Method of enhancing cognition of individual having at least normal cognition

Abstract

AC-# imgabs0 # is a federal registered trademark which encompasses a product consisting of an aqueous extract of the plant uncaria. Applicants have found that administration of an AC-# imgabs1 # product in a pharmaceutically effective amount and for a sufficient period of time can enhance the cognition of a normal person prior to the start of administration. A method of applying an AC-# imgabs2 product is disclosed and claimed.

Description

Background of the Invention

[0002] The present invention relates to a method of enhancing cognition in an individual with at least normal cognition. For nearly 20 years, Applicant's assignee, Optigenex Inc. (Optigenex), has been refining, distributing and selling federally registered trademark product (registration number 2,930,140, ​​registered on March 8, 2005, and claimed first use date at least as early as July 30, 2003). The product sold under the trademark ANTIQUID® consists of an aqueous extract of the plant Uncaria tomentosa. Products are often sold as vitamin supplements.

[0003] Optigenex found use The product can cause telomere lengthening in cells. Therefore, on November 30, 2017, Optigenex filed a U.S. patent application, number 15 / 827,223. On October 16, 2018, the application became U.S. Patent No. 10,098,922, and the corresponding international applications have been approved or are pending.

[0004] Subsequently, Optigenex conducted studies to determine whether the use of Whether it can help promote human health. In the process, it was found that, as explained in more detail below, the use of this Uncaria rhynchophylla extract can enhance cognition in individuals who were at least cognitively normal before taking the product. This patent application is filed to request patent protection This application of Uncaria rhynchophylla material.

[0005] Subsequently, Optigenex conducted studies to determine whether giving people Uncaria rhynchophylla could produce positive health effects. After extensive experiments, the applicant found that taking prescription doses of Uncaria rhynchophylla could enhance cognition in relatively healthy, cognitively normal people, including statistically significant improvements in attention, memory, and executive function, as well as improved social cognition. These results were obtained by conducting a randomized, double-blind, crossover, placebo-controlled trial. The experiment concluded that a daily oral dose of Uncaria rhynchophylla statistically significantly improved various aspects of cognition in relatively healthy patients who had normal cognitive function before starting to take Uncaria rhynchophylla. The present invention is different from all prior art known to the applicant.

[0006] The applicant is aware of the following prior art:

[0007] It is reported that many US patents disclose the uses of various substances, including the administration of Uncaria rhynchophylla for treating Alzheimer's disease and / or other diseases associated with amyloidosis. These patents are U.S. Patent No. 6,264,994 to Castillo et al.; U.S. Patent No. 6,346,280 to Castillo et al.; U.S. Patent No. 6,607,758 to Castillo et al.; U.S. Patent No. 6,797,286 to Bobrowski; U.S. Patent No. 6,929,808 to Castillo et al.; U.S. Patent No. 6,939,570 to Snow et al.; U.S. Patent No. 7,029,710 to Castillo et al.; U.S. Patent No. 7,285,293 to Castillo et al.; U.S. Patent No. 7,314,642 to Castillo et al.; U.S. Patent No. 7,754,250 to Castillo et al.; Published Application No. 2011 / 0097428 to Lake et al. and Published Application No. 2017 / 0333512 to Cam et al.

[0008] The present invention differs significantly from the teachings of these patents and published applications because each of these prior art references assumes cognitive decline, such as that found in patients with Alzheimer's disease. In contrast, a core feature of the present invention is that applicants have discovered that administering Uncaria rhynchophylla to people of normal health and cognition can enhance their cognition.

[0009] U.S. Patent No. 8,115,031 to Yates et al. discloses the synthesis of quinic acid lactone, which is a component of the hot aqueous extract of Uncaria rhynchophylla. The patent discloses a method of treating inflammatory conditions. It does not teach enhancing cognitive function in initially cognitively normal people.

[0010] Cam et al., published application number US2016 / 0250273, discloses a mixed preparation of Uncaria rhynchophylla extract and oolong tea extract for treating pathological plaques and tangles accumulated in the aging brain in amyloidosis and taupathies. Similarly, as described above, patients with amyloidosis and related disorders (including Alzheimer's disease) have cognitive decline, and therefore, they are not known to be able to improve cognition by the method of the present invention.

[0011] A publication published by Cosentino et al. and L. Torres in 2008 (Reversible deterioration of motor symptoms of Parkinson's disease after oral administration of Uncaria rhynchophylla (eat'sclaw). Clinical Neuropharmacology 31(5):293-294.) disclosed that oral administration of Uncaria rhynchophylla could reverse the deterioration of Parkinson's disease. The present invention is distinguished from the publication because the present invention is related to enhancing cognition in normal cognitive populations.

[0012] A publication by Quinn et al. in 2004 (Phytochemicals in Alzheimer's Disease: Development of Clinical Trials. Pharmaceutical Biology 42 (Suppl): 64-73) discloses the use of hydrophobic Uncaria extract to treat oxidative stress, amnesia, tangles and plaques in Alzheimer's disease. The publication does not teach any improvement in cognitive function in cognitively normal people before the administration of Uncaria.

[0013] The publication by Shi et al. in 2013 (Neuroprotective effects of an aqueous extract of Uncaria rhynchophylla: Implications from 6-OHDA-induced cell injury and transgenic Caenorhabditis elegans models. Int Neurochem 62:940-947) disclosed the neuroprotective effects of an aqueous extract of Uncaria rhynchophylla. The publication did not teach or suggest the use of Uncaria rhynchophylla to enhance cognitive function in people whose cognitive function was relatively normal before taking the substance.

[0014] International Publication WO 98 / 51302 to Castillo et al. discloses compositions and methods for treating Alzheimer's disease and other amyloidoses. This reference does not teach or suggest enhancing cognition in cognitively normal individuals prior to administration of Uncaria rhynchophylla or the like.

[0015] The above references represent the prior art efforts in treating mental decline including dementia and Alzheimer's disease. What they have in common is that they all disclose potential treatments aimed at reversing mental decline caused by brain cell diseases in people, and the results vary. In sharp contrast to the prior art known to the above applicants, in the present invention, the starting point for treatment is tested people with normal cognition, and the application of Uncaria rhynchophylla substances is intended to enhance the cognitive function of such people. This is significantly different from the teachings of the prior art known to the applicants. Summary of the invention

[0016] The present invention relates to a method for enhancing cognition in an individual with at least normal cognition. The present invention includes the following interrelated objects, aspects and features:

[0017] (1) In a first aspect, the present invention comprises carboxyalkyl esters (CAE) as active ingredients of Uncaria rhynchophylla (UT), which is also known as de gato, or cat's claw, is a versatile medicinal vine that has been used for more than 2,000 years by ancient civilizations including the Tahuantinsuyo (Inca) Empire. The bioactive components of UT are classified into hydrophobic and hydrophilic phytochemicals. Hydrophobic chemicals include uncarine F, speciophylline, mitraphylline, isomitraphylline, pteropodine, isopteropodine, etc. These hydrophobic chemicals are derived from tinctures (using alcohol to extract the chemicals from UT). Hydrophilic chemicals include CAE, which is an ester of quinic acid. These hydrophilic chemicals are derived from decoctions (using hot water to extract the chemicals from UT). Hydrophobic and hydrophilic chemicals are structurally, chemically, and functionally distinct / independent chemicals. Although both types of chemicals can be derived from the same vine (e.g., UT), research conclusions drawn from one class of chemicals do not predict the other. For example, hydrophobic chemicals may be toxic, whereas hydrophilic chemicals such as CAEs show no signs of toxicity at physiological doses.The present invention is based on a specific class of hydrophilic chemicals known as CAEs.

[0018] (2) CAE is extracted and purified by known procedures to produce a specific preparation. Briefly, the bark of UT (~150 g) is heated in water at 90-100°C for 12-24 hours, then the soluble extract is decanted and ultrafiltered to remove components with a molecular weight greater than 10 kDa (such as tannins and flavonoids), while the remaining low molecular weight components are spray dried on maltodextrin. Various analytical methods have validated the CAE composition obtained from this procedure, which can produce up to 20% CAE per extract. Therefore, the present invention is based on UT obtained from a specific process for producing this specific CAE composition.

[0019] (3) The applicant found that CAE can improve attention, memory, executive function and / or social cognition in cognitively healthy individuals. The applicant conducted a randomized double-blind crossover placebo-controlled human trial, which is described in more detail below, and showed that daily (30 days) oral administration of CAE The pills (trademarks cover Uncaria rhynchophylla substances) improved cognitive function in relatively healthy individuals who were initially cognitively normal. This statistically significant improvement was seen as early as taking The effects appear already after one month and can last up to three months. Thus, the present invention teaches cognitive improvement in relatively healthy individuals with normal cognition. The key point is that the present invention focuses on healthy individuals with normal cognition, rather than disease states (Alzheimer's disease, Parkinson's disease, inflammatory diseases, etc.) or pathological preparations (plaques, tangles, etc. in vitro or in vivo).

[0020] (4) The key difference between the present invention and the prior art known to the applicant is that the present invention has been found to be an effective treatment method to enhance cognition in people with normal cognition (generally speaking). In the field of determining cognition, the Mini-Mental State Examination (MMSE) is a widely used tool for assessing time orientation, place orientation, immediate memory recall, calculation disorders, attention, delayed memory, verbal repetition, verbal 3-stage command, reading skills and motor function. People are examined using this test and the test results are converted into numerical scores. A score ≤20 indicates that cognition is below normal. A score greater than 20 indicates that cognition is at least normal. In determining whether the present invention is indeed an effective way to enhance cognition, it was found that the MMSE scores of the subjects tested were all greater than 20, and in all cases were ≥30. The MMSE test used in the above experiments is the Folstein Mini-Mental State test, as described in the Journal of Psychiatry, J.Psychiat, Res. 1974, Vol. 12, pp. 189-198, The test was described in Pergamon Press, 1975. In this test, a score greater than 20 indicates normal cognition. When testing one cognitive type (e.g., "attention"), the maximum score is 30. When testing multiple cognitive types (e.g., "attention" and "calculation"), the maximum score achievable is 35. In the test, each subject was tested on multiple cognitive types, and each subject received a score of ≥30.

[0021] (5) To determine whether the present invention is truly successful in improving cognition in individuals with normal cognition, Applicants conducted a randomized, double-blind, crossover, placebo-controlled trial, which is a procedure known to scientists that helps to reliably determine whether certain scientific results are merely random or are repeatable and verifiable.

[0022] (6) The study found that 18 individuals had MMSE scores greater than 20. In fact, the MMSE score of every participant in the study was ≥30, which means that the mental function of every participant in the study has reached a high cognitive level.

[0023] (7) At the end of the study, each participant was tested again. The results showed that daily oral administration of After taking Uncaria rhynchophylla in tablet form sold under the trademark, attention, memory, and executive function all improved significantly. Most participants also showed improvements in social cognition. The improvements in attention were the most resilient and long-lasting. Therefore, the applicant appropriately concludes that the present invention actually achieves results worthy of patent protection.

[0024] It is therefore a first object of the present invention to provide a method of enhancing cognition in an individual having at least normal cognition.

[0025] It is another object of the present invention to provide such an invention, wherein Uncaria rhynchophylla (UT) is administered to cognitively normal individuals to enhance their cognition.

[0026] Another object of the present invention is to provide such a method wherein a randomized double-blind crossover placebo-controlled trial demonstrates the efficacy of the present invention.

[0027] It is another object of the present invention to provide such a method which improves attention, memory, executive function and social cognition.

[0028] These and other objects, aspects and features of the present invention will be better understood by reading the following detailed description of the preferred embodiments in conjunction with the accompanying drawings.

[0029] BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 A computer screenshot of the neuropsychological assessment used to study the present invention is shown.

[0031] Figure 2 A bar graph is shown demonstrating the improvement in attention through application of the present invention.

[0032] Figure 3 A bar graph indicating that late oral administration of Uncaria rhynchophylla resulted in improved attention is shown.

[0033] Figure 4 A graph is shown demonstrating the improvement in memory resulting from application of the present invention.

[0034] Figure 5 A graph is shown demonstrating that implementation of the present invention improves executive function, ie, the ability to retain and process visual-spatial information.

[0035] Figure 6 A bar graph is shown demonstrating that practicing the present invention improves social cognition.

[0036] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0037] is a widely used commercial dietary supplement that includes Uncaria rhynchophylla as an active ingredient. of people have shown health benefits including improved DNA repair, longer telomeres, reduced inflammation, and increased bioavailability of aromatic amino acids. The effects on neuropsychological function have not been resolved. The present invention is concerned with testing the following hypothesis: Will improve neuropsychological function in people with normal cognitive function.

[0038] To test this hypothesis, a randomized, double-blind, crossover placebo-controlled trial was performed.

[0039] Standardized unsupervised neuropsychological assessments were used as the primary method. These assessments included individual tests measuring attention, memory, executive function, and social cognition. A total of 18 individuals participated in the study, and each individual was relatively healthy and had normal cognition at baseline.

[0040] The results of the study showed that daily oral Statistically significant (t=2.4, p<0.05) improvements in attention, memory, and executive function. In addition, 64% of participants demonstrated improvements in social cognition. Improvements in attention were most resilient and long-lasting. Therefore, the applicants conclude that healthy individuals with normal cognition can use the drug as needed. to provide a “cognitive boost”.

[0041] Cognition is a fuzzy concept. However, a reasonable concept of cognition is the coordinated response of multiple brain regions in order to perform specific functions. These functions can range from the detection of stimuli to complex behavioral and emotional tasks. Throughout history, healthy individuals have sought to improve their cognition in order to gain a competitive advantage in education, occupations, recreation, and social activities. For example, college students in the United States often abuse prescription stimulants to improve their cognition in order to gain educational benefits.

[0042] In the wider population, up to 62% of individuals misuse prescription medications to enhance cognition (Maher, 2008). Survey data suggest that one in five respondents may take medication to improve their cognitive performance (Maher, 2008). It appears that the general population has a need / desire to boost cognitive function when needed (before taking an exam, completing a work-related task, etc.). However, misusing prescription medications to improve cognition can be illegal and risky due to side effects such as psychosis, insomnia, and irritability (Nicholson and Wilson, 2017; Wozniak-Karczewska et al., 2018). Furthermore, it is unclear whether misusing prescription medications actually improves cognition in healthy individuals who already have normal cognition. Therefore, the perception of cognitive enhancement brought about by prescription drug misuse may be questionable at best.

[0043] The perception of cognitive enhancement can be achieved in at least three ways. One is the placebo effect, where the act of taking a drug with supposed benefits can lead to positive cognitive outcomes when in fact the drug has no real effect on cognition. The second is the self-evaluation effect, where the drug changes people's perception of a given task (e.g., the amount of work to be done and the quality of the work) but does not improve cognitive performance on the task (Hurst et al., 1967). The third is the arousal effect, where the drug enhances energy, wakefulness, or motivation, thereby improving task performance, but cognition remains unchanged. Because of these confounding variables, a randomized, double-blind, placebo-controlled trial with quantitative measures of cognition is needed to demonstrate whether the present invention is truly effective in enhancing cognition. Therefore, this study aims to determine Whether cognitive performance can be improved in relatively healthy individuals with normal cognition.

[0044] Participants in the study were recruited through digital and print announcements in northern Arizona, USA. These announcements instructed potential participants to schedule an initial interview. Before the initial interview, each subject was randomly assigned to either the drug-then-placebo (DP) group or the placebo-then-drug (PD) group. During the initial interview, subjects were screened for cognitive deficits by participating in and passing the Mini-Mental State Examination (MMSE) (Folstein et al., 1975). The MMSE is a widely used tool (e.g., doctor's office, hospital, or clinical setting) to assess time orientation, place orientation, immediate recall (memory), dyscalculia, attention, delayed verbal recall (delayed memory), language repetition, language 3-stage command, reading, and motor function. Scores ≤ 20 indicate less than ideal cognition. Each participant in this study showed extremely high scores of ≥ 30 in multiple types of cognitive tests, indicating that each participant already had a high level of cognition.

[0045] Each participant was also asked to determine their overall health and neurological status. They were all asked whether they considered themselves to be cognitively normal. All answered affirmatively. All participants showed relatively normal health and no neurological defects. In addition, the participants were investigated for their eligibility for the study, and basic demographic data (gender, age, education level, etc.) were collected from each participant. A total of 18 healthy individuals with high cognitive status completed the entire study. Adult women (N=11) and men (N=7) participated in the study. The ages of the participants ranged from 19 to 66 years old. Their education levels ranged from high school to doctoral degrees. These participants self-identified as Caucasian, Asian, and Hispanic. All participants submitted written informed consent to participate in the study, and the study was approved and supervised by the Institutional Review Board (IRB).

[0046] Neuropsychological Assessments. Neurocognitive function was assessed in the study using an unsupervised computer automated assessment from the Cambridge Neuropsychological Test Automated Battery (CANTAB). CANTAB has been published in more than 2,000 peer-reviewed articles and is widely used in clinical, academic, and pharmacological research (Backx et al., 2020; Barnett et al., 2016; Wild et al., 2008). The CANTAB assessment is fully automated (from testing to scoring and data tabulation) with visual screens and auditory voiceover guidance from training to final assessment.

[0047] Each assessment began with a training paradigm to familiarize participants with the expected tasks. Once a given participant was fully trained, the subsequent assessments began. Training, assessments, and transitions between them (as well as transitions between assessments) were all unsupervised and driven by artificial intelligence (AI) to eliminate bias caused by interference from the researcher (investigator). A total of four neuropsychological assessments were conducted in the study (rapid visual information processing; paired associate learning; spatial working memory; and an emotional bias task). Each assessment was designed to limit learning effects, so each assessment could be conducted on the same participant over time (Backx et al., 2020). For example, for each testing session, test stimuli were randomly presented from a large stimulus library or alternative test stimuli were selected, which limited the possibility that a given participant would complete the same stimulus-induced task more than once. This adaptive paradigm ensures that there is little or no practice effect from conducting the same assessment multiple times. Figure 1 Live screenshots of exemplary assessments are provided.

[0048] Rapid Visual Processing (RVP). This assessment evaluates sustained attention (Backx et al., 2020; Sahakian et al., (1989). Numbers from 1 to 9 were presented continuously in a pseudo-random order at a rate of 100 numbers per minute. The participant's task was to make a motor response to a target sequence as quickly as possible, such as three consecutive odd numbers or three even numbers (3-5-7, 2-4-6, 4-6-8, etc.). The stimulus duration was 600 milliseconds (ms) with no inter-stimulus interval. The target sequence could be one or more simultaneous sequences. The outcomes measured included the average latency to respond to the target (in ms).

[0049] Paired Associate Learning (PAL). This assessment evaluates visual episodic memory (Barnett et al., 2016). A number of boxes are displayed, and for some boxes, their unique pattern (content) appears randomly and then disappears briefly. A given pattern (the content inside a specific box) is then displayed in the middle of the computer screen, and the participant's task is to remember which of the original set of boxes contains the pattern and where the box is located. The difficulty of this task increases after each successful attempt. The outcomes measured include the number of errors in task completion (number of memory errors).

[0050] Assessment of Spatial Working Memory (SWM). This assessment evaluates executive function by retaining and processing visual-spatial information (Owen et al., 1990; Rabbitt and Lowe, 2000). The test involves the presentation of multiple colored squares (boxes). The participant's task is to select the boxes and using a method of elimination, the participant finds a yellow "marker" in each of the multiple boxes and uses them to fill in the blank columns on the right side of the computer screen. The number of boxes is gradually increased until a maximum of 12 boxes are displayed for the participant to search. The color and position of the boxes used vary from trial to trial to prevent the use of stereotyped search strategies. The outcomes measured include the number of errors in selecting a box that was found to be empty and the number of errors in revisiting a box that was found to contain a mark (number of errors in executive function).

[0051] Emotion Bias Task (EBT). This assessment evaluates social cognition by detecting perceptual biases in facial emotions, using facial images showing a magnitude between happy and disgust emotions (Kelaiditis et al., 2021; Tristao et al., 2022). Facial expressions were presented at a rate of 150 ms followed by a forced choice in which participants had to select one of two emotions. Outcome measures included the percentage of bias towards happy or disgust emotions.

[0052] Experimental Study Design. The study used in accordance with the teachings of the present invention employed a randomized double-blind placebo crossover study design. Prior to the initial interview, participants were randomly assigned to one of two groups (DP or PD). No attempt was made to equalize the number of participants in each group, so randomization resulted in 11 participants in the DP group and 7 participants in the PD group. The DP group initiated the study by undergoing a neuropsychological assessment at baseline, and then they took 1 month. The dose consisted of one 350 mg capsule taken orally twice daily (700 mg / day in total) for 30 days. At the end of this 30-day period, participants underwent a neuropsychological assessment to determine Whether the score can be improved from the baseline level.

[0053] These same participants then underwent a washout period during which they did not take any of the medication for 1 month. or placebo. At the end of this washout period, the same participants underwent neuropsychological assessments again. They then took placebo (350 mg capsules twice daily, 700 mg / day total) for 1 month and underwent a final neuropsychological assessment at the end of that month. This specific experimental study design allows for within-group comparisons. For example, within the same group of subjects, one can determine whether Whether there is an effect on cognitive function, and whether placebo has a similar or no effect can be determined. Therefore, the research question pursued in the study can be answered by this crossover design for the DP group. However, to further explore the research question, the PD group was also investigated.

[0054] The PD group started the study by having a neuropsychological assessment at baseline, and then they took a placebo for 1 month. At the end of that month, they had another neuropsychological assessment to determine if the placebo had a positive effect relative to baseline. These same participants then went through a washout period during which they did not take the placebo or At the end of this washout period, the same participants underwent neuropsychological assessments again. They then took 1 month, with a final neuropsychological assessment at the end of that month.

[0055] This specific experimental study design allows for within-group comparisons. Thus, one can determine the effect of placebo or The combination of two crossover designs (DP group and PD group design) provides a rigorous, definitive and powerful experimental method to determine and evaluate whether there is an effect on cognitive function. Efficacy in improving cognition.

[0056] In addition, all study personnel (investigators) were unaware of the scoring and tabulation of test results for each participant for each neuropsychological assessment. After the test scoring and data tabulation, the blinding was performed. Likewise, each participant was unaware of the type of medication they were taking. Or a placebo. The capsules are identical in appearance to the placebo capsules. The capsules contained carboxyalkyl esters (CAE; active ingredient) and tapioca maltodextrin (starch). The placebo capsules were made of tapioca maltodextrin. The capsule material consisted of titanium dioxide (food coloring).

[0057] Statistical analysis. The purpose of this study was to determine Whether it can improve cognitive function in individuals with normal cognitive function. Statistical comparisons between cognitive function after and after treatment provide data that directly address this objective. Therefore, paired sample t-tests were used to detect statistically significant differences relative to baseline levels. Two experimental groups (DP and PD) were deployed, each serving as its own internal control, so that specific objectives could be evaluated with either group (DP or PD). A p-value of <0.05 was used as the significance criterion. All graphics and statistical calculations were performed using a professional graphics and statistical software suite (GraphPad Software, La Jolla, CA, USA).

[0058] Results. The aim of this study was to determine the Whether it would improve cognitive function in relatively healthy individuals with normal cognition. The cognitive assessment results after the study were compared with the cognitive assessment results at baseline (at the beginning of the study). Treatment that improves cognitive test results over baseline can be interpreted as Improvements in specific cognitive functions have been induced. To improve the rigor of the experimental study design and further validate the interpretation of the results, a placebo treatment was also included. Therefore, the cognitive assessment results after daily oral placebo were compared with the cognitive assessment results at baseline (at the beginning of the study). This study assessed four cognitive domains, including attention, memory, executive function, and social cognition.

[0059] attention: Figure 2 Display, oral Improved attention above baseline levels (at the start of the study). Furthermore, this improvement lasted for two months (the second month of the study). Figure 2 A shows the baseline attention scores and the oral Attention scores after 1 month and after 1 month of taking placebo. The group taking the drug showed improvements in attention compared to baseline, while the group taking the placebo showed no improvement. This suggests that oral 1 month is sufficient to improve attention in normal / healthy individuals. Figure 2 B shows that this positive The effect lasted for two months (stop taking 1 month after taking Concentration was enhanced, and this enhancement lasted for two months.

[0060] like Figure 2 Shown: Application Improved attention within one month. Panel A shows that daily oral After one month, there was a statistically significant improvement in mean latency compared to baseline (at the start of the study) (lower scores mean better performance). Note that there was no statistically significant improvement compared to baseline with oral placebo at one month. Panel B shows that Induced attention significantly improved in the second month (stop taking The effect of placebo on the sham group was not statistically significant (P < 0.05 or statistically significant).

[0061] Statistical calculations were performed and the results confirmed Conclusion: Improved "Attention". Comparison of baseline attention scores with those taking Comparison of attention scores after 1 month (1 month after the start of the study) showed a statistically significant improvement (t

[10] =2.376, p=0.0389; two-tailed). This statistically significant effect was still maintained 1 month later (2 months after the start of the study) (t[9]=2.388, p=0.0407; two-tailed). However, when the baseline attention scores were compared with the attention scores after 1 month of placebo (1 month after the start of the study), there was no statistically significant improvement (t[6]=0.9216, p=0.3926; two-tailed). One month after the placebo was discontinued (2 months after the start of the study), there was still no statistically significant placebo effect (t[5]=1.563, p=0.1787; two-tailed). Therefore, only The treatment improved concentration.

[0062] Figure 3 Shows confirmation Additional data that has a positive effect on attention. Figure 3 A shows the results for a group of participants who received a placebo in the first month of the study and whose attention scores were similar to their baseline scores. This suggests that the placebo had no effect on attention. These participants then underwent a one-month washout period (rest or rest period). After the washout period, their scores did not change and remained the same as their baseline levels. However, when the placebo was introduced and had the same participants take After 1 month, their attention scores were significantly improved compared to their baseline scores. This suggests that introducing Improved their attention scores.

[0063] Figure 3 This conclusion is further supported by Figure 2, which shows the results for a group of participants who received , their attention scores improved relative to their baseline scores. This suggests There was a positive effect on attention. These participants then went through a one-month washout period (rest or rest period). After the washout period, their scores were still improved relative to baseline. Interestingly, when a placebo was introduced and the same participants took the placebo for 1 month, their scores were still higher than baseline. This further confirms that The introduction of sedatives improved attention, and this improvement was not observed after discontinuation of sedatives. It may last for several months.

[0064] Figure 3 Explanation: Late oral administration Panel A shows that participants took a placebo orally every day (month 1), then they went through 30 days without treatment (washout period: month 2), and finally, these same participants took 30 days (3rd month). Treatment, attention only showed statistically significant improvement at 3 months (the lower the score, the better the performance). Panel B shows that participants took oral , they then underwent 30 days without treatment (washout period: month 2), and finally, these same participants took a placebo for 30 days (month 3). Treatment improved attention after one month of treatment, and this improvement persisted to 3 months. Furthermore, taking a placebo did not hinder the duration of this positive effect. Bars = mean ± SE; ms = milliseconds; NS = not statistically significant; * = p < 0.05 or statistically significant.

[0065] right Figure 3 Statistical calculations were performed on the data in the study. There was no statistically significant difference between the baseline attention score and the attention score after placebo treatment (t[6]=0.9216, p=0.3923; two-tailed). Similarly, there was no statistically significant difference between the baseline attention score and the attention score after the washout period (t[5]=1.563, p=0.1787; two-tailed). However, there was a statistically significant difference between the baseline attention score and the attention score after the placebo treatment. There was a statistically significant difference in attention scores between the first and second doses of placebo (t[8]=3.468, p=0.0085; two-tailed). This suggests that In the group of participants, Successfully improved concentration.

[0066] Interestingly, taking Then, in the placebo group, It also successfully improved attention. For example, the baseline attention score was significantly higher than that of the control group. There was a statistically significant difference between the attention scores at baseline and after the washout period (t

[10] =2.376, p=0.0389; two-tailed). Similarly, there was a statistically significant difference between the attention scores at baseline and after the washout period (t[9]=2.388, p=0.0407; two-tailed). Finally, there was a statistically significant difference between the attention scores at baseline and after taking the placebo (t[8]=3.468, p=0.0085; two-tailed). Therefore, The induced attention improvements persisted after the washout period and even after taking the placebo.

[0067] memory: Figure 4 Daily oral administration May improve memory. The group of participants who received the placebo showed no evidence of improved memory relative to their baseline memory scores. This suggests that taking the placebo did not increase or decrease their memory performance. Interestingly, these same participants showed improved memory after a 1-month washout period. It is unclear why participants showed improved memory at this stage of the study, as the washout period is when they are not taking the placebo and When these same participants took Their memory scores continued to improve when they took It will not hinder the improvement of memory, but will help to get a better memory.

[0068] Figure 4 :oral Improved Memory. This graph shows a quantification of memory errors for participants at baseline (at the beginning of the study). These participants first took a placebo by mouth for one month. Notice that their memory error count did not improve after taking the placebo for one month. Next, the participants went through a one-month washout (resting period). Their memory error count decreased, but was still not statistically different from baseline. Finally, the participants took the placebo by mouth. One month. Note that their number of memory errors now showed a statistically significant improvement compared to the scores at baseline (lowest score). Boxes = mean ± SE; NS = not statistically significant; * = p < 0.05 or statistically significant.

[0069] Statistical calculations showed that there was no significant difference between the baseline memory score and the memory score after taking the placebo (t[6]=0.7101, p=0.5043; two-tailed). This suggests that the placebo has no effect on memory. In addition, there was no statistically significant difference between the baseline memory score and the memory score after the 1-month washout period (t[5]=1.736, p=0.1431; two-tailed). This means that although the memory score showed some degree of improvement, the effect was not significantly different from chance. However, statistical calculations showed that there was no significant difference between the baseline memory score and the memory score after taking the placebo. There was a significant difference in the memory scores after the test (t[5]=2.951, p=0.0318; two-tailed). This means The induced improvements in memory scores were not accidental.

[0070] Execution function: Figure 5 Show daily oral Improves executive function in healthy individuals with normal cognitive function. Executive function improved significantly after one month. This improvement persisted and even became more pronounced after a one-month washout period. Both short-term and long-term benefits were provided for executive function, with the long-term benefits being the most prominent. However, taking a placebo reversed this trend, with worse scores in the same participants. It is unclear why participants scored lower after taking the placebo, but the data suggest that The positive effects on executive function may only last for 2 months. After this 2-month time point, executive function may return to levels closer to baseline.

[0071] Figure 5 :oral Improved executive function (e.g., maintaining and processing visual-spatial information). This figure shows a quantification of executive function errors among participants at baseline (at the beginning of the study). The participants first received 1 month of oral administration of . Note that when taking After 1 month, their executive function error counts had not improved. Next, the participants underwent a 1-month washout period (rest period). Their executive function error counts were significantly reduced and statistically different from baseline. This means that taking had a delayed effect on improving their executive function. This was confirmed by the fact that placebo treatment led to an increase in the number of executive function errors. Bar graph = mean ± SE; NS = not statistically significant;

[0072] * = p < 0.05 or statistically significant.

[0073] Statistical calculations further confirmed that positive role. One month after treatment, the mean score was better than the baseline level, but it did not reach statistical significance (t

[10] =1.656, p=0.1287; two-tailed). However, after another month (2-month study duration), there was a statistically significant improvement in executive function (t[9]=3.712, p=0.0048; two-tailed). This suggests that after stopping taking It may take up to 2 months after taking ED to see significant improvements in executive function. In contrast, other cognitive domains, such as attention, improve after stopping ED. Improvements were shown one month after the last exercise. Statistical calculations also showed that executive function may return to baseline levels after three months (t[8]=2.253, p=0.0543; two-tailed). Further evidence suggests that The induced improvements in executive function may last only for 2 months.

[0074] Social cognition: Figure 6 It shows that daily oral Can generate positive social tendencies. Figure 6 A shows that most (64%) take of participants showed social ratings consistent with a happy orientation. Figure 6 B confirmed this, with only a small percentage (36%) taking Of the participants who took the placebo, 14% showed social ratings consistent with a tendency toward disgust. In contrast, only 14% of the participants who took the placebo showed social ratings consistent with a tendency toward happiness. Furthermore, 86% of the participants who took the placebo showed social ratings consistent with a tendency toward disgust.

[0075] Figure 6 :oral Can improve social cognition. Panel A shows that taking or the percentage (%) of participants who showed a “happy” preference after 1 month of placebo. Treatment resulted in more happy facial expressions. Panel B shows that taking or the percentage (%) of participants who showed a “disgusting” preference after 1 month of placebo. The treatment resulted in fewer interpretations of disgust facial expressions.

[0076] Based on the above detailed research, the applicant has reached the following conclusions.

[0077] Discover daily oral Improved cognitive performance in healthy individuals with normal cognition. Given that the participants were healthy and already had normal cognition, the task of improving their cognition was particularly challenging because they were already at a relatively high level (e.g., ceiling effect). Nonetheless, the results suggest that taking Can significantly improve cognition. The results were effective in improving cognition in four cognitive domains: attention, executive function, memory, and social cognition. The results in attention appeared to be more significant and lasting than those in the other domains. Participants who received a placebo in the final month of the study were then given Improved attention. of participants, In both cases, showed statistically significant improvements in attention. Improvements in executive function, memory, and social cognition were also demonstrated, but these improvements may be attributed to improvements in attention. The primary improvement in attention subsequently enhanced various other cognitive functions. Alternatively, Performance in each cognitive domain can be improved independently, with attention being the most affected. In this case, long-term use (For example, taking a few more months of ) or increase Concentration results in improvements that match or exceed attention in other neurocognitive domains.

[0078] Baseline cognitive test results This suggests that the participants This gain is obtained as early as taking The effects were already evident 1 month after treatment and were also observed after 2 and 3 months. Improvements were seen after 1 month, and these improvements persisted through 3 months. Given that the study ended after 3 months, these gains may last longer. Memory, executive function, and social cognition also showed improvements with taking the drug. However, these benefits are less persistent than attention. can lead to long-term improvements in attention, but improvements in other cognitive areas require appropriate planning. For example, improvements in executive function occur after taking After 2 months, memory improvement occurred in 3 months later.

[0079] Cohort Effect: An important result of the above study is The group that took the drug showed cognitive improvements, while the placebo group did not. This suggests a group effect, where one group performs better than another. The group effect was most prominent in attention. For example, The group that received the placebo showed no improvement in attention, but the same group that received the For memory, only the placebo group In this group, participants started with a placebo, followed by a washout period, and then took . It may be taking improved their memory scores, but it is equally possible that the improvement in their memory scores was due to the placebo effect. Supporting the effect of the placebo is the fact that their scores did not improve after taking However, support The fact that the placebo effect failed to reach statistical significance is As for executive function, There is a clear These participants took This was followed by a washout period and then placebo administration. The induced executive functioning improved from 1 month onwards and continued to improve after 1 month. Interestingly, taking the placebo reversed this positive improvement, suggesting that unlike attention, the improvements in executive functioning are less resilient. Therefore, a prominent conclusion of this study is that different groups can benefit from induced cognitive improvement.

[0080] Implications: The results of the exploratory pilot study support five implications. First, daily oral Improves cognition in healthy individuals who already have normal cognitive function. This is demonstrated by improvements in attention scores relative to baseline levels. Therefore, individuals who require a "cognitive boost" prior to occupational, recreational, educational, or social activities may benefit from daily oral administration of benefit from it.

[0081] second, The beneficial effects on specific neurocognitive domains are time-dependent. For example, improvements in attention can occur within 1 month, while improvements in executive function can occur within 2 months and memory within 3 months. With proper planning, individuals can take the drug for the necessary period of time. to achieve desired neurocognitive outcomes.

[0082] third, The induced improvements in attention were significant across all groups. The induced improvements in other cognitive domains were group-dependent. These findings suggest that may more directly target the neural substrates underlying attention. Improved attention may be a general / overall result for most individuals. However, improvements in other neurocognitive domains may only be specific to certain individuals.

[0083] Fourth, daily oral May improve social cognition. This is a rarely assessed neurocognitive domain, but it is fundamental to normal social interaction and, when disrupted, can be a hallmark of a variety of abnormal psychiatric / psychological conditions (Adolphs, 2009; Cotter et al., 2018). Therefore, individuals may take to improve their social cognition.

[0084] Fifth, given the daily oral Improved cognitive performance in cognitively normal individuals, then It may also improve cognitive function in individuals with cognitive decline. However, further research is needed to confirm the results of this study and explore Is it effective for individuals with cognitive decline?

[0085] Applicants have found that daily doses of 56 to 700 mg Will result in improved cognitive function. The dose may be taken in 2 or more spaced daily doses. Cognitive improvements have been seen in as little as one day to as long as 30 days or more. This varies due to different physiology in different people. Body weight or mass, degree of systemic inflammation, epigenetic activity, genetic mutations, and fat percentage all vary.

[0086] Substances can be delivered to patients in a variety of ways, including capsules, tablets, liquids, syrups, gels, transdermal patches, intranasal sprays, and / or suppositories.

[0087] Thus, there has been disclosed an invention in its preferred embodiments which satisfies each of the objects of the invention as set forth above and which provides a new and useful method for enhancing cognition in individuals with at least normal cognition which method is of great novelty and utility.

[0088] Of course, those skilled in the art may envision various changes, modifications and variations on the teachings of the present invention without departing from the intended spirit and scope of the invention.

[0089] Accordingly, the present invention is limited only by the terms of the appended claims.

Claims

1. A method of enhancing cognition in a human subject exhibiting substantially normal cognition, comprising the steps of: a) testing the subjects to determine their cognitive level; b) confirming that the subject exhibits normal cognition; c) administering to the subject a substance comprising an aqueous extract of an Uncaria species comprising Uncaria tomentosa in a pharmaceutically effective amount and for a period of time sufficient to enhance cognition in the subject; d) after the end of the time period, retesting the subject to determine whether their cognitive performance has improved compared to their cognitive performance before the start of administration of the substance; e) said method results in said subject exhibiting enhanced cognition.

2. The method of claim 1, wherein the substance is administered orally.

3. The method of claim 1, wherein the pharmaceutically effective amount is in the range of 56 to 700 mg / day.

4. The method of claim 3, wherein the substance comprises a minimum of 8% weight / weight (w / w) carboxyalkyl ester (CAE).

5. The method of claim 3, wherein the pharmaceutically effective amount comprises about 700 mg / day.

6. The method of claim 5, wherein the substance is administered as 350 mg twice daily.

7. The method of claim 1, wherein the substance is administered in a delivery mode selected from the group consisting of a capsule, a tablet, a liquid, a syrup, a gel, a transdermal patch, an intranasal spray, and a suppository. The method of claim 1 , wherein the time period is at least one day.

9. The method of claim 1, wherein the substance is administered orally.

10. The method of claim 1, wherein the substance is administered via a transdermal patch.

11. The method of claim 9, wherein the substance is administered in a delivery mode selected from the group consisting of a capsule, a tablet, a liquid, a syrup, and a gel.

12. The method of claim 1, wherein the test comprises a mini-mental state examination.

13. A method according to claim 12, wherein the test asks the person a series of questions and the number of correct answers determines the level of cognition.

14. The method of claim 1, wherein the pharmaceutically effective amount comprises about 700 mg / day.

15. The method of claim 1, wherein the substance comprises a minimum of 8% weight / weight (w / w) carboxyalkyl ester (CAE).

16. The method of claim 1, wherein the enhanced cognition belongs to the following categories: attention, memory, executive function, and social cognition.

17. A method of enhancing cognition in a human subject comprising the steps of: a) administering to the subject a substance comprising an aqueous extract of an Uncaria species comprising Uncaria rhynchophylla in a pharmaceutically effective amount and for a period of time sufficient to enhance cognition in the subject; b) after the end of the time period, the subject exhibits enhanced cognition.

18. The method of claim 17, wherein the substance is administered orally.

19. The method of claim 17, wherein the pharmaceutically effective amount is in the range of 56 to 700 mg / day.

20. The method of claim 17, wherein the substance comprises a minimum of 8% weight / weight (w / w) carboxyalkyl ester (CAE).

21. The method of claim 19, wherein the pharmaceutically effective amount comprises about 700 mg / day.

22. The method of claim 21, wherein the substance is administered as 350 mg taken twice daily.

23. The method of claim 17, wherein the substance is administered in a delivery mode selected from the group consisting of a capsule, a tablet, a liquid, a syrup, a gel, a transdermal patch, an intranasal spray, and a suppository.

24. The method of claim 17, wherein the time period is at least one day.

25. The method of claim 23, wherein the substance is administered via a transdermal patch.

26. The method of claim 17, wherein the enhanced cognition belongs to the following categories: attention, memory, executive function, and social cognition.

Images