloud Upload comprises: The adherence data is securely transmitted from the RFID-retrieval device to the cloud-based database, ensuring no data is lost during the disposal process. QR code metadata from the mailing box is also uploaded to the cloud, providing complete traceability for each disposal event. d). In alternative embodiments, User Access comprises: As with the primary method, physicians and patients access the adherence data stored on the cloud-based database through the digital BSC platform via an application, web interface, or electronic health record system. QR code data integration ensures that adherence and disposal workflows are seamlessly captured and accessible to users. Data Security In alternative embodiments, adherence data is transmitted using secure, industry-standard protocols to ensure data integrity and privacy throughout all stages of the process, from the smart blister card to the cloud, and ultimately to the user- accessible platform. QR codes provide an additional layer of data security by encoding anonymized metadata, linking adherence events to individual packaging without revealing sensitive patient information. In alternative embodiments, provided are methods for data flow Escalation Pathways in the Smart Prescription Ecosystem. PATENT 7279.154670PCT Figure 24 depicts the Smart Prescription Ecosystem, a comprehensive workflow integrating data exchange, patient engagement, and algorithmic decision- making to optimize medication use. The system connects healthcare providers, specialty pharmacies, patients, and the disposal center through a unified data architecture, ensuring seamless coordination and addressing anomalies to enhance therapeutic outcomes. The process begins with the prescribing physician, who inputs the prescription either through their Electronic Health Record (EHR) system or, if unavailable, through an optional web interface, via a Physician Web Portal. This information flows into the Integration Layer, which serves as the primary interface for connecting with external data sources. Once the prescription reaches the specialty pharmacy, a QR code is generated and printed on both the smart blister card and the return package. This QR code serves as a unique patient identifier, enabling consistent tracking throughout the workflow. The specialty pharmacy ships the smart blister card system to the patient, completing the initial stage. Upon receiving the shipment, the patient accesses the QR code to report their drug use, either directly through a scanning interface or via embedded RFID / NFC technology in the smart blister card. After completing the medication cycle, the patient places the used smart blister cards into the return package, which is then shipped to the disposal center. At this point, the disposal center uses an RFID- retrieval device to obtain data from the returned blister cards, logs the usage data, and disposes of the materials responsibly. The QR code remains a crucial element, ensuring accurate data logging and patient identification at every step. The Integration Layer consolidates data from diverse sources, including health records, pharmacy systems, and storage facilities, and facilitates its progression through subsequent layers of the DBSC ecosystem. Information from these sources first flows into the Security Layer, where it is processed and safeguarded to maintain compliance with data privacy and protection standards. From there, it enters the Data Layer for organized and structured storage, enabling efficient retrieval. This data progresses to the Analytical Layer, where advanced algorithms generate actionable insights. Simultaneously, information provided directly by patients bypasses earlier layers and flows directly into the Application Layer, where it is integrated with insights from other layers to inform real-time decision-making. PATENT 7279.154670PCT The Application Layer utilizes this comprehensive data to support dynamic user interfaces, proactive interventions, and enhanced patient engagement, while multi-directional feedback loops ensure continuous system optimization and adaptability. Advanced algorithms, developed using expert input, statistical methods, or machine learning, analyze data alongside patient-designated preferences, such as their preferred communication method and contact frequency. This allows the system to detect anomalies, such as missed doses or improper disposal. When irregularities are identified, the system initiates an escalation pathway designed to address the issue proactively. Initially, gentle reminders are sent to the patient through their preferred communication channel. If the problem persists, the escalation progresses to direct intervention by a care navigator, who contacts the patient to understand the nature of the issue and provide support. If necessary, the matter is escalated further to the prescribing physician or other healthcare providers for clinical resolution. This tiered approach ensures that patient challenges are addressed promptly while maintaining a patient-centered focus. For physicians without access to an EHR or whose access to the Physician Web Portal is restricted, the system relies on data from the specialty pharmacy to maintain workflow continuity. These physicians can optionally use the Physician Web Portal to enter prescription information manually, offering a flexible solution that accommodates diverse clinical settings. By integrating multi-layered data flow, patient interaction, and adaptive algorithmic insights, the Smart Prescription Ecosystem creates a robust framework for medication management. The combination of QR code technology and escalation pathways ensures proactive interventions, accurate monitoring, and improved adherence, ultimately fostering better therapeutic outcomes. In any embodiment of methods as provided herein, the plasma concentration for the drug, or therapeutic combination, pharmaceutical dosage form is: (a) the trough level or trough concentration (Ctrough), or the lowest concentration reached by the drug, or therapeutic combination or pharmaceutical dosage form before a second or next dose is administered, or (b) determined from blood samples taken between about 0.5 hours to 24 hours, or 4 to 12 hours, or 1, 2, 3, 4, 5, 6, 7,8, 9,or 10 or more hours, after the last dose or administration of the drug, or therapeutic combination, pharmaceutical dosage form. PATENT 7279.154670PCT In alternative embodiments, "Individualized dosing" and "PK-guided dosing", "precision dosing" are interchangeable terms, mean administering each patient by a drug's PK properties in the patient. In alternative embodiments, terms of "plasma concentration", "plasma drug concentration", "serum concentration", "serum drug concentration", "plasma level", "level" in the context of drug concentration, are interchangeable, and mean drug concentration in humans or animals, and measured by and interpreted by those skilled in the art (see Loftsson T. Essential Pharmacokinetics - 1st Edition. Elsevier.2015.) In alternative embodiments, “target therapeutic plasma drug concentration”, or a similar term, is within the therapeutic plasma range, optionally about the mid-point of a therapeutic level range of plasma concentration. In alternative embodiments, therapeutic in the context of plasma concentration means effective or efficacious in treating a medical condition(s). In alternative embodiments, the term "GLP-1 receptor agonist" encompasses not only selective GLP-1 agonists, such as liraglutide or semaglutide, but may also refer to agents with broader activity, including dual GLP-1 / GIP receptor agonists, dual GLP-1 receptor agonists and GIP receptor antagonist, GLP-1 / Glucagon (GCG) receptor dual agonists, GLP-1 / GIP / GCG receptor tri-agonists, and amylin / GLP-1 dual agonists. In alternative embodiments, the term “receptor agonist” and “agonist” have the same meaning. For example, "GLP-1 receptor agonist" and “GLP-1 agonist” can be used interchangeably. Products of manufacture and Kits Provided are products of manufacture and kits for practicing methods as provided herein; and optionally, products of manufacture and kits can further comprise instructions for practicing methods as provided herein. Any of the above aspects and embodiments can be combined with any other aspect or embodiment as disclosed here in the Summary, Figures and / or Detailed Description sections. As used in this specification and the claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Unless specifically stated or obvious from context, as used herein, the term “or” is understood to be inclusive and covers both “or” and “and”. PATENT 7279.154670PCT Unless specifically stated or obvious from context, as used herein, the term “about” is understood as within a range of normal tolerance in the art, for example within 2 standard deviations of the mean. About (use of the term “about”) can be understood as within 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12% 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear from the context, all numerical values provided herein are modified by the term “about.” Unless specifically stated or obvious from context, as used herein, the terms “substantially all”, “substantially most of”, “substantially all of” or “majority of” encompass at least about 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 99.5%, or more of a referenced amount of a composition. The entirety of each patent, patent application, publication and document referenced herein hereby is incorporated by reference. Citation of the above patents, patent applications, publications and documents is not an admission that any of the foregoing is pertinent prior art, nor does it constitute any admission as to the contents or date of these publications or documents. Incorporation by reference of these documents, standing alone, should not be construed as an assertion or admission that any portion of the contents of any document is considered to be essential material for satisfying any national or regional statutory disclosure requirement for patent applications. Notwithstanding, the right is reserved for relying upon any of such documents, where appropriate, for providing material deemed essential to the claimed subject matter by an examining authority or court. Modifications may be made to the foregoing without departing from the basic aspects of the invention. Although the invention has been described in substantial detail with reference to one or more specific embodiments, those of ordinary skill in the art will recognize that changes may be made to the embodiments specifically disclosed in this application, and yet these modifications and improvements are within the scope and spirit of the invention. The invention illustratively described herein suitably may be practiced in the absence of any element(s) not specifically disclosed herein. Thus, for example, in each instance herein any of the terms "comprising", "consisting essentially of", and "consisting of" may be replaced with either of the other two terms. Thus, the terms and expressions which have been employed are used as terms of description and not of limitation, equivalents of the features shown and PATENT 7279.154670PCT described, or portions thereof, are not excluded, and it is recognized that various modifications are possible within the scope of the invention. Embodiments of the invention are set forth in the following claims. The invention will be further described with reference to the examples described herein; however, it is to be understood that the invention is not limited to such examples. EXAMPLES Example 1: Phase I, double-blind, randomized, placebo-controlled, single-ascending dose (SAD) study to assess the safety and tolerability of an 5-HT3 receptor modulator This example provides insight on a Phase I, double-blind, randomized, placebo-controlled, single-ascending dose (SAD) study to assess the safety and tolerability of an 5-HT3 receptor modulator that possesses molecular structure identical to (S)-7-(quinuclidine-3-yl)-8,9-dihydro-2H-azepino [5,4,3-cd]indazol- 6(7H)-one (Compound I). The study featured 48 subjects, randomly distributed between male and female participants, aged 18 to 59. Criteria for inclusion mandated that participants fall within specific bodyweight and BMI parameters and show no history of clinically significant illness or surgical interventions. Participants were advised against the consumption of products that might influence their safety or pharmacokinetic profile. These subjects were structured into six cohorts, each containing 8 subjects, with every cohort containing at least three members of each gender. Within each cohort, six subjects were randomly selected to receive the study drug, while the remaining two received a placebo. The regimen comprised administering to each study drug recipient in cohort 1 and cohort a dosage of 2 mg and a dosage of 0.5 mg, respectively. Throughout the duration of the study, subjects were closely monitored by clinical staff, and all adverse events were documented. The dosages for cohorts 3 through 6 were determined by a Safety Review Committee (SRC) based on the pharmacological response data gathered from the previous cohort. To ensure controlled conditions, dietary restrictions were enforced, with participants being instructed to abstain from food 10 hours prior to and 4 hours post-drug administration. After receiving the single dose, adverse events were recorded during an evaluatory period lasting 8 to 10 days post-administration. PATENT 7279.154670PCT Figure 1 illustrates the difference in documented gastrointestinal and dermatological adverse events experienced between subjects who received a placebo dose, a 0.5 mg dose Compound I, a 1 mg dose Compound I, a 2 mg dose Compound I, a 3 mg dose Compound I, and a 4.5 mg dose of Compound I in the SAD study. As depicted in Figure 1, no dermatological or gastrointestinal adverse events were associated with subjects who received either the placebo dose or the 0.5 mg dose. As the dose increased, gastrointestinal and dermatological adverse events became increasingly prevalent, reaching the point where every study drug recipient in the 4.5 mg dose cohort experienced either one or both categories of adverse events, leading the Safety Review Committee to halt the administration of a larger dose to the 6thand final cohort. The lack of adverse events associated with the 0.5 mg dose provides evidence towards its safety and tolerability. A refined criteria categorizes ‘flushing’ as a separate category of adverse events, due to its prevalence, instead of being included in the ’Dermatological’ category. Figure 17 (FIG.17) illustrates the instances of flushing, the most commonly reported AE in the study, experienced between subjects who received either a placebo dose, a 0.5 mg dose, a 1 mg dose, a 2 mg dose, a 3 mg dose, and a 4.5 mg dose of Compound I in the SAD study. Similar to what is depicted in Figure 1, the incidence of flushing was positively correlated with the dose escalation of Compound I, with no incidences of flushing reported in either the placebo or 0.5 mg dose cohorts. Further mirroring Figure 1, every subject in the 4.5 mg dose cohort displayed flushing. The correlation between the dose of Compound I and the incidence of flushing is further demonstrated in the 1 mg, 2 mg, and 3 mg dose cohorts, with the number of subjects per cohort reporting instances of flushing increasing in congruence with the amount of each dose. Across the six dose cohorts of the study, fifteen subjects displayed either gastrointestinal (GI) or dermatological (derm, excluding flushing) related-adverse events (AEs), none of which were categorized as severe. In both the placebo and 0.5 mg dose cohorts, no subjects displayed any GI or derm adverse events. The first GI or derm AEs of the study were displayed in the 1 mg dose cohort, with only GI AEs reported. Three subjects reported a total of four instances of GI AEs, with one subject reporting bowel irregularity, and the other two reporting PATENT 7279.154670PCT abdominal discomfort, along with gastrointestinal sounds and constipation, respectively. In the 2 mg dose cohort, three subjects reported a total of five instances of GI or derm-related AEs, marking the first dose a derm AE was reported in the study. One subject reported pruritus and eye irritation, one subject reported abdominal discomfort and diarrhea (the only reported diarrhea AE in the SAD study), and one subject reporting nausea. In the 3 mg cohort, three subjects reported a total of five instances of GI or derm AEs. Notably, this dose cohort was the first to include a subject reporting ‘Both’ categories of AEs. The subject reported pruritus, constipation, and gastrointestinal sounds, while another subject reported nausea, and the other subject reported pruritus. (including language about how this was a five subject cohort, so we adjusted its bar on the graph to normalize). In the final, 4.5 mg dose cohort, all six subjects reported a total of thirteen related GI or derm-related adverse events. Three of the subjects reporting have ‘Both’ GI and derm-related AEs. One subject reported having three derm AEs, and two subjects reported having one GI AE each. One subject in the 0.5 mg cohort displayed an adverse event of diarrhea that was not included in the analysis featured in this example. Only one other diarrhea AE was reported in the SAD drug treated cohorts, occurring in the 2 mg dose cohort. No diarrhea AEs were reported from subjects in the 1 mg, 3 mg, and 4.5 mg cohorts, suggesting that diarrhea AEs are not dose-dependent with Compound I in the SAD study. Example 2: Phase I, double-blind, randomized, placebo-controlled, multiple- ascending dose (MAD) study to assess the safety and tolerability of an 5-HT3 receptor modulator This example provides insight on a Phase I, double-blind, randomized, placebo-controlled, multiple-ascending dose (MAD) study to assess the safety and tolerability of an 5-HT3 receptor modulator that possesses molecular structure identical to (S)-7-(quinuclidine-3-yl)-8,9-dihydro-2H-azepino [5,4,3-cd]indazol- 6(7H)-one (Compound I). The study featured 24 subjects, aged 18 to 59. Criteria for inclusion mandated that participants fall within specific bodyweight and BMI parameters and show no history of clinically significant illness or surgical PATENT 7279.154670PCT interventions. Participants were advised against the consumption of products that might influence their safety or pharmacokinetic profile. The subjects were structured into three cohorts, each containing 8 subjects, with every cohort comprised of at least three members of each gender. In each cohort, six subjects were randomly selected to receive the study drug, while the remaining two received a placebo. The regimen comprised administering the drug or placebo twice daily from Days 1 through 6 and a singular dosage on the morning of Day 7. Throughout the duration of the study, subjects were closely monitored by clinical staff, and all adverse events were documented. The doses administered to each cohort were determined by the safety, tolerability, and PK data obtained in the SAD study described in Example 1. Due to an escalation in the rate of adverse events, no study drug was administered to the third and final cohort. To ensure controlled conditions, dietary restrictions were enforced, with participants being instructed to abstain from food 10 hours prior to and 4 hours post-drug administration. After receiving the single and final dose on Day 7, adverse events were recorded for each subject during an evaluatory period lasting 8 to 10 days post-administration. Sequential visual representations provided in Figure 2 and Figure 3 elucidate the adverse event profiles observed in the phase I study of Compound I in the placebo and 1.5 mg dose study cohorts. In the placebo cohort, an adverse event was displayed by at least one subject every day throughout the first ten days of the study, whereas in the 1.5 mg dose cohort, no subjects in the 1.5 mg cohort reported any adverse events by the sixth day of the study. This state of tolerability was sustained for the 1.5 mg dose cohort throughout the remainder of the study, including the fourteen-day observational follow-up. Quantitatively, the placebo cohort had twenty-one instances of separate patients reporting adverse events, compared to the 1.5 mg cohort (Figure 4), which had only fifteen, indicating an enhanced safety profile at this dosing level. The 2.75 mg dose cohort initially presented with a high incidence of adverse events, but as depicted in Figure 5, demonstrated a significant attenuation as the study progressed. By the sixth day of the study, there was a 33% decrease in the number of subjects reporting an adverse event, and by the twelfth day, only a singular subject in the cohort reported an adverse event. This collected data points suggest a dose- dependent acclimatization and tolerability, and provide compelling evidence for the safety of Compound I, particularly at a lower dose. PATENT 7279.154670PCT Example 3: Pharmacokinetics (PK) in Healthy Human Subjects Methods: This was a 2-part, single center, randomized, double-blind, placebo-controlled study to assess the PK of Compound I in healthy participants. Pharmacokinetic parameters were derived from plasma concentration-time profiles using non-compartmental methods. Dose proportionality assessments using the power model were conducted for Part A (Single Ascending Dose or SAD). For Part B (Multiple Ascending Dose or MAD), where two doses were considered, dose proportionality was assessed visually. Attainment of steady state was assessed by repeated measures analysis on the pre- dose (Ctrough of Days 1 through 7) and an analysis of accumulation of CMAX and AUC0-^ (from Days 1 and 7) of Compound I was also undertaken as described in the statistical analysis plan (SAP). Results and Conclusion: Following administration of Compound I in Parts A and B, the following conclusions can be made: Part A (SAD): • Median TMAX occurred between 1.0 and 1.5 hours post-dose for the dose range 0.5 mg to 4.5 mg. • CMAX, AUC0-24, AUC0-inf satisfied dose proportionality using the power model. • Mean T1 / 2el results ranged between 7.412 (1.0305) h to 11.296 (6.8996) h post-dose for the doses 2, 3 and 4.5 mg. • Mean (SD) Cl / F were 60.25 (14.142) L / h and 85.67 (23.856) L / h and Vz / F between 650.21 (195.228) L to 969.98 (424.963) L. Part B (MAD): • Concentration profiles and CMAX obtained on Day 1 for 1.5 mg BID (3.214 (0.4005) ng / mL) and 2.75 mg BID (5.730 (2.8620) ng / mL) were broadly in line with results of the SAD study part. • The geometric mean ratio estimate of the accumulation ratios at 1.5 mg BID and 2.75 mg BID for CMAX were 1.510 and 1.352 and for AUC were 1.766 and 1.740. These results were supportive of initial observations from plasma profiles. PATENT 7279.154670PCT • Mean t1 / 2el was highly consistent across all dose levels, varying from 12.094 to 13.971 h. • On increasing the Compound I dose, no increase in Clss / F (mean range 48.32 – 53.80 L / h) or Vz / F (mean range 828.4 – 1124.34 L) was observed, which further supported linear PK in the dose range examined. Assessment of gender revealed no discernible PK trends for either SAD or MAD study parts. The individual PK data points for the subjects treated with Compound I are tabulated in Tables 1-7. No Compound I was detected in samples from any subjects on placebo. “PK time point” means duration from first study drug administration (hours). “Conc.” means plasma concentration of Compound I (ng / ml). “BLQ” means below qualification limits. Compound I concentrations in plasma were analyzed by validated methodology of LC / MS. The upper limit of quantification (ULOQ) was 200 ng / mL, and the lower limit of quantification (LLOQ) was 0.2 ng / ml. Example 4: Human PK Modeling of Compound I for Dosing Regimens Background: In the SAD part of the study, Compound I was administered as single oral doses ranging from 0.5 mg, 1 mg, 2 mg 3 mg and 4.5 mg. PK analysis revealed a median half-life of 8.57 hours which may necessitate a change in dosage regimen from once daily dosing. Following BID dosing over 7 days, some accumulation was noted by Day 7 and a slightly longer mean t1 / 2 (12 to 13 h) was observed following attainment of steady state on Day 7 than following single administration (t1 / 2: 7.5-8.5 h). Pharmacokinetic Analysis: Methods and Procedures The pharmacokinetic results from Compound I SAD: Cohort 5 (4.5 mg single dose) were processed according to standard procedures for Nonparametric Superposition (PHOENIX™ WINNONLIN® v 8.3, Pharsight Corporation, USA). This highest dose had the more accurate terminal phase determination due to detectable levels to between 24 and 72 h post-dose (in contrast to lower doses where TLAST was 12 h). This approach allows the prediction of concentrations at steady state in blood or plasma based upon the concentration data from a single dose. The principle of PATENT 7279.154670PCT superposition does not assume any PK model and the predictions are based upon an accumulation ratio computed from the terminal slope (Lambdaz). The results can be used to help predict steady state plasma levels. The following pharmacokinetic data was used in Superposition: Cohort 5 (4.5 mg) SAD. By way of verification of results, PK data from the subjects administered 4.5 mg was used to predict the multiple doses for Cohorts 1 (1.5 mg BID) for 7 days. Once this was shown to be predictive, the concentrations were scaled to the equivalent of 1 mg (for TDS) and 3 mg (QD) dosing. Results: Steady State Verification Cohort 5 (SAD) and Cohort 1 (MAD), Day 7 Actual plasma profiles (one day at steady state) were plotted for each subject in Cohort 1 (1.5 mg once daily at 7 days) (figure 1). This was overlaid with the predicted average profile obtained using the procedure described above. The predicted steady state concentration for Cohort 1 was a reasonable approximation of the actual data as shown in Figure 6 and 7. Conclusion: The scaling of the 4.5 mg single dose to 3 mg and 1 mg was acceptable to allow approximation of PK profiles under different dosage regimes. Steady State Prediction 1 mg three times a day (TID) for 7 Days Figure 8 indicates the average predicted steady state profile. The notable features are: • Accumulation due to dosing at approximately every half-life (8 hourly). Hence steady state is reached by approximately 40 h post-dose (about 5 x t1 / 2). • The CMAXs (CMAX at steady state) is approximately 3 ng / mL. The single dose 1 mg mean (SD) CMAX: 1.949 (0.844) ng / mL. This equates to accumulation of approximately 1.5 which is in line with determinations following MAD studies. 3 mg Daily for 7 Days Figure 9 indicates the average predicted steady state profile. The notable features are: PATENT 7279.154670PCT • Steady state is reached by approximately 40 h post-dose (about 5 x t1 / 2) or the second dose. • The CMAXs is approximately 7 ng / mL. The single dose 3 mg mean (SD) CMAX: 4.802 (0.871) ng / mL. This equates to accumulation of approximately 1.5 which is in line with determinations following MAD studies. • Considerable fluctuation can be observed between peak and trough levels. Conclusion: Prediction of plasma profiles using nonparametric superposition has enabled estimation of likely CMAXs following 1 mg TID and 3 mg daily doses of Compound I. Example 5: Exemplary Method for Chronic Weight Management This example describes exemplary methods as adjunct in combination with a reduced calorie diet and increased physical activity for chronic weight management in adolescents and adults 12 years of age and older. Exemplary Adjunct Therapy for Chronic Weight Management Adjunct in combination with a reduced calorie diet and increased physical activity for chronic weight management in adolescents and adults 12 years of age and older. To accelerate attaining therapeutic dose of semaglutide and Compound I while incurring minimal GI discomfort. • Initiate dose of Compound I at 1 mg per day. • After one week increase the dose to 2 mg per day of Compound I, and initiate semaglutide at 0.25 mg once weekly for two weeks. • Continue the dose of Compound I at 2 mg per day and, in two-week intervals, increase the dose of semaglutide to 0.5 mg, 1.0 mg, or 1.7 mg until a dose of 2.4 mg once weekly is reached. • The maintenance dose of Compound I is 2 mg per day and the maintenance dose of semaglutide is 2.4 mg once weekly. Example 6: Exemplary Method for Chronic Weight Management Adjunct treatment in combination with a reduced calorie diet and increased physical activity for chronic weight management in adolescents and adults 12 years of age and older. These exemplary methods describe alternative methods to accelerate attaining a therapeutic dose level of semaglutide and Compound I. Exemplary Adjunct Therapy for Chronic Weight Management. PATENT 7279.154670PCT Adjunct treatment for chronic weight management in combination with a reduced calorie diet and increased physical activity in adolescents and adults 12 years of age and older. To accelerate attaining therapeutic doses of semaglutide with a short course treatment of Compound I while incurring minimal GI discomfort. • Initiate dose of Compound I at 1 mg per day, and optionally divided into three equal doses. • After 1 week increase the dose to 2 mg per day of Compound I and initiate semaglutide at 0.25 mg once weekly for two weeks. • Continue Compound I at 2 mg per day and in two-week intervals, increase the dose to 0.5 mg, 1.0 mg, or 1.7 mg until a dose of 2.4 mg once weekly is reached. • After 2 weeks at semaglutide at 2.4 mg once weekly, reduce the dose of Compound I to 1 mg per day. • After 2 weeks at semaglutide at 2.4 mg once weekly and Compound I at 1 mg per day, continue semaglutide at 2.4 mg once weekly and cease administration of Compound I. • The maintenance dose of semaglutide is 2.4 mg once weekly. Example 7: Exemplary Method for Treating Irritable Bowel Disorder with Diarrhea This example describes exemplary methods for treating Irritable Bowel Disorder with Diarrhea (IBS-D), including methods for determining the drug dosages and dose escalation for treating IBS-D. Exemplary Treatment of Irritable Bowell Disorder with Diarrhea Treatment of adolescents and adults 12 years of age and older with IBS-D. • Initiate dose of Compound I at 1 mg per day. • After 1 week increase the dose to 2 mg per day of Compound I and initiate semaglutide at 0.25 mg once weekly for four weeks. • Continue with Compound I at 2 mg per day and in four-week intervals, increase the dose of semaglutide to 0.5 mg, 1.0 mg, or 1.7 mg, until a dose of 2.4 mg once weekly is reached. • The maintenance dose of Compound I is 2 mg per day and the maintenance dose of semaglutide is 2.4 mg once weekly. Example 8: Exemplary Method for Treating Irritable Bowel Disorder with Diarrhea PATENT 7279.154670PCT This example describes exemplary methods for treating IBS-D, including methods for determining the drug dosages and dose escalation for treating IBS-D Exemplary Treatment of Irritable Bowell Disorder with Diarrhea. Treatment of adolescents and adults 12 years of age and older with IBS-D. • Start dose of Compound I at 1 mg per day, optionally divided into three equal doses. • After 1 week increase the dose of Compound I to 2 mg, optionally divided into three equal doses. • The maintenance dose of Compound I is 2 mg per day, optionally divided into three equal doses. Example 9: Exemplary Method for Treating Irritable Bowel Disorder with Diarrhea This example describes exemplary methods for treating IBS-D, including methods for determining the drug dosages and dose escalation for treating IBS-D. Exemplary Treatment of Irritable Bowell Disorder with Diarrhea. Treatment of adolescents and adults 12 years of age and older with IBS-D. • Start dose of Compound I at 0.33 mg three times per day and rifaximin at 550 mg three times per day. •After 1 week increase the dose of Compound I to 0.66 mg three timesper day and rifaximin at 550 mg three times per day. • The maintenance dose of Compound I is 0.66 mg three times per day. Patients who experience recurrence can be treated up to two times with rifaximin at 550 mg three times per day for 14 days. Example 10: Exemplary Method for Treating Carcinoid Syndrome-associated Diarrhea This example describes exemplary methods for treating Carcinoid Syndrome- associated Diarrhea in combination with somatostatin analog (SSA) therapy in adults inadequately controlled by SSA, including methods for deterring the drug dosages and dose escalation for treating Carcinoid Syndrome-associated Diarrhea. Exemplary Treatment of Carcinoid Syndrome-associated Diarrhea. Treatment of Carcinoid Syndrome-associated Diarrhea in combination with SAA therapy in adults inadequately controlled by SSA. • Start dose of Compound I at 0.33 mg three times per day and telotristat (or XERMELO™) at 250 mg three times per day. PATENT 7279.154670PCT • After 2 weeks increase the dose of Compound I to 0.66 mg three times per day and telotristat (or XERMELO™) at 250 mg three times per day. • The maintenance dose of Compound I is 0.66 mg three times per day and telotristat (or XERMELO™) is 250 mg three times per day. Example 11: Exemplary Method for Treating Mixed-type Irritable Bowel Syndrome This example describes exemplary methods for treating Mixed-type Irritable Bowel Syndrome (IBS-M), including methods for determining the drug dosages and dose escalation for treating IBS-M. Exemplary Treatment of Mixed-type Irritable Bowel Syndrome Treatment of adolescents and adults 12 years of age and older with IBS-M. • Initiate dose of Compound I at 1 mg per day. • After 1 week increase the dose to 2 mg per day of Compound I and initiate liraglutide at 0.6 mg once daily for 1week. • Continue with Compound I at 2 mg per day and in 1-week intervals, increase the dose of liraglutide to 1.2 mg, 1.8 mg, or 2.4 mg, until a dose of 3.0 mg once daily is reached. •The maintenance dose of Compound I is 2 mg per day and themaintenance dose of liraglutide is 3.0 mg once weekly. Example 12: Exemplary Method for Treating Irritable Bowel Syndrome with Constipation This example describes exemplary methods for treating IBS-C, including methods for determining the drug dosages and dose escalation for treating IBS-C Exemplary Treatment of Irritable Bowel Syndrome with Constipation Treatment of adolescents and adults 12 years of age and older with IBS-C. • Start dose of Compound I at 1 mg per day, optionally divided into three equal doses. • After 1 week increase the dose of Compound I to 2 mg, optionally divided into three equal doses. • The maintenance dose of Compound I is 2 mg per day, optionally divided into three equal doses. Example 13: Exemplary Method for Treating Irritable Bowel Syndrome with Diarrhea PATENT 7279.154670PCT This example describes exemplary methods for treating IBS-D, including methods for determining the drug dosages and dose escalation for treating IBS-D. Exemplary Treatment of Irritable Bowel Syndrome with Constipation. Treatment of adolescents and adults 12 years of age and older with IBS-. • Start dose of Compound I at 0.33 mg three times per day and rifaximin at 550 mg three times per day and liraglutide at 0.6 mg once daily. • After 1 week increase the dose of Compound I to 0.66 mg three times per day and rifaximin at 550 mg three times per day and liraglutide at 1.2 mg once daily. • After 2 weeks maintain the dose of Compound I at 0.66 mg three times per day, discontinue rifaximin and increase liraglutide at 1.8 mg once daily. • After 3 weeks maintain the dose of Compound I at 0.66 mg three times per day and increase liraglutide at 2.4 mg once daily. • After 4 weeks maintain the dose of Compound I at 0.66 mg three times per day and increase liraglutide at 3.0 mg once daily. • The maintenance dose of Compound I is 0.66 mg three times per day and Liraglutide is 3.0 mg once daily. Patients who experience recurrence can be treated up to two times with rifaximin at 550 mg three times per day for 14 days. Example 14: Exemplary Method for Treating Bile Acid Diarrhea This example describes exemplary methods for treating Bile Acid Diarrhea in combination with GLP-1 agonist therapy in adults, including methods for deterring the drug dosages and dose escalation for treating Bile Acid Diarrhea. Exemplary Bile Acid Diarrhea. Treatment of Bile Acid Diarrhea in combination with GLP-1 agonist therapy. • Start dose of Compound I at 0.25 mg three times per day and liraglutide (or SAXENDA™ or VICTOZA™) at 0.6 mg once daily. • After 1 week, increase the dose of Compound I to 0.5 mg three times per day and liraglutide (or SAXENDA™ or VICTOZA™) at 1.2 mg once daily. PATENT 7279.154670PCT • After 2 weeks, increase the dose of Compound I to 0.75 mg three times per day and liraglutide (or SAXENDA™ or VICTOZA™) at 1.8 mg once daily. • After 3 weeks, increase the dose of Compound I to 1.0 mg three times per day and liraglutide (or SAXENDA™ or VICTOZA™) at 2.4 mg once daily. • After 4 weeks, maintain dose of Compound I to 1.0 mg three times per day and increase liraglutide (or SAXENDA™ or VICTOZA™) at 3.0 mg once daily. • The maintenance dose of Compound I is 1.0 mg three times per day and liraglutide (or SAXENDA™ or VICTOZA™) at 3.0 mg once daily. Example 15: Personalized Intervention Regimen for Irritable Bowel Syndrome with Diarrhea (IBS-D) Using Compound I and Liraglutide A cohort of patients diagnosed with refractory IBS-D is enrolled in a clinical program utilizing the described digital health system to enhance adherence and add the Clinical Trial Effect or Digital Best Supportive Care to their therapeutic regimen using the drug product Compound I and liraglutide. The following steps illustrate how the system operates to create and manage personalized intervention regimens for these patients: 1. Pre-Assessment: o Each patient begins by interacting with the digital health system through a customized user interface on their smartphone or computer. The system's algorithms and models guide them through a pre-assessment questionnaire, collecting information about their medical history, current symptoms, lifestyle, and adherence challenges specific to IBS-D. Additionally, the system integrates data from connected health devices including the digitally-enabled therapeutic kit and, optionally, eToilets and wearable activity trackers, via Bluetooth. 2. Data Processing and Profile Generation: o The collected data is stored in the system's physical memories and processed to generate individual patient profiles and pre-assessment data. Each profile includes PATENT 7279.154670PCT detailed information about the patient's current health condition, frequency and severity of IBS-D episodes, dietary habits, stress levels, and medication adherence patterns. 3. Creating the Personalized Intervention Regimen: o Using the processed data, the system's algorithms generate patient condition data and create a personalized intervention regimen for each patient. This regimen includes: • Therapeutic Drug Treatment Components: Specific dosage and administration schedule of Compound I and liraglutide. • Adherence Modules: Reminders and alerts for taking Compound I and liraglutide, and maintaining digital health diaries. • Behavior Change Modules: Educational content on managing IBS-D symptoms, dietary adjustments, stress management, and mindfulness techniques. • Electronic Consent Module: An electronic consent form for participation in the clinical program and data sharing with healthcare providers. 4. Recommending Therapeutic Components: o The system recommends the personalized intervention regimen to each patient's healthcare provider through the user interface. The healthcare provider reviews the recommended regimen, makes any necessary adjustments, and approves the final personalized intervention regimen. The approved regimen is then communicated to the patient via the user interface on their smartphone or computer. 5. Monitoring and Data Collection: o Patients' interactions with the therapeutic components are continuously monitored by the system, including the eDiaries and ePROs. RFID readers track the timing and adherence to Compound I and liraglutide administration, enabling real- time updates from the connected health devices. The system collects data on patients' adherence to the regimen, eDiary entries, dietary intake, and other relevant health metrics. 6. Generating Intervention Modification Data: o Based on the collected interaction data, the system's algorithms process the information to generate intervention modification data. For example, if a patient consistently experiences IBS symptoms despite adherence to Compound I and PATENT 7279.154670PCT liraglutide, the system identifies this issue and suggests modifications, such as adjusting the dosage or incorporating additional dietary recommendations. 7. Dynamic Adjustment of the Regimen: o The system dynamically modifies each patient's personalized intervention regimen based on the intervention modification data. The updated regimen includes new strategies to improve adherence and symptom management, such as telehealth visits, motivational messages, personalized stress reduction techniques, and microlearning modules to encourage compliance. 8. Ensuring Compliance with Regulatory Standards: o Throughout the process, the system ensures that all patient data is encrypted and access-controlled, in compliance with HIPAA regulations for data privacy and security. The therapeutic drug treatment components in the regimen are designed to meet FDA requirements for safety and efficacy, with RFID packaging and Bluetooth connectivity to facilitate tracking and reporting. Outcome: Improved Adherence and Health Outcomes As a result of the personalized intervention regimens and continuous monitoring, patients experience improved adherence and add the Clinical Trial Effect to Compound I and liraglutide and related lifestyle recommendations. Their IBS-D symptoms are better managed, leading to enhanced overall health outcomes. The system's ability to dynamically adjust the regimen based on real-time data ensures that each patient receives tailored support to manage their refractory IBS-D effectively. Example 16: Clinical study 1: Controlled Efficacy Study in Low Anterior Resection Syndrome Low Anterior Resection Syndrome (LARS) is a serious and debilitating condition that affects patients following rectal cancer surgery. It is characterized by bowel urgency, increased frequency of bowel movements, incontinence, and social isolation, severely impacting patients' quality of life. Despite its prevalence, there are no FDA-approved therapies—either pharmacological or digital—available for LARS, making it a significant unmet medical need. PATENT 7279.154670PCT A randomized, double-blind, placebo-controlled study evaluating oral Compound I with DBSC platform in severe Low Anterior Resection Syndrome (LARS) patients is conducted. The study enrolls 240 patients meeting criteria including: documented low anterior resection completed ≥6 months prior, LARS score ≥30, stable symptoms for 3 months, and no planned reconstruction. Treatment comprises two arms: (1) Compound I with DBSC platform, and (2) placebo with DSBC platform. Drug administration follows systematic titration: 0.5mg BID Week 1, 1.0mg BID Week 2, 1.5mg BID Week 3, continuing 1.5mg BID Week 4 for response assessment. Maintenance phase continues at 1.5mg BID through Week 12. Smart packaging records dose administration timing and communicates with the DBSC platform. The exemplary DBSC platform provides: Adherence Monitoring: Smart packaging with real-time alerts for missed doses. Symptom Tracking: Patient-reported outcome measures (PROMs) with AI- driven insights. Dietary Guidance: Personalized meal plans and real-time analysis of dietary triggers. Cognitive Support: Self-guided digital cognitive behavioral therapy (CBT) modules targeting stress and anxiety management. Supportive Telehealth: • Virtual Cognitive Behavioral Therapy (CBT): Modules targeting belief reconstruction and stress management to reduce the psychological burden of LARS. • Moderated Patient Groups: Peer-support forums led by trained moderators to enhance engagement, adherence, and social connection Primary endpoint evaluates LARS score change at Week 12. Secondary endpoints include individual LARS components, anxiety / depression measures, social functioning, quality of life, and healthcare utilization. Primary Endpoint: • LARS Score Improvement at 12 Weeks: o STX-101 + DBSC: 40% reduction. PATENT 7279.154670PCT o Placebo + DBSC: 15% reduction (p < 0.01). Secondary Endpoints: 1. Symptom Progression: o Urgency Episodes: ▪ 45% reduction in the STX-101 + DBSC group. ▪ 20% reduction in the placebo group (p < 0.01). o Bowel Movement Frequency: ▪ 35% reduction in the STX-101 + DBSC group. ▪ 10% reduction in the placebo group (p < 0.01). Clinical study 2: Enhanced Digital Care Assessment A randomized, open-label study evaluating DBSC versus Real World Care (RWC) in LARS patients receiving Compound 1 is conducted. The study enrolls 200 patients meeting criteria including: documented low anterior resection completed ≥6 months prior, LARS score ≥30, stable symptoms for 3 months, and no planned reconstruction. Treatment comprises two arms: (1) Compound 1 with RWC, and (2) Compound 1 and DSBC. Both arms receive smart packaging and use a central disposal site to record drug usage and dispose of used blister cards. Drug administration follows systematic titration: 0.5mg BID Week 1, 1.0mg BID Week 2, 1.5mg BID Week 3, continuing 1.5mg BID Week 4 for response assessment. Maintenance phase continues at 1.5mg BID through Month 12. Study duration is 12 months with clinic visits at Week 0, Week 4, Month 6, and Month 12. Primary endpoint evaluates LARS score at Month 12. Secondary endpoints include adherence metrics of Proportion of Days Covered and Medication Possession Ratio. Primary Endpoint: • The Compound 1 + DBSC group achieved an average adherence rate of 90%, compared to 75% in the Compound 1 and RWC group (p < 0.01). Secondary Endpoints: • Patients in the Compound 1 + DBSC group demonstrated a 40% reduction in LARS Score, compared to a 25% reduction in the Compound 1+ RWC group (p < 0.05). PATENT 7279.154670PCT • Urgency Episodes: Decreased by 45% in the Compound 1+ DBSC group compared to a 25% in the reduction in the Compound 1+ RWC group (p < 0.05). • Bowel Movement Frequency: Reduced by 35% in the Compound 1+ DBSC group compared to 20% in the placebo group (p < 0.05). Example 17: A Refractory Ileal Resection-Associated Bile Acid Diarrhea (BAD) Study Background Refractory Ileal Resection-Associated Bile Acid Diarrhea (BAD) is a severe and debilitating condition affecting patients following ulcerative colitis surgery. It is characterized by frequent, uncontrollable bowel movements, urgency, and social isolation, significantly impacting patients' quality of life. Despite its prevalence, there are no FDA-approved therapies for Refractory Ileal Resection-Associated BAD, making it a critical unmet medical need. This study evaluates liraglutide, a GLP-1 receptor agonist, in combination with smart packaging and a Digital Best Supportive Care (DBSC) platform to address this condition. Study 1 Design Study Population: • 200 patients with: o Documented ileal resection. o Chronic bile acid diarrhea (≥4 episodes / day). o SeHCAT retention <10% or elevated serum C4 levels. o Prior bile acid sequestrant failure or intolerance. Treatment Arms: 1. Active Treatment: o Liraglutide: Weight-based dosing up to 1.8 mg / day. o Smart Packaging: Tracks injection timing and adherence. o DBSC: Comprehensive digital support platform. 2. Control Treatment: o Placebo Injection: Mimics liraglutide dosing. o Smart Packaging: Tracks placebo injection timing. o DBSC: Identical platform features. PATENT 7279.154670PCT Dosing Schedule: • Week 1: 0.6 mg daily. • Week 2: 1.2 mg daily. • Week 3 to Week 12: 1.8 mg daily. Smart Packaging: • Features: o Electronic timestamping for dose verification. o Alerts for missed injections. Digital Best Supportive Care (DBSC): • Features: o Adherence Monitoring: Real-time feedback and reminders. o Symptom Tracking: AI-driven insights from PROMs. o Dietary Guidance: Personalized meal plans. o Cognitive Support: Self-guided CBT modules. o Supportive Telehealth: ▪ Virtual CBT for belief reconstruction and stress management. ▪ Moderated patient groups for peer support. Endpoints Primary Endpoint: • Change in weekly bile acid diarrhea episodes from Week 4 to Week 12. Key Secondary Endpoints: 1. Abdominal pain scores. 2. Urgency episodes. 3. Quality of life measures (e.g., SF-36 or EQ-5D). 4. Healthcare utilization (e.g., ER visits or hospitalizations). 5. Work productivity (e.g., absenteeism and presenteeism). Prophetic Results Primary Endpoint: • Active Treatment (Liraglutide + DBSC): o 60% reduction in weekly bile acid diarrhea episodes. • Control (Placebo + DBSC): o 20% reduction in weekly bile acid diarrhea episodes (p < 0.001). Key Secondary Endpoints: PATENT 7279.154670PCT 1. Abdominal Pain: o 45% reduction in the active group vs.15% in the control group (p < 0.01). 2. Urgency Episodes: o 50% reduction in the active group vs.25% in the control group (p < 0.01). 3. Quality of Life: o Significant improvement (40% increase) in the active group compared to 20% in the control group (p < 0.01). 4. Healthcare Utilization: o 30% fewer ER visits in the active group compared to 10% in the control group (p < 0.05). 5. Work Productivity: o 50% reduction in absenteeism in the active group, compared to 20% in the control group. Study 2 Design: Real-World Study of Liraglutide + Smart Packaging +DBSC Objective To evaluate the real-world effectiveness of liraglutide + smart packaging + Digital Best Supportive Care (DBSC) versus liraglutide + smart packaging + real-world care in improving adherence, symptom management, and quality of life for patients with Refractory Ileal Resection-Associated BAD. Study Design Study Population: • 300 patients with: o Documented ileal resection. o Chronic bile acid diarrhea (≥4 episodes / day). o SeHCAT retention <10% or elevated serum C4 levels. Treatment Arms: 1. Liraglutide + Smart Packaging + DBSC: o Patients receive liraglutide therapy with adherence tracked by smart packaging and comprehensive DBSC. 2. Liraglutide + Smart Packaging + Real-World Care: PATENT 7279.154670PCT o Patients receive liraglutide therapy with adherence tracked by smart packaging and standard real-world care (e.g., occasional dietary advice and no structured telehealth or CBT). Primary Endpoint: • Change in adherence rates (Proportion of Days Covered, PDC) over 6 months. Key Secondary Endpoints: 1. Change in weekly bile acid diarrhea episodes. 2. Urgency episodes. 3. Quality of life measures. 4. Healthcare utilization. Prophetic Results Primary Endpoint: • DBSC Arm: 85% adherence (PDC). • Real-World Care Arm: 65% adherence (PDC) (p < 0.01). Key Secondary Endpoints: 1. Weekly Diarrhea Episodes: o DBSC Arm: 55% reduction. oReal-World Care Arm: 30% reduction (p < 0.01).2. Urgency Episodes: o DBSC Arm: 50% reduction. o Real-World Care Arm: 25% reduction (p < 0.01). 3. Quality of Life: o Significant improvements (40% in DBSC arm vs.20% in Real-World Care arm) (p < 0.01). 4. Healthcare Utilization: o 35% fewer ER visits in the DBSC arm, compared to 15% in the Real- World Care arm (p < 0.05). Conclusions Both studies demonstrate the effectiveness of combining liraglutide with smart packaging and DBSC in improving adherence, symptom control, and quality of life in patients with Refractory Ileal Resection-Associated BAD. The DBSC platform significantly enhances patient outcomes compared to real-world care, highlighting the potential of integrated drug-digital therapies for addressing unmet medical needs. PATENT 7279.154670PCT Example 18 Prophetic Examples Metopimazine + Smart Packaging + DBSC Controlled Efficacy Study in Severe Refractory Functional Dyspepsia Background Functional dyspepsia is a chronic, debilitating gastrointestinal disorder characterized by epigastric pain, bloating, and meal-related distress. Refractory functional dyspepsia is particularly challenging, with symptoms persisting despite multiple lines of treatment, severely impacting patients' quality of life and work productivity. Current pharmacological therapies often fail to achieve sustained symptom relief, and adherence challenges further reduce their real-world efficacy. Metopimazine, a dopamine D2 receptor antagonist, offers a novel pharmacological approach by targeting the altered gut-brain signaling underlying functional dyspepsia. It reduces visceral hypersensitivity and normalizes gastric motility, directly addressing the core mechanisms of the disease. However, achieving sustained benefits in real-world settings is hindered by poor adherence, lack of patient engagement, and inadequate integration of behavioral and cognitive support. The Digital Best Supportive Care (DBSC) platform is designed to overcome these barriers. It leverages a suite of digital tools, including: 1. Symptom Tracking: Real-time patient-reported data to monitor therapeutic response and adjust interventions. 2. Adherence Monitoring: Smart packaging with electronic dose tracking and reminders to ensure consistent therapy. 3. Dietary Guidance: AI-driven analysis of dietary triggers and personalized meal plans to reduce symptom severity. 4. Cognitive-Behavioral Support: Self-guided modules targeting maladaptive beliefs and stress-related exacerbations. By integrating smart packaging with DBSC, the system creates a synergistic feedback loop: • Pharmacological relief from Metopimazine reduces visceral hypersensitivity, enabling patients to engage more effectively with digital interventions. • DBSC amplifies adherence and engagement, sustaining Metopimazine’s pharmacodynamic benefits. PATENT 7279.154670PCT • Real-time data from smart packaging and patient-reported outcomes dynamically inform personalized therapeutic adjustments. This combination aligns with the predictive processing and active inference framework, addressing maladaptive priors and minimizing prediction errors within the gut-brain axis. The integrated system not only reshapes symptom perception but also extends the "clinical trial effect" into real-world care, providing sustainable and holistic symptom relief. Prophetic Study 1: Controlled Efficacy Study in Severe Refractory Functional Dyspepsia Study Design A randomized, double-blind, placebo-controlled study evaluated the efficacy of Metopimazine (10 mg TID) + Smart Packaging + DBSC versus placebo + Smart Packaging + DBSC in 300 patients with severe refractory functional dyspepsia. Population: • Patients meeting the following criteria: o Symptoms persisting for ≥12 months despite treatment with ≥2 proton pump inhibitors and ≥2 prokinetic agents. oDaily symptoms affecting >50% of meals.o Significant impact on work productivity and quality of life. o Regular healthcare utilization for dyspepsia-related symptoms. Treatment Arms: 1. Active Arm: Metopimazine (10 mg TID) + Smart Packaging + DBSC. 2. Control Arm: Placebo + Smart Packaging + DBSC. Duration: 12 weeks with a 2-week run-in period. Endpoints: • Primary Endpoint: Change in validated symptom severity score at Week 12. • Secondary Endpoints: 1. Adherence rates (Proportion of Days Covered, PDC). 2. Proportion of meals symptom-free. 3. Reduction in healthcare utilization (emergency visits, hospitalizations). 4. Improvement in quality of life (EQ-5D). 5. Work productivity. Prophetic Results PATENT 7279.154670PCT Primary Endpoint: • Active Arm: Mean reduction in symptom severity score: 65% from baseline (baseline: 8.0 ± 1.0; post-treatment: 2.8 ± 0.9). • Control Arm: Mean reduction in symptom severity score: 30% from baseline (baseline: 8.0 ± 1.1; post-treatment: 5.6 ± 1.1). • Statistical significance: p < 0.001. Secondary Endpoints: 1. Adherence Rates: o Active Arm: 90% adherence (PDC: 0.90 ± 0.05). o Control Arm: 78% adherence (PDC: 0.78 ± 0.07). o Statistical significance: p < 0.01. 2. Symptom-Free Meals: o Active Arm: 60% of meals symptom-free by Week 12. o Control Arm: 25% of meals symptom-free. o Statistical significance: p < 0.01. 3. Healthcare Utilization: o Active Arm: 35% reduction in emergency visits and hospitalizations. oControl Arm: 15% reduction.o Statistical significance: p < 0.05. 4. Quality of Life (EQ-5D): o Active Arm: 40% improvement. o Control Arm: 20% improvement. o Statistical significance: p < 0.01. 5. Work Productivity: o Active Arm: 50% improvement. o Control Arm: 20% improvement. o Statistical significance: p < 0.01. Prophetic Study 2: Enhanced Digital Care Study Study Design A randomized, controlled study evaluated the long-term effectiveness of Metopimazine + Smart Packaging + DBSC versus Metopimazine + Smart Packaging + Real-World Care in 200 patients over 12 months. Endpoints: PATENT 7279.154670PCT • Primary Endpoint: Proportion of patients maintaining therapeutic response at 12 months, defined by: o Symptom control. o Functional status improvement. o Reduction in healthcare utilization. • Secondary Endpoints: 1. Symptom severity score at 12 months. 2. Functional status improvement. 3. Reduction in healthcare utilization. 4. Patient engagement with DBSC features. Results Primary Endpoint: • DBSC Arm: 70% of patients maintained therapeutic response at 12 months. • Real-World Care Arm: 45% of patients maintained therapeutic response. • Statistical significance: p < 0.001. Secondary Endpoints: 1. Symptom Severity: oDBSC Arm: Mean reduction: 65% (baseline: 8.0 ± 1.0; 12-month: 2.8± 1.0). o Real-World Care Arm: Mean reduction: 40% (baseline: 8.0 ± 1.1; 12- month: 4.8 ± 1.1). o Statistical significance: p < 0.01. 2. Functional Status: o DBSC Arm: 50% improvement. o Real-World Care Arm: 25% improvement. o Statistical significance: p < 0.01. 3. Healthcare Utilization: o DBSC Arm: 30% reduction in ER visits and hospitalizations. o Real-World Care Arm: 15% reduction. o Statistical significance: p < 0.05. 4. Patient Engagement: o DBSC Arm: 85% engagement with DBSC features (e.g., CBT modules, moderated patient groups). PATENT 7279.154670PCT o Patient satisfaction: 90% rated DBSC as "very helpful." A number of embodiments of the invention have been described. Nevertheless, it can be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims.

Claims

PATENT 7279.154670PCT WHAT IS CLAIMED IS:

1. A pharmaceutical composition comprising: (a) A Glucagon-like Peptide-1 (GLP-1) receptor agonist, wherein optionally the GLP-1 agonist is liraglutide (or SAXENDATMor VICTOZATM), or a 5-HT3 receptor modulator of Formula I, or a dopamine D2 receptor antagonist wherein optionally the dopamine D2 receptor antagonist is selected from Bromopride (DIGESANTM), Domperidone (MOTILIUMTM), Metoclopramide (REGLANTMor MAXOLONTM), Metopimazine (VOGALENETM), and Metopimazine MesylateFormula I wherein: Q is a saturated, bicyclic, heterocyclic amine, wherein the saturated, bicyclic, heterocyclic amine comprises at least two atoms between the amide nitrogen of the compound of Formula I and any amine nitrogen of Q and wherein the saturated, bicyclic, heterocyclic amine is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from the group consisting of C1-C3 alkyl, halogen, —CN, —OR7, and —NR7R8; X is CH, CR3, or N; J is selected from the group consisting of a direct bond, C==O, and SO2; each R1is independently selected from the group consisting of H, halogen, —OR4, — NR4R5, —NR4C(O)R5, —NR4C(O)2R5, —NR5C(O)NR5R6, —S(O)qR5, —CN, —C(O)R5, —C(O)NR4R5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, aryl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C1-C3 alkyl, halogen, —CN, —OR7,PATENT 7279.154670PCT —NR7R8, and phenyl which is optionally substituted 1-3 times with halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, —CN, —OR7, or —NR7R8; R2is selected from the group consisting of H, halogen, —OR7, —NR4R5, — NR4C(O)R5, —NR4C(O)2R5, —NR5C(O)NR5R6, —S(O)qR5, —CN, —C(O)R5, —C(O)NR4R5, C1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, aryl, and heteroaryl, with the proviso that when J=SO2, R is not H, and wherein each of C1- C6 alkyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, aryl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C1-C3 alkyl, halogen, —CN, —OR7, —NR7R8, and phenyl which is optionally substituted 1-3 times with halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, —CN, —OR7, or —NR7R8; R3is selected from the group consisting of H, halogen, —OR4, —NR4R5, — NR4C(O)R5, —NR4C(O)2R5, —NR5C(O)NR5R6, —S(O)qR5, —CN, —C(O)R5, —C(O)NR4R5, C1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, aryl, and heteroaryl is optionally substituted with from 1 to 3 substituents independentlyselected at each occurrence thereof from C1-C3 alkyl, halogen, —CN, —OR7, —NR7R8, and phenyl which is optionally substituted 1-3 times with halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, —CN, —OR7, or —NR7R8; R4is H, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxyalkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, —C(O)R6, phenyl, or benzyl, wherein phenyl or benzyl is optionally substituted 1 to 3 times with halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy; R5is H, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxyalkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, phenyl, or benzyl, wherein phenyl or benzyl is optionally substituted 1 to 3 times with halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy; R6is C1-C4alkyl, C1-C4haloalkyl, or phenyl; R7and R8are each independently H, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxyalkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, —C(O)R6, phenyl, or benzyl, wherein phenyl or benzyl is optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy;PATENT 7279.154670PCT n is 1, 2, or 3; p is 0, 1, 2, or 3; and q is 0, 1, or 2; or an oxide thereof, a co-crystal thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or prodrug thereof; and optionally (b) at least one agent selected from the group consisting of: (1) a tryptophan hydroxylase inhibitor, wherein optionally the tryptophan hydroxylase inhibitor comprises telotristat ethyl (or XERMELOTM); (2) a 5-HT2 receptor antagonist, wherein optionally the 5-HT2 receptor antagonist comprises sarpogrelate or teguride; (3) a somatostatin analog, wherein optionally the somatostatin analog comprises octreotide (or SANDOSTATINTM), octreotide LAR (or SANDOSTATIN LARTM), lanreotide LAR (or SOMATULINETM Depot), or pasireotide LAR (or SIGNIFOR LARTM); (4) a somatostatin type 2 receptor agonist, wherein optionally the somatostatin type 2 receptor agonist comprises paltusotine; (5) smectite dioctadec (or SMECTATM), (6) rifaximin (or XIFAXANTM), (7) an opioid receptor agonist, wherein optionally the opioid receptor agonist comprises eluxadoline (or VIBERZITM), loperamide (or IMODIUMTM), asimadoline, or ORP-101; (8) a guanylate cyclase-C agonist, wherein optionally the guanylate cyclase-C agonist comprises linaclotide (or LINZESSTM), or plecanatide (or TRULANCETM), (9) a chloride channel activator, wherein optionally the chloride channel activator comprises lubiprostone (or AMITIZATM); (10) a 5-HT4 receptor agonist,PATENT 7279.154670PCT wherein optionally the 5-HT4 receptor agonist comprises tegaserod (or ZELNORMTM); (11) a Glucagon-Like Peptide-1(GLP-1) receptor agonist, wherein optionally the GLP-1 receptor agonist comprises dulaglutide (or TRULICITYTM), exenatide (or BYETTATM), exenatide extended-release (or BYDUREONTM), liraglutide (or SAXENDATMor VICTOZATM), lixisenatide (or ADLYXINTM), semaglutide injection (or OZEMPICTMor WEGOVYTM), semaglutide tablets (or RYBELSUSTM), albiglutide (or TANZEUMTMor EPERZANTM), CT-996 (Carmot Therapeutics), ECC5004 (AstraZeneca), GSBR-1290 (Structure Therapeutics), LY307161(Eli Lilly), danuglipron (or PF-06882961, Pfizer), LY2189265 (Eli Lilly), ecnoglutide (Sciwind Biosciences), HM11260C (Hanmi Pharm Co., Ltd), beinaglutide, JY09 (Beijing Dongfang Baitai Biotechnology Co., Ltd), HRS-7535 (Hercules CM NewCo), or orforglipron (or LY-3502970, Eli Lilly), (12) a dual GLP-1 / GIP agonist, wherein optionally the GLP-1 / GIP agonist comprises tirzepatide (or MOUNJAROTMor ZEPBOUNDTM), AZD9550, VK2735(Viking Therapeutics), SCO-094 (Scohia Pharma, Inc.), HRS-9531 (Hercules CM NewCo), CT-388 or CT- 868(Carmot Therapeutics), (13) a GLP-1 / Glucagon (Gcg) receptor co-agonist, wherein optionally the GLP-1 / Gcg receptor co-agonist comprises AZD-9550, (AstraZeneca), Mazdutide (or IBI362, orLY3305677, Eli Lilly), DD01 (D&D Pharmatech), RGT-075 (Regor Therapeutics Group), Efinopegdutide (or MK-6024) (Merck & Co., Inc.), Pemvidutide (Altimmune, Inc.), or Survodutide (or BI-456906, C.H. Boehringer Sohn AG & Co. KG) , (14) a GLP-1 / GIP / Gcg receptor tri-agonist, wherein optionally the GLP- 1 / GIP / Gcg receptor tri-agonist is LY3437943 (Eli Lilly), SAR425899, MEDI0382 (AstraZeneca), HM15275, Efocipegtrutide (or HM15211), Hanmi Pharm Co., Ltd), or SAR441255 (Sanofi), (15) a live biotherapeutic product (LBP) wherein optionally the LBP is CJRB-205 (or BLAUTIXTM); (16) an amylin analogue, wherein optionally the amylin analogue comprises pramlintide (or SYMLINTM), cagrilintide, or AZD-6234;PATENT 7279.154670PCT (17) an amylin / GLP-1 dual agonist, wherein optionally the amylin / GLP-1 dual agonist comprises NNC-0487- 0111; (18) a cannabinoid receptor (CBR1) antagonist, wherein optionally the cannabinoid receptor (CBR1) antagonist comprises INV-202; (19) a cannabinoid receptor (CBR2) agonist, wherein optionally the cannabinoid receptor (CBR2) agonist comprises olorinab; (20) a bitter taste receptor (TAS2R) agonist, wherein optionally the bitter taste receptor (TAS2R) agonist comprises ARD- 101; (21) anti-histamines, wherein optionally the anti-histamine comprises diphenhydramine, (22) A GIP receptor antagonist conjugated to GLP-1 analogues, wherein optionally the GIP receptor antagonist conjugated to GLP-1 analogues is AMG-133; (23) a GLP-1 / GLP-2 receptor co-agonist, Wherein optionally the GLP-1 / GLP-2 receptor co-agonist comprises dapiglutide (or ZP7570) (Zealand Pharma), (24) a GLP-1 agonist / GIP antagonist, wherein optionally the GLP-1 agonist / GIP antagonist comprises AMG-133 (Amgen Inc.), or (25) a dopamine D₂ antagonist, wherein optionally the dopamine D₂ antagonist comprises Bromopride (or DIGESANTM), Domperidone (or MOTILIUMTM), Metoclopramide (or REGLANTMor MAXOLONTM), Metopimazine (or VOGALENETM), or Metopimazine Mesylate; (26) an aminosalicylate, wherein optionally the aminosalicylate comprises Sulfasalazine (or AZULFIDINETM), or Mesalamine (also known as mesalazine) (or ASACOLTM, PENTASATM, LIALDATM, APRISOTM, DELZICOLTM, ROWASATM, or CANASATM);PATENT 7279.154670PCT (27) a corticosteroid, wherein optionally the corticosteroid comprises budesonide (or ENTOCORT ECTMor UCERISTM), Deflazacort (or EMFLAZATM), Prednisone (or DELTASONETMor RAYOSTM), or Methylprednisolone (or MEDROLTMor SOLU- MEDROLTM); (28) an immunomodulator, wherein optionally the immunomodulator comprises Azathioprine (or IMURANTM), Cyclosporine (or NEORALTM, SANDIMMUNETM, or GENGRAFTM), Methotrexate (or TREXALLTMor RHEUMATREXTM), Mercaptopurine (or PURINETHOLTMor PURIXANTM), or Tacrolimus (or PROGRAFTM, ASTAGRAF XLTM, or ENVARSUS XRTM); (29) a sphingosine-1-phosphate modulator, wherein optionally the sphingosine-1-phosphate modulator comprises Ozanimod (or ZEPOSIATM), Siponimod (MayzentTM), Ponesimod (PonvoryTM); or Fingolimod (GilenyaTM), (30) an integrin receptor antagonist, wherein optionally the integrin receptor antagonist comprises vedolizumab (or ENTYVIOTM);(31) a Janus Kinase Inhibitor, wherein optionally the Janus Kinase Inhibitor comprises Tofacitinib (or XELJANZTM); (32) an anti-tumor necrosis factor (anti-TNF) agent, wherein optionally the anti-TNF agent comprises Adalimumab (or HUMIRATM), Golimumab (or SIMPONITM), or Infliximab (or REMICADETM); (33) an interleukin-12 / 23 (IL-12 / 23) inhibitor, wherein optionally the IL-12 / 23 inhibitor comprises briakinumab or Ustekinumab (or STELARATM), (34) an interleukin-23 (IL-23) inhibitor, wherein optionally the IL-23 inhibitor comprises brazikumab, guselkumab (or TREMFYATM), mirikizumab, and Risankizumab (or SKYRIZITM); or (35) any combination of (1) to (34).PATENT 7279.154670PCT wherein each of the drugs or molecules in b) is either in the form of a salt, hydrate, solvate, oxide, or co-crystal when the drug or molecule is a non-peptide small molecule, or in a form selected from the group consisting of PEGylated, albumin- conjugated, liposome-encapsulated, microsphere-encapsulated, amide, ester, multimer, cyclic form, fusion protein, D-amino acid modified form, or analogue thereof when the drug or molecule is a peptide.

2. The pharmaceutical composition according to claim 1, wherein the 5-HT3 receptor modulator is the following formula:wherein: X is CH or N: each R' is independently selected from the group consisting of H, halogen, - OR4, or C1-C4 alkyl, wherein C1-C4 alkyl is optionally substituted with from 1 to 3 Substituents independently selected at each occurrence thereof from C1-C4 alkyl, halogen, —CN, -OR7, NR7R8, and phenyl which is optionally substituted 1-3 times with halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, -CN, -OR7, or – NR7R8; R2is H; R4is H, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxyalkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, -C(O)R6, phenyl, or benzyl, wherein phenyl or benzyl is optionally substituted 1 to 3 times with halogen, cyano, C1-C4alkyl, C1-C4haloalkyl, or C1-C4 alkoxy; R6is C1-C4 alkyl, C1-C4 haloalkyl, or phenyl:PATENT 7279.154670PCT R7and R8are each independently H, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxyalkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, -C(O)R6, phenyl, or benzyl, wherein phenyl or benzyl is optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4, alkoxy; n is 1 or 2; and p is 0, 1, 2, or 3: or an oxide thereof or a pharmaceutically acceptable salt thereof.

3. The pharmaceutical composition according to claim 1, wherein the 5-HT3 receptor modulator is (S)-7-(quinuclidine-3-yl)-8,9-dihydro-2H-azepino [5,4,3- cd]indazol-6(7H)-one or Compound I.

4. A method for treating, ameliorating, slowing the progress of, reducing the symptoms of, reducing adverse events associated with, or preventing a disease or condition, the method comprising administering an effective amount of a pharmaceutical composition to an individual in need thereof, wherein the pharmaceutical composition comprises: (a) A Glucagon-like Peptide-1 (GLP-1) receptor agonist, wherein optionally the GLP-1 agonist is liraglutide (or SAXENDATMor VICTOZATM), or a 5-HT3 receptor modulator of Formula I, or a dopamine D2 receptor antagonist wherein optionally the dopamine D2 receptor antagonist is selected from Bromopride (DIGESANTM), Domperidone (MOTILIUMTM), Metoclopramide (REGLANTMor MAXOLONTM), Metopimazine (VOGALENETM), and Metopimazine MesylatePATENT 7279.154670PCT wherein: Q is a saturated, bicyclic, heterocyclic amine, wherein the saturated, bicyclic, heterocyclic amine comprises at least two atoms between the amide nitrogen of the compound of Formula I and any amine nitrogen of Q and wherein the saturated, bicyclic, heterocyclic amine is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from the group consisting of C1-C3 alkyl, halogen, —CN, —OR7, and —NR7R8; X is CH, CR3, or N; J is selected from the group consisting of a direct bond, C==O, and SO2; each R1is independently selected from the group consisting of H, halogen, —OR4, — NR4R5, —NR4C(O)R5, —NR4C(O)2R5, —NR5C(O)NR5R6, —S(O)qR5, —CN, —C(O)R5, —C(O)NR4R5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, aryl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C1-C3 alkyl, halogen, —CN, —OR7, —NR7R8, and phenyl which is optionally substituted 1-3 times with halogen, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, —CN, —OR7, or —NR7R8;R2is selected from the group consisting of H, halogen, —OR7, —NR4R5, — NR4C(O)R5, —NR4C(O)2R5, —NR5C(O)NR5R6, —S(O)qR5, —CN, —C(O)R5, —C(O)NR4R5, C1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, aryl, and heteroaryl, with the proviso that when J=SO2, R is not H, and wherein each of C1- C6 alkyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, aryl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C1-C3 alkyl, halogen, —CN, —OR7, —NR7R8, and phenyl which is optionally substituted 1-3 times with halogen, C1-C4 alkyl, C1-C4haloalkyl, C1-C4alkoxy, —CN, —OR7, or —NR7R8; R3is selected from the group consisting of H, halogen, —OR4, —NR4R5, — NR4C(O)R5, —NR4C(O)2R5, —NR5C(O)NR5R6, —S(O)qR5, —CN, —C(O)R5, —C(O)NR4R5, C1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, aryl, and heteroaryl is optionally substituted with from 1 to 3 substituents independentlyPATENT 7279.154670PCT selected at each occurrence thereof from C1-C3 alkyl, halogen, —CN, —OR7, — NR7R8, and phenyl which is optionally substituted 1-3 times with halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, —CN, —OR7, or —NR7R8; R4is H, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxyalkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, —C(O)R6, phenyl, or benzyl, wherein phenyl or benzyl is optionally substituted 1 to 3 times with halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy; R5is H, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxyalkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, phenyl, or benzyl, wherein phenyl or benzyl is optionally substituted 1 to 3 times with halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy; R6is C1-C4 alkyl, C1-C4 haloalkyl, or phenyl; R7and R8are each independently H, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxyalkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, —C(O)R6, phenyl, or benzyl, wherein phenyl or benzyl is optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy; n is 1, 2, or 3; p is 0, 1, 2, or 3; and q is 0, 1, or 2; or an oxide thereof, a co-crystal thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or prodrug thereof; and optionally (b) at least one agent selected from the group consisting of: (1) a tryptophan hydroxylase inhibitor, wherein optionally the tryptophan hydroxylase inhibitor comprises telotristat ethyl (or XERMELOTM); (2) a 5-HT2 receptor antagonist, wherein optionally the 5-HT2 receptor antagonist comprises sarpogrelate or teguride; (3) a somatostatin analog, wherein optionally the somatostatin analog comprises octreotide (or SANDOSTATINTM), octreotide LAR (or SANDOSTATIN LARTM), lanreotide LAR (or SOMATULINETM Depot), or pasireotide LAR (or SIGNIFOR LARTM);PATENT 7279.154670PCT (4) a somatostatin type 2 receptor agonist, wherein optionally the somatostatin type 2 receptor agonist comprises paltusotine; (5) smectite dioctadec (or SMECTATM), (6) rifaximin (or XIFAXANTM), (7) an opioid receptor agonist, wherein optionally the opioid receptor agonist comprises eluxadoline (or VIBERZITM), loperamide (or IMODIUMTM), asimadoline, or ORP-101; (8) a guanylate cyclase-C agonist, wherein optionally the guanylate cyclase-C agonist comprises linaclotide (or LINZESSTM), or plecanatide (or TRULANCETM), (9) a chloride channel activator, wherein optionally the chloride channel activator comprises lubiprostone (or AMITIZATM); (10) a 5-HT4 receptor agonist, wherein optionally the 5-HT4 receptor agonist comprises tegaserod (or ZELNORMTM); (11) a Glucagon-Like Peptide-1(GLP-1) receptor agonist, wherein optionally the GLP-1 receptor agonist comprises dulaglutide (or TRULICITYTM), exenatide (or BYETTATM), exenatide extended-release (or BYDUREONTM), liraglutide (or SAXENDATMor VICTOZATM), lixisenatide (or ADLYXINTM), semaglutide injection (or OZEMPICTMor WEGOVYTM), semaglutide tablets (or RYBELSUSTM), albiglutide (or TANZEUMTMor EPERZANTM), CT-996 (Carmot Therapeutics), ECC5004 (AstraZeneca), GSBR-1290 (Structure Therapeutics), LY307161(Eli Lilly), danuglipron (or PF-06882961, Pfizer), LY2189265 (Eli Lilly), ecnoglutide (Sciwind Biosciences), HM11260C (Hanmi Pharm Co., Ltd), beinaglutide, JY09 (Beijing Dongfang Baitai Biotechnology Co., Ltd), HRS-7535 (Hercules CM NewCo), or orforglipron (or LY-3502970, Eli Lilly), (12) a dual GLP-1 / GIP agonist, wherein optionally the GLP-1 / GIP agonist comprises tirzepatide (or MOUNJAROTMor ZEPBOUNDTM), AZD9550, VK2735(Viking Therapeutics), SCO-094 (Scohia Pharma, Inc.), HRS-9531 (Hercules CM NewCo), CT-388 or CT- 868(Carmot Therapeutics),PATENT 7279.154670PCT (13) a GLP-1 / Glucagon (Gcg) receptor co-agonist, wherein optionally the GLP-1 / Gcg receptor co-agonist comprises AZD-9550, (AstraZeneca), Mazdutide (or IBI362, orLY3305677, Eli Lilly), DD01 (D&D Pharmatech), RGT-075 (Regor Therapeutics Group), Efinopegdutide (or MK-6024) (Merck & Co., Inc.), Pemvidutide (Altimmune, Inc.), or Survodutide (or BI-456906, C.H. Boehringer Sohn AG & Co. KG), (14) a GLP-1 / GIP / Gcg receptor tri-agonist, wherein optionally the GLP- 1 / GIP / Gcg receptor tri-agonist is LY3437943 (Eli Lilly), SAR425899, MEDI0382 (AstraZeneca), HM15275, Efocipegtrutide (or HM15211), Hanmi Pharm Co., Ltd), or SAR441255 (Sanofi), (15) a live biotherapeutic product (LBP) wherein optionally the LBP is CJRB-205 (or BLAUTIXTM); (16) an amylin analogue, wherein optionally the amylin analogue comprises pramlintide (or SYMLINTM), cagrilintide, or AZD-6234; (17) an amylin / GLP-1 dual agonist, wherein optionally the amylin / GLP-1 dual agonist comprises NNC-0487- 0111; (18) a cannabinoid receptor (CBR1) antagonist, wherein optionally the cannabinoid receptor (CBR1) antagonist comprises INV-202; (19) a cannabinoid receptor (CBR2) agonist, wherein optionally the cannabinoid receptor (CBR2) agonist comprises olorinab; (20) a bitter taste receptor (TAS2R) agonist, wherein optionally the bitter taste receptor (TAS2R) agonist comprises ARD- 101; (21) anti-histamines, wherein optionally the anti-histamine comprises diphenhydramine, (22) A GIP receptor antagonist conjugated to GLP-1 analogues, wherein optionally the GIP receptor antagonist conjugated to GLP-1 analogues is AMG-133; (23) a GLP-1 / GLP-2 receptor co-agonist,PATENT 7279.154670PCT Wherein optionally the GLP-1 / GLP-2 receptor co-agonist comprises dapiglutide (or ZP7570) (Zealand Pharma), (24) a GLP-1 agonist / GIP antagonist, wherein optionally the GLP-1 agonist / GIP antagonist comprises AMG-133 (Amgen Inc.), or (25) a dopamine D₂ antagonist, wherein optionally the dopamine D₂ antagonist comprises Bromopride (or DIGESANTM), Domperidone (or MOTILIUMTM), Metoclopramide (or REGLANTMor MAXOLONTM), Metopimazine (or VOGALENETM), or Metopimazine Mesylate; (26) an aminosalicylate, wherein optionally the aminosalicylate comprises Sulfasalazine (or AZULFIDINETM), or Mesalamine (also known as mesalazine) (or ASACOLTM, PENTASATM, LIALDATM, APRISOTM, DELZICOLTM, ROWASATM, or CANASATM); (27) a corticosteroid, wherein optionally the corticosteroid comprises budesonide (or ENTOCORTECTM or UCERISTM), Deflazacort (or EMFLAZATM), Prednisone (orDELTASONETMor RAYOSTM), or Methylprednisolone (or MEDROLTMor SOLU- MEDROLTM); (28) an immunomodulator, wherein optionally the immunomodulator comprises Azathioprine (or IMURANTM), Cyclosporine (or NEORALTM, SANDIMMUNETM, or GENGRAFTM), Methotrexate (or TREXALLTMor RHEUMATREXTM), Mercaptopurine (or PURINETHOLTMor PURIXANTM), or Tacrolimus (or PROGRAFTM, ASTAGRAF XLTM, or ENVARSUS XRTM); (29) a sphingosine-1-phosphate modulator, wherein optionally the sphingosine-1-phosphate modulator comprises Ozanimod (or ZEPOSIATM), Siponimod (MayzentTM), Ponesimod (PonvoryTM); or Fingolimod (GilenyaTM), (30) an integrin receptor antagonist, wherein optionally the integrin receptor antagonist comprises vedolizumab (or ENTYVIOTM);PATENT 7279.154670PCT (31) a Janus Kinase Inhibitor, wherein optionally the Janus Kinase Inhibitor comprises Tofacitinib (or XELJANZTM); (32) an anti-tumor necrosis factor (anti-TNF) agent, wherein optionally the anti-TNF agent comprises Adalimumab (or HUMIRATM), Golimumab (or SIMPONITM), or Infliximab (or REMICADETM); (33) an interleukin-12 / 23 (IL-12 / 23) inhibitor, wherein optionally the IL-12 / 23 inhibitor comprises briakinumab or Ustekinumab (or STELARATM), (34) an interleukin-23 (IL-23) inhibitor, wherein optionally the IL-23 inhibitor comprises brazikumab, guselkumab (or TREMFYATM), mirikizumab, and Risankizumab (or SKYRIZITM); or (35) any combination of (1) to (34). wherein each of the drugs or molecules in b) is either in the form of a salt, hydrate, solvate, oxide, or co-crystal when the drug or molecule is a non-peptide small molecule, or in a form selected from the group consisting of PEGylated, albumin- conjugated, liposome-encapsulated, microsphere-encapsulated, amide, ester, multimer, cyclic form, fusion protein, D-amino acid modified form, or analogue thereof when the drug or molecule is a peptide, to a subject in need thereof, wherein the disease or condition is selected from the group consisting of: abdominal migraine, aerophagia, alcohol dependency, altered central nervous system (CNS) processing, altered gut microbiota, altered mucosal and immune function, anxiety, Bechet’s disease, bile acid diarrhea, bile acid malabsorption, biliary pain,PATENT 7279.154670PCT binge-eating disorder, bronchial asthma, cannabinoid hyperemesis syndrome (CHS), carbohydrate malabsorption, carcinoid syndrome-associated conditions including diarrhea, fibrosis, and itch, cardiovascular disorders mediated by serotonin, centrally-mediated abdominal pain syndrome (CAPS), chemotherapy-induced nausea and vomiting (CINV), chronic nausea vomiting syndrome (CNVS), Crohn’s disease, cyclic vomiting syndrome (CVS), depression, diarrhea associated with various causes including bacterial infections, bacterial overgrowth, bile acid malabsorption, bariatric surgery including gastric sleeve surgery, gastric bypass surgery (Roux-en-Y gastric bypass) bariatric resection, celiac disease, ulcerative colitis, Crohn’s disease, chemotherapy, cholecystectomy, cholera, clostridium difficile infection, cytotoxic therapy, Dumping Syndrome, GLP-1 agonist therapy, GLP-1 / GIP dual agonist therapy, GLP-1 / GIP / Gcg tri-agonist therapy, ileoanal anastomosis, ileal resection, inflammatory bowel disease (IBD), metabolite therapy, pancreatic insufficiency, platinum therapy, rotavirus, vagotomy, and type 2 diabetes, drug withdrawal effects, dyssynergic defecation, epigastric pain syndrome (EPS), fecal incontinence, fibromyalgia syndrome, functional abdominal bloating, functional abdominal distension, functional abdominal pain disorders, functional abdominal pain – NOS, functional anorectal pain, functional biliary sphincter of Oddi disorder,PATENT 7279.154670PCT functional constipation, functional defecation disorders, functional diarrhea, functional dyspepsia, functional gallbladder disorder, functional nausea, functional neurological disorders, functional pancreatic sphincter of Oddi disorder, functional vomiting, gastrointestinal disorders, gastroesophageal reflux disease (GERD), hepatic encephalopathy, inadequate defecatory propulsion, infant colic, infant dyschezia, infant regurgitation, irritable bowel syndrome irritable bowel syndrome-diarrhea (IBS-D), irritable bowel syndrome-unclassified (IBS-U), irritable bowel syndrome-constipation (IBS-C), mixed-irritable bowel syndrome (IBS-M), levator ani syndrome (LAS), low anterior resection syndrome (LARS), Major LARS, motility disturbance, narcotic bowel syndrome (NBS), nausea and vomiting arising from obesity syndrome treatment, nausea and vomiting disorders, non-retentive fecal incontinence, opioid-induced constipation, opioid-induced gastrointestinal hyperalgesia, opioid-induced pruritis, pain and inflammation associated with osteoarthritis,PATENT 7279.154670PCT post-operative-induced nausea and vomiting (RINV), postprandial distress syndrome (PDS), post-surgical bowel dysfunctions, proctalgia fugax, pruritus and pruritus secondary to liver dysfunction, psoriasis, radiation skin injury, rosacea, rumination syndrome, serotonin-induced pruritus, short bowel syndrome, small intestine bacterial overgrowth (SIBO), diversion colitis, indeterminant colitis, microscopic colitis, ulcerative colitis, unspecified functional anorectal pain, unspecified functional bowel disorder, visceral hypersensitivity, Pancreatic Insufficiency, Diabetic Nephropathy, Obesity, Diabetes Mellitus, Gestational Diabetes Mellitus, Non-alcoholic Fatty Liver Disease, NASH, Hyperlipidemia, gastroparesis, -early dumping syndrome, late dumping syndrome, dumping syndrome post-gastrectomy, SIBO after gastric bypass, - nutritional deficiencies in gastric bypass,PATENT 7279.154670PCT belching disorders, supragastric belching, centrally mediated abdominal pain syndrome (caps), defecation disorders, functional chest pain of esophageal original, functional diarrhea of infancy, functional dysphagia, functional fecal incontinence, functional heartburn, globus, opioid-induced constipation, upper gastrointestinal disorders.

5. The method according to claim 4, wherein the 5-HT3 receptor modulator is Compound I, or comprises Compound I.

6. The method according to claim 4, wherein the pharmaceutical composition comprises Compound I, and wherein the pharmaceutical composition is administered for the treatment of irritable bowel syndrome, including diarrhea-predominant (IBS- D), constipation-predominant (IBS-C), mixed-type (IBS-M), and unclassified (IBS-U) subtypes.

7. The method according to claim 4, wherein the pharmaceutical composition comprises Compound I and a GLP-1 receptor agonist as defined herein, and wherein the pharmaceutical composition is administered for the treatment of irritable bowel syndrome, including diarrhea-predominant (IBS-D), constipation-predominant (IBS- C), mixed-type (IBS-M), and unclassified (IBS-U) subtypes.

8. The method according to claim 4, wherein the pharmaceutical composition comprises Compound I and a GLP-1 receptor agonist selected from the group consisting of liraglutide, semaglutide, tirzepatide , danuglipron, and HRS-7535, and wherein the pharmaceutical composition is administered for the treatment of irritablePATENT 7279.154670PCT bowel syndrome, including diarrhea-predominant (IBS-D), constipation-predominant (IBS-C), mixed-type (IBS-M), and unclassified (IBS-U) subtypes.

9. The method according to claim 4, wherein the pharmaceutical composition comprises Compound I and a GLP-1 receptor agonist as defined herein, and wherein the pharmaceutical composition is administered for the treatment of patients with inflammatory bowel disease (IBD) in clinical remission, referred to as "IBD-IBS," wherein the IBD is selected from ulcerative colitis and Crohn’s disease.

10. The method according to claim 4, wherein the pharmaceutical composition comprises Compound I and a GLP-1 receptor agonist selected from the group consisting of liraglutide, semaglutide, and tirzepatide, danuglipron, and HRS-7535, and wherein the pharmaceutical composition is administered for the treatment of patients with inflammatory bowel disease (IBD) in clinical remission, referred to as "IBD-IBS," wherein the IBD is selected from ulcerative colitis and Crohn’s disease. 11, The method according to claim 4, wherein the pharmaceutical composition comprises Compound I and a sphingosine-1-phosphate modulator selected from the group consisting of Ozanimod (or ZEPOSIATM), Siponimod (MayzentTM), Ponesimod (PonvoryTM); or Fingolimod (GilenyaTM),, and wherein the pharmaceutical composition is administered for the treatment of patients with inflammatory bowel disease (IBD) in clinical remission, referred to as "IBD-IBS," wherein the IBD is selected from ulcerative colitis and Crohn’s disease. 12.The method according to claim 4, wherein the pharmaceutical composition comprises Compound I, and wherein the pharmaceutical composition is administered for the treatment of low anterior resection syndrome (LARS).

13. The method according to claim 4, wherein the pharmaceutical composition comprises Compound I and a GLP-1 receptor agonist as defined herein, and wherein the pharmaceutical composition is administered for the treatment of low anterior resection syndrome (LARS).PATENT 7279.154670PCT 14.The method according to claim 4, wherein the pharmaceutical composition comprises Compound I and a GLP-1 receptor agonist selected from the group consisting of liraglutide, semaglutide, and tirzepatide, danuglipron, HRS-7535, and wherein the pharmaceutical composition is administered for the treatment of low anterior resection syndrome (LARS).

15. The method according to claim 4, wherein the pharmaceutical composition comprises a dopamine D2 antagonists, selected from the group consisting of Bromopride (DIGESANTM), Domperidone (MOTILIUMTM), Metoclopramide (REGLANTM or MAXOLONTM), Metopimazine (VOGALENETM), Metopimazine Mesylate, and wherein the pharmaceutical composition is administered for the treatment of Functional Dyspepsia.

16. A drug-digital combination product for the treatment of functional gastrointestinal disorders (FGIDs), comprising: (a) A therapeutically effective amount of a drug selected from: o 5-HT3 receptor modulators as defined herein, oGLP-1 agonists as defined herein, ando Dopamine D2 receptor antagonists herein, wherein the drug comprises one, a combination of two, or a combination of all three of the listed drugs, one from each category. (b) Smart packaging physically integrated with the drug, configured to: o Record and transmit time-stamped drug or pen needle dispensing events using RFID or NFC-enabled technology; and / or (c) A digital best supportive care (BSC) platform comprising: o A symptom tracking module collecting patient-reported outcomes (PROMs), with features tailored to FGID-specific symptoms such as pain, stool consistency, and frequency; o A behavioral guidance module delivering cognitive-behavioral therapy (CBT) interventions specifically designed to address brain-gut interactions in FGIDs, including stress management and maladaptive belief correction;PATENT 7279.154670PCT o A dietary recommendation module providing personalized dietary adjustments based on symptom tracking and FGID-specific dietary triggers; o An adherence support system using time-stamped drug or pen needle usage data to provide real-time feedback, automated reminders, and escalation protocols for nonadherence.

17. The drug-digital combination product according to Claim 16, wherein the digital BSC platform comprise: • (a) Monitors: o Drug adherence using time-stamped data from the smart packaging; o FGID-specific patient-reported symptoms via the symptom tracking module; o Patient engagement with behavioral and dietary guidance modules; and / or • (b) Collects monitored data and transmits it to a centralized database for real- time analysis.

18. The drug-digital combination product according to Claim 17, wherein the monitored data comprises: • Adherence metrics derived from time-stamped drug or pen needle dispensing data, analyzed to detect patterns of consistent or missed doses; • Symptom severity scores tracked over time using validated scales such as the IBS Severity Scoring System (IBS-SSS); and / or • Behavioral engagement metrics reflecting patient interactions with the digital BSC platform.

19. The drug-digital combination product according to Claim 17, further comprising: • (a) Analyzing monitored data using predefined algorithms to: o Detect patterns of adherence and nonadherence; o Identify trends in FGID-specific symptom improvement or exacerbation;PATENT 7279.154670PCT o Correlate behavioral engagement with changes in symptom severity; • (b) Generating actionable recommendations for modifying behavioral, dietary, or adherence interventions based on real-time analysis of the monitored data.

20. The drug-digital combination product of Claim 19, wherein the adherence support system comprises: • (a) Providing automated reminders for missed doses, delivered via the digital BSC platform; • (b) Triggering escalated interventions, including virtual counseling or moderated peer group interactions, if: o Adherence rates fall below 50-99% or 80%, or o Symptom severity exceeds predefined thresholds; and • (c) Offering tailored feedback and support to patients based on analyzed adherence and symptom data.

21. The combination product of according to Claim 20, wherein interventions are customized to individual patients using: •Decision-tree or other algorithms that integrate adherence metrics, symptomseverity data, and engagement trends to determine appropriate interventions; and / or • Dynamic adjustments to behavioral guidance or dietary recommendations informed by real-time PROMs and adherence data.

22. A method of treating functional gastrointestinal disorders (FGIDs) in a patient using the drug-digital combination product according to Claim 16, wherein the integration of the drug, smart packaging, and digital BSC platform produces synergistic therapeutic effects, comprising: • (a) A statistically significant reduction in symptom severity compared to the drug alone during the treatment period, as measured by validated scales such as the IBS Severity Scoring System (IBS-SSS) or other clinician-approved tools, with statistical significance defined as p < 0.05; and • (b) A statistically significant improvement in adherence rates compared to the drug alone during the treatment period, with adherence rates measured as aPATENT 7279.154670PCT percentage of prescribed doses taken and recorded via time-stamped data from the smart packaging, with statistical significance defined as p < 0.

05. wherein:

1. Mechanism of Synergy comprise: o The synergistic therapeutic effects result from combining: ▪ Enhanced drug adherence facilitated by real-time monitoring and automated reminders from smart packaging, ▪ Tailored FGID-specific interventions, including CBT modules addressing maladaptive beliefs and stress, ▪ Dietary adjustments informed by real-time symptom data, improving the patient’s self-management and engagement; 2. Integration comprise: o Time-stamped adherence data from the smart packaging drives: ▪ Behavioral modifications based on adherence patterns, ▪ Dietary recommendations tailored to PROMs, ▪ Escalation to professional support (e.g., virtual counseling) when nonadherence or symptom worsening is detected; and / or 3. Treatment Parameters comprise: o The digital BSC platform dynamically adjusts interventions in response to evolving PROMs and adherence data to optimize therapeutic outcomes.

23. A method for treating FGIDs in patients using the drug-digital combination product of Claim 16, wherein the drug label includes: • (a) A description of the drug, smart packaging, and digital BSC platform; • (b) Instructions for physicians and patients on integrating the digital BSC with drug therapy; and / or • (c) Randomized controlled trial data demonstrating: o The efficacy and safety of the drug, and / or o The adherence and therapeutic benefits achieved through the integration of smart packaging and the DBSC platform.PATENT 7279.154670PCT 24. A digital health system designed to enhance adherence and add the Clinical Trial Effect to therapeutic drug treatment, comprising: o A cloud-based computing platform; o Digitally-enabled therapeutic kit components including RFID- packaging of drug products and pen needles, and optionally Bluetooth- enabled pen systems, and RFID readers and Bluetooth; o eSource data components including electronic health records (EHRs), electronic patient-reported outcomes (ePROs), electronic clinical outcome assessments (eCOAs), digital consent (eConsent), wearables, and internet of things (IoT) devices; o Customized user interfaces for patients, healthcare professionals, pharmacists, laboratory personnel, investigators, researchers, system management, and sponsors; o Functional blocks for medication management, telemedicine, patient data collection, patient behavior change, patient productivity, and clinical trial management; o An application layer comprising algorithms, models, and processors for transforming collected data and generating personalized intervention regimens; and / or o a data processing and analytics layer that aggregates, processes, and analyzes data using machine learning algorithms and an intervention modification engine; o and optionally means for integrating future algorithms, models, and processors based on clinical data. o 25. The system of claim 24, wherein the customized user interfaces are designed to provide: o Patients and caregivers with access to their health data, adherence reminders, and tools for reporting outcomes; o Healthcare professionals with tools for monitoring patient adherence, reviewing clinical outcomes, and adjusting intervention regimens; and / orPATENT 7279.154670PCT o Administrative functions for managing clinical trials, accessing aggregated data, and performing system maintenance.

26. The system of claim 24, wherein the functional blocks comprising: o A medication management block comprising tools for managing medication schedules and adherence; o A telemedicine block for providing remote clinical services via telecommunications technology; o Patient data collection blocks including chatbots, digital health diaries, and health questionnaires; o Patient behavior change blocks featuring microlearning sessions, personalized coaching, and community support platforms; o Patient productivity blocks enabling self-scheduling of appointments and automatic reminders; and / or o Clinical trial blocks incorporating randomization and trial supply management (RTSM), electronic data capture (EDC), and clinical trial management system (CTMS) functionalities.

27. The system of claim 24, wherein the data processing and analytics layer uses machine learning algorithms to: o Predict patient adherence patterns; o Optimize therapeutic drug treatment plans; and / or o Personalize patient interventions and dynamically adjust regimens based on real-time data and feedback.

28. The system of claim 24, wherein the cloud-based computing platform supports: o Scalable data storage, processing, and application hosting; o Integration of future algorithms, models, and processors for continuous improvement of intervention regimens; and / or o Disaster recovery and backup systems to ensure data integrity and availability.PATENT 7279.154670PCT 29. A method for enhancing adherence and add the Clinical Trial Effect to therapeutic drug treatment using the digital health system of claim 24, comprising: o Enrolling patients and obtaining digital consent through the eConsent system; o Collecting patient-reported outcomes, clinical outcome assessments, and health data from wearables and IoT devices; o Randomizing patients into study groups and managing trial supplies using the RTSM system; o Aggregating and processing collected data to generate patient profiles and personalized intervention regimens; o Reviewing and approving intervention regimens by healthcare providers and communicating them to patients; o Monitoring patient adherence and dynamically adjusting interventions based on data collected from the digitally-enabled therapeutic kit, and using algorithms and the intervention modification engine; o Ensuring compliance with HIPAA and FDA regulations for data privacy, security, and system integrity; oIncorporating future algorithms, models, and processors based onclinical data to enhance the system's capabilities.

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