How to protect human glands from radiation damage

Abstract

The present invention relates to the field of radiation oncology. The method according to the present invention comprises the use of a botulinum toxin and an anticholinergic agent to protect glands from radiation damage and side effects caused by a radioligand. The method according to the present invention further comprises the use of a botulinum toxin to protect glands from radiation damage, the radiation damage being caused by a radioligand. By using the method according to the present invention, the present invention can provide effective protection of glands to avoid radiation damage.

Description

[Technical Field]

[0001] The present invention relates to the field of radiation oncology. The use of botulinum toxin and anticholinergic drugs can avoid radiation damage caused by radioligands in human glands. Optimized treatment regimens can give this method further advantageous properties. This includes both diagnostic imaging procedures and therapeutic procedures. [Background technology]

[0002] Radioligand is a substance labeled with a radionuclide, which can bind to target proteins, such as receptors, as a ligand.Such radioligands are used in the diagnosis and treatment of, for example, tumor diseases.A prominent example is the PSMA radionuclide in the diagnosis and treatment of prostate cancer.

[0003] Prostate-specific membrane antigen (PSMA) is a transmembrane protein expressed by prostate cancer cells up to 1,000 times more than normal prostate cells. Therefore, PSMA is an ideal target protein for prostate cancer diagnosis and simultaneous targeted therapy. PSMA is also expressed by other carcinomas, albeit at lower levels compared to prostate cancer. PSMA is also expressed by salivary and ocular glands. Persistent damage to these glands can result in chronic dry eye, which can cause severe dry mouth and visual impairment, along with various complications, such as dental damage.

[0004] PSMA radionuclides are used both diagnostically and therapeutically.

[0005] PSMA radionuclide 68 Ga-PSMA and 18 F-PSMA is used to diagnose primary and recurrent prostate cancer and to detect metastases. The diagnostic ligand accumulates in prostate cancer cells and other organs / tumors mentioned above, and the diagnostic PSMA radioligand can damage the ocular and salivary glands.

[0006] Therapeutically used PSMA radioligands always cause damage to the salivary glands, the severity of which varies and often persists depending on the radioligand, resulting in significant health problems and a reduced quality of life (e.g., dry mouth, ulcers throughout the mouth area, difficulty swallowing, risk of aspiration, dental damage, etc.). Another related problem is that PSMA radioligands are frequently administered repeatedly, resulting in cumulative glandular damage. PSMA radioligands also cause damage to the ocular glands, the severity of which varies depending on the radioligand, with health consequences including dry eyes, recurrent eye inflammation, chronic eye inflammation, and visual impairment. This damage caused by PSMA therapy is often irreversible. Furthermore, this damage and complications often mean that prostate cancer patients no longer have access to life-sustaining treatments.

[0007] Presumably, different PSMA radioligands have different affinities for individual salivary glands and therefore different toxicities. The various radionuclides are either alpha, beta, or gamma emitters. For example, 177 Lu (a beta emitter in the 2 mm range) and 225Ac (an alpha emitter in the 50-90 μm range) are currently used. In the future, even more potent PSMA radioligands that emit strongly over very short distances (50-90 μm) are expected for therapeutic use. 225 Ac 177 There is increasing evidence that it damages the salivary glands more than Lu.

[0008] The use of even more potent radioligands, such as alpha emitters, carries an even greater risk of glandular damage.

[0009] Glands perform various tasks in the human body. In particular, a distinction is made between endocrine and exocrine glands. If the target is not only expressed in tumors but also in glands, such as PSMA expression in salivary glands and also in ocular glands, healthy glands will also be attacked.

[0010] This is where botulinum toxin can be useful: botulinum toxin injections can protect the gland as part of a coordinated procedure. Botulinum toxin is the collective name for a family of toxins produced by the bacterium Clostridium botulinum. Currently, there are seven different known botulinum toxins (A, B, C, D, E, F, and G), each with different properties. The mechanisms of action of the various botulinum toxin types also differ: for example, the primary effect of type A is based on cleavage of intracellular SNAP-25, whereas type B primarily cleaves "vesicle-associated membrane protein" (=VAMP). Botulinum toxin type B also has other differences compared to type A: type B binds presynaptically to the Syt II protein, and there is also partial presynaptic interaction between type B and tetanus toxin residues, as well as neurotoxin-ganglioside interactions with gangliosides GD1a, GD1b, and GM1a. Localized botulinum toxin injections produce a dose-dependent decrease in saliva production after a few days, so the onset of action is within a few days. Efficacy, duration of action, and side effects depend primarily on the administered dose. Generally, the duration of action is 4 to 16 weeks, depending on the type used: types E and F have a significantly shorter duration of action, approximately 3 to 6 weeks. Botulinum toxin does not permanently or irreversibly damage the salivary glands. Over time, salivary gland function is fully restored under botulinum toxin. Injections can be repeated as many times as desired without organ damage.

[0011] The mechanism of action of botulinum toxin on the salivary glands is known and has been previously described in detail. All botulinum toxin formulations and types (A-G) induce dose-dependent denervation of the glands, which varies in time, from 1 to 10 days after injection, and thus induce a temporary dose-dependent decrease in saliva secretion. Type B begins to act relatively quickly, at approximately 3 days, while type A begins to act at approximately 6 days. The decrease in saliva secretion affects both the serous and mucous portions of the involved salivary glands. The decrease in glandular function reduces saliva production and blood flow to the glands. Both mechanisms (individually or in combination) result in a decrease in glandular activity during radionuclide-PSMA therapy, which is permanent and prevents irreversible damage to the glands. Here again, there is a difference between botulinum toxin types B and A: type B has a higher affinity for autonomic nerve endings than type A. This is particularly important because salivary glands (as opposed to muscles) are innervated only autonomically. Therefore, botulinum toxin type B has a more potent and long-lasting effect on salivary glands than type A. Compared to type A, local injections with type B have a higher affinity for autonomic structures and a greater spread throughout the body. Therefore, when remote glands are injected, type B may result in autonomic effects on uninjected glands, such as ocular glands. This means that salivary gland injections with botulinum toxin type B may have a specific protective effect on ocular glands. This means that salivary gland injections with botulinum toxin type B may have a specific protective function due to its higher affinity for autonomic structures and greater local spread to glands that would otherwise be inaccessible to direct botulinum toxin injection, such as the sublingual gland, minor salivary glands, and ocular glands. This mechanism of action applies to all glands treated with BTX, even though the degree of denervation associated with reduced saliva production varies in individual glands.

[0012] Salivary glands also contain androgen receptors. The majority of patients with advanced prostate cancer undergo antiandrogen therapy. Antiandrogens significantly increase PSMA uptake, leading to enhanced salivary gland damage caused by PSMA radioligands. Therefore, the present invention is particularly suitable for patients who are already undergoing antiandrogen therapy or radioligand therapy, because these patients are particularly susceptible to gland damage caused by PSMA radioligands.

[0013] Additionally, all salivary glands express numerous alpha-1 adrenergic receptors. Stimulation of alpha-1 receptors results in significant salivary gland activation and saliva secretion. Botulinum toxin type A downregulates alpha-1 adrenergic receptors, resulting in decreased salivary gland activation and decreased PSMA radioligand binding to botulinum toxin-injected salivary glands.

[0014] Furthermore, aquaporins significantly increase PSMA radioligand binding, particularly in the submandibular gland. Aquaporins are proteins that form channels in cell membranes to facilitate the passage of water and other molecules, such as metalloids. Radionuclides are primarily metalloids. The submandibular gland, in particular, expresses high levels of aquaporins (AQPs) in the apical membrane of salivary glands, particularly the submandibular gland acinar cells. After approximately one to two weeks, botulinum toxin types A and B significantly reduce aquaporin mRNA (e.g., AQP 5) and AQP distribution in the apical membrane in the submandibular gland. In addition, botulinum toxin types A and B induce acinar apoptosis. Therefore, botulinum toxin injection into the submandibular gland significantly reduces aquaporin-mediated radionuclide uptake into cells, thus protecting the salivary gland, particularly the submandibular gland, from permanent damage. As the effects of botulinum toxin wear off, the aquaporin changes noted are completely reduced.

[0015] In particular, the frequent need for repeated radionuclide PSMA therapy (typically up to four treatments within six months) results in cumulative, permanent, extensive damage to the salivary glands. The effects of botulinum toxin diminish without any adverse effects after approximately six to sixteen weeks, and salivary gland function resumes.

[0016] Not only botulinum toxin but also anticholinergics can protect the salivary and ocular glands. Anticholinergics, also known as parasympatholytics, suppress the effects of acetylcholine by competitively inhibiting acetylcholine receptors. This blocks nerve impulses that lead to increased glandular secretion. Therefore, the protective effects of botulinum toxin and anticholinergics complement and reinforce each other: botulinum toxin inhibits the release of acetylcholine into the synaptic cleft (presynaptic), while anticholinergics block acetylcholine receptors (postsynaptic). Only combined presynaptic and postsynaptic blockade by either substance (botulinum toxin and anticholinergic) allows optimal protection of the salivary and ocular glands during radioligand therapy. During radioligand therapy or the use of radioligands for diagnosis, parasympathetic nerve fibers increase saliva production, and serous saliva is mainly produced in the parotid gland, which is why this function is particularly protected by systemically effective anticholinergics during PSMA radionuclide therapy. This effect is utilized in the present invention as a glandular protective effect. Anticholinergics are effective in a dose-dependent and systemic manner, and therefore can reach glands that cannot be directly treated with botulinum toxin injection, including the sublingual gland, minor salivary glands, and ocular glands. Due to their anatomical location and the risk of side effects, these glands cannot be directly treated with botulinum toxin. Therefore, these glands, such as ocular glands, are protected by anticholinergics to prevent them from being permanently damaged by radioligands, thereby avoiding dry eyes and chronic severe inflammation of the eye and eyelid margin, which significantly limits quality of life. In addition, anticholinergics enhance the effects of botulinum toxin on, for example, the parotid and submandibular glands.

[0017] In particular, the submandibular gland benefits from the combination of botulinum toxin and anticholinergic drugs because it is a serous mucous gland. Dual protection allows patients to mechanically prepare food in the oral cavity during the chewing process, ensuring that the food pulp continues to slide smoothly and digestion is not impaired. Furthermore, saliva contains antibacterial components, thus ensuring tooth remineralization, and thus tooth damage is avoided by dual protection.

[0018] The protective effect on the glands can be further enhanced by combining botulinum toxin with an anticholinergic. Combination with an anticholinergic results in an enhanced effect of botulinum toxin on the parotid and submandibular glands, as well as partial effects on other salivary and ocular glands during the period of effectiveness of each anticholinergic. Thus, the combination of botulinum toxin and an anticholinergic is most effective in terms of salivary gland secretion, followed by botulinum toxin monotherapy and then anticholinergic monotherapy.

[0019] However, not all patients benefit from combination therapy consisting of botulinum toxin and anticholinergic drugs: Patients with cognitive impairment, including those with all severities of cognitive impairment (mild to moderate and severe cognitive impairment), should not take anticholinergic drugs because of the potential for cognitive-altering effects. In other words, there are restrictions. Similarly, patients with cardiac arrhythmias should not be treated with anticholinergic drugs because they increase heart rate and conduction disturbances, potentially resulting in tachyarrhythmia, heart failure, and angina. Therefore, these patient groups exposed to radioligand diagnostics or therapy are treated with botulinum toxin without anticholinergic drugs. Here, botulinum toxin type A exerts its effects both directly in the injected gland and by passive diffusion in adjacent glands. For example, when botulinum toxin type A is injected into both submandibular glands, the sublingual gland is also protected by diffusion. Botulinum toxin B exerts its effects both directly in the injected gland and by passive diffusion in other glands, with a larger radius of diffusion than botulinum toxin type A. In addition, botulinum toxin type B has a higher affinity for autonomic nervous structures, and as a result, botulinum toxin type B also acts on distant glands that were not injected with botulinum toxin type B, such as the ophthalmic, sublingual, and minor salivary glands.

[0020] In summary, there is an urgent need for methods to protect, in diagnostic or therapeutic situations, particularly the crucial ocular and salivary glands, which are not target structures of radioligand diagnosis or radioligand therapy.

[0021] The method of the present invention provides a prophylactic solution to prevent irreversible glandular damage caused by diagnostic or therapeutic radioligands. Summary of the Invention

[0022] The present invention relates to a botulinum toxin in combination with an anticholinergic agent for use in a method for preventing radiation damage to glands, where the radiation damage is caused by a radioligand. Additionally, the present invention also includes a botulinum toxin for use in a method for preventing radiation damage to glands, where the radiation damage is caused by a radioligand.

[0023] In some embodiments, a botulinum toxin is used in combination with an anticholinergic agent for use in the method and the radiation damage is caused by a PSMA radioligand.

[0024] In some embodiments, a botulinum toxin is used in combination with an anticholinergic agent for use in the method, and the radiation damage is 225 Ac-PSMA-617, 68 Ga-PSMA, 18 F-PSMA or 177 Caused by Lu-PSMA.

[0025] In some embodiments, the botulinum toxin is selected from the group consisting of botulinum toxin types A, B, C, D, E, F and G.

[0026] In some embodiments, the botulinum toxin is botulinum toxin type A.

[0027] In some embodiments, the botulinum toxin comprises between 1 unit and 10,000 units.

[0028] In some embodiments, the botulinum toxin comprises between 1 unit and 1,500 units of type A.

[0029] In some embodiments, the botulinum toxin is botulinum toxin type B.

[0030] In some embodiments, the botulinum toxin comprises between 100 units and 10,000 units of type B.

[0031] In some embodiments, the botulinum toxin is botulinum toxin type E or F.

[0032] In some embodiments, the botulinum toxin comprises between 1 unit and 10,000 units of type E or F.

[0033] In some embodiments, the anticholinergic is selected from the group consisting of tropicamide, atropine, scopolamine, glycopyrrolate, amitriptyline, clonidine, ipratropium bromide, and trihexyphenidyl. Also included are all other medications that act as anticholinergics or parasympathetic depressants.

[0034] In some embodiments, the anticholinergic is administered transdermally, orally, or intravenously.

[0035] In some embodiments, the anticholinergic is scopolamine, and the scopolamine is administered transdermally.

[0036] In some embodiments, the botulinum toxin is botulinum toxin type B for the prevention of radiation damage to parotid, submandibular, sublingual, minor salivary, and ocular glands, where the radiation damage is caused by a radioligand.

[0037] In some embodiments, the botulinum toxin is botulinum toxin type A for reducing aquaporin-mediated radionuclide uptake in submandibular and salivary gland cells.

[0038] In some embodiments, the botulinum toxin is botulinum toxin type A, and the botulinum toxin type A is administered in a dosage ratio of 2 / 3 in the parotid gland and 1 / 3 in the submandibular gland.

[0039] In some embodiments, the botulinum toxin is botulinum toxin type B, and the botulinum toxin type B is administered in a dosage ratio of 2 / 3 in the parotid gland and 1 / 3 in the submandibular gland.

[0040] In some embodiments, the use involves administering the botulinum toxin one day to eight weeks prior to imaging or radiation therapy using one or more radionuclides.

[0041] In some embodiments, the use includes administering the anticholinergic agent 3 days, 2 days, 1 day, and the same day as a diagnostic imaging procedure or radiation therapy using one or more radionuclides, and about 7 to 30 days after the diagnostic imaging procedure or radiation therapy.

[0042] In some embodiments, the use comprises administering a botulinum toxin 1 day to 8 weeks before a diagnostic imaging procedure or radiation therapy using one or more radionuclides, and an anticholinergic agent 3 days, 2 days, 1 day, and the same day, and about 7 days to 30 days after the diagnostic imaging procedure or radiation therapy.

[0043] In some embodiments, the gland is an exocrine gland and / or an endocrine gland.

[0044] In some embodiments, the gland is a serous mucous gland.

[0045] In some embodiments, botulinum toxin type A acts by downregulating alpha-1 adrenergic receptors in the gland.

[0046] In some embodiments, the use is preferably carried out in a group of patients who are already undergoing antiandrogen therapy or who are undergoing antiandrogen therapy during radionuclide therapy.

[0047] Advantages of the Invention In the method of the present invention, the use of botulinum toxin and anticholinergic agents protects the salivary glands and ocular glands. This means that permanent and irreversible side effects such as dry mouth, ulcers throughout the mouth, difficulty swallowing, risk of aspiration, and dental damage are prevented, and therefore further treatment of these side effects is also prevented. This relieves the healthcare system. In the worst-case scenario, severe side effects may lead to dose adjustments or even the discontinuation of radioligand therapy. The present invention also prevents these scenarios.

[0048] In some embodiments, the method includes the use of botulinum toxin and an anticholinergic agent. This further enhances the protective effect on the glands. The combination with an anticholinergic agent results in the strengthening of the effect of botulinum toxin on the parotid and submandibular glands, and as long as each anticholinergic agent remains effective, this results in the additional protective effect on other salivary and ocular glands. This means that permanent and irreversible side effects such as dry eye, repeated eye inflammation, visual disturbances, and vision loss are prevented, in addition to dry mouth, ulcers throughout the mouth area, difficulty swallowing, the risk of aspiration, and dental damage, and therefore the further treatment of these side effects is also prevented.

[0049] The following diagram shows an example of a preferred treatment regimen. This means that other treatment regimens are also possible and are encompassed by the present invention. This means that monotherapy with botulinum toxin type A or B also represents a representative treatment regimen. [Brief explanation of the drawings]

[0050] [Figure 1] A treatment regimen for the prevention of radiation damage from the use of botulinum toxin types A or B in the therapeutic use of a radioligand (in this example, four administrations of radioligand are shown as part of the treatment procedure, every eight weeks, so administrations may occur more than four times). [Figure 2]A therapeutic regimen for the prevention of radiation damage from the use of botulinum toxin type A or B and anticholinergic agents in the diagnostic and primary therapeutic use of radioligands. [Figure 3] A treatment regimen for the prevention of radiation damage from the use of botulinum toxin type A or B and an anticholinergic agent in the therapeutic use of a radioligand (in this example, three of four administrations of the radioligand are shown as part of the treatment procedure, every 56 days). DETAILED DESCRIPTION OF THE INVENTION

[0051] Definition: "Botulinum toxin" is a general term for a family of toxins produced by the bacterium Clostridium botulinum. There are currently seven different known botulinum toxins (A, B, C, D, E, F, and G), which differ in their properties. In this application, botulinum toxin is meant to encompass all different types. Currently, there are three botulinum toxin type A preparations and one botulinum toxin type B preparation in clinical use.

[0052] "Anticholinergics" is the collective name for active ingredients that antagonize the effects of the neurotransmitter acetylcholine on effector cells, so that the initial release of acetylcholine remains unaffected.

[0053] "Prevention," also called prophylaxis, refers to a strategy for avoiding adverse events or conditions that may occur with a certain probability if nothing is done. In the context of this application, prevention means avoiding damage or side effects to human glands and other parts of the body that may occur as a result of diagnosis or treatment with a radioligand. This damage includes, for example, dry mouth, ulcers throughout the mouth area, difficulty swallowing, risk of aspiration, dental damage, dry eyes, vision impairment and (chronic) inflammation of the eyes and loss of vision.

[0054] "Radiation damage" is damage caused to an organism by ionizing radiation. The effects of ionizing radiation on an organism can consist of many physical, chemical, biochemical and biological processes. In the context of the present invention, it means damage or side effects caused by the use of radioligands for diagnosis and / or treatment. These damage or side effects include, for example, dry mouth, ulcers throughout the mouth, difficulty swallowing, risk of aspiration, dental damage, dry eyes, vision impairment and (chronic) eye inflammation, and loss of vision.

[0055] A "radionuclide" is a nuclide when it is unstable and therefore radioactive. The radionuclides of the present invention are radionuclides used for medical purposes, particularly in diagnosis or therapy, such as imaging.

[0056] A "radioligand" is a substance labeled with a radionuclide that, as a ligand, can bind to a target protein, e.g., a receptor. Such radioligands are used, e.g., in both the diagnosis and treatment of, e.g., neoplastic diseases.

[0057] A "gland" is an organ, or more specifically, an individual cell, that can synthesize and secrete a specific substance. Glands can simultaneously have serous and mucous components, which has an effect on the substance produced. Non-limiting examples of such substances are saliva or tears. Another classification of glands is the division of glands into exocrine and endocrine glands.

[0058] "Dose ratio": The amount of active pharmaceutical ingredient or drug, here the amount of botulinum toxin, intended to be administered is typically referred to as a dose. Dose ratios can be expressed as a fraction (e.g., 1 / 3) or as a ratio, such as 1:1, 1:2, etc.

[0059] "Cognitive impairment" refers to any type of memory impairment, including mild, moderate, and severe cognitive impairment. Mild cognitive impairment or mild cognitive impairment (MCI) is a disturbance in thinking skills that is beyond what is normal for a person's age and education, but does not represent a significant impairment in daily life.

[0060] "Reduced life expectancy"Reduced life expectancy is 6 to 8 months from the time of diagnosis, preferably 6 months.

[0061] "High-dose therapy" High-dose therapy is understood to mean the administration of a total of 100 to 300 units of botulinum toxin type A, particularly preferably a total of 150 units. In this case, 75 to 150 units, particularly preferably 100 units, are administered to the parotid gland, and 25 to 75 units, more preferably 50 units, are administered to the submandibular gland. High-dose botulinum toxin type A is particularly preferably administered asymmetrically (contralaterally).

[0062] "Asymmetric (contralateral) application" In the case of asymmetric (contralateral) application, botulinum toxin is injected into one gland and into a gland on the opposite side of the body. For example, botulinum toxin is applied (50 units) to the right parotid gland and the (opposite) left submandibular gland. This means that, for example, the right parotid gland and the left submandibular gland, or vice versa, can be selected for injection.

[0063] "Dementia" Dementia is a collection of symptoms of various diseases, the main feature of which is a decline in some cognitive abilities compared to a previous state. Dementia can result from various degenerative and non-degenerative diseases of the brain.

[0064] "Comorbidity" or "multimorbidity" means that a patient has another medical condition or syndrome in addition to the underlying disease, or has several different diseases at the same time.

[0065] Embodiments of the present invention The method of the present invention is suitable for a variety of applications. It is suitable for the diagnosis of diseases for which radionuclides or radioligands are used, as well as for the treatment of diseases for which radionuclides or radioligands are used. Exemplary radionuclides include: 32 P, 60 Co, 90 Sr, 90 Y, 103 Pd, 125 I, 131 I, 137 Cs, 188 Re, 192 Ir, 198 Au, 226 The diseases include neoplastic diseases such as bronchial carcinoma, such as small cell or large cell bronchial carcinoma, colon cancer, breast cancer, prostate cancer, liver cancer, pancreatic cancer, bladder cancer, skin cancer, ovarian cancer, cancer of the genitourinary tract, adrenocortical carcinoma (pheochromocytoma), brain cancer, stomach cancer, kidney cancer, uterine cancer, osteosarcoma, esophageal cancer, oropharyngeal cancer, testicular cancer, thyroid cancer, adrenocortical carcinoma, gallbladder cancer, small intestine cancer, anal cancer, pancreatic cancer, bile duct cancer, cervical cancer, uterine cancer, urethral cancer, pharyngeal cancer, osteosarcoma, Wilms' tumor, plasmacytoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, or retinoblastoma. Other diseases requiring diagnosis or treatment with a radioligand are also included.

[0066] The present invention relates to a botulinum toxin in combination with an anticholinergic drug for use in a method for preventing radiation damage to glands, where the radiation damage is caused by a radioligand. A radioligand within the meaning of this specification includes all radionuclides bound to the ligand.

[0067] In some embodiments, a botulinum toxin is used in combination with an anticholinergic agent for use in methods in which radiation damage is caused by a PSMA radioligand. A particularly preferred PSMA radioligand is PSMA-617.

[0068] In some embodiments, the botulinum toxin is 225 Ac-PSMA-617, 68 Ga-PSMA, 18 F-PSMA or 177In some embodiments, the PSMA is used in combination with an anticholinergic agent for use in the methods described above. 111 In, or bound to other diagnostically and therapeutically suitable radionuclides.

[0069] In some embodiments, the botulinum toxin is selected from the group consisting of botulinum toxin types A, B, C, D, E, F, and G. In some embodiments, botulinum toxin type A is preferred. In some embodiments, botulinum toxin type B is preferred. In further embodiments, combinations of different botulinum toxin types, such as types A and B, A and E, A and F, B and E, or B and F, are preferred. Modified, recombinant, and synthetic botulinum toxins are also included. Modified botulinum toxins include amino acid substitutions, deletions, or insertions made in the codons of a polynucleotide, which in turn encodes a modified polypeptide. Chemical modifications, such as PEGylation of a botulinum toxin or phosphorylation of amino acids, are also included. Recombinant botulinum toxins are recombinantly produced botulinum toxins; recombinant DNA technology methods for the production of such recombinant botulinum toxins are well known. A synthetic botulinum toxin is a polypeptide having a defined sequence. Synthetic botulinum toxins may represent an exact copy of a naturally occurring botulinum toxin or may be produced with a variety of modifications. For example, synthetic botulinum toxins may contain non-natural amino acids or peptide backbone modifications.

[0070] In some embodiments, the botulinum toxin comprises between 1 unit and 10,000 units, preferably between 10 units and 5,000 units, and most preferably between 20 units and 4,000 units.

[0071] In some embodiments, the botulinum toxin comprises type A between 1 unit and 1,500 units, preferably between 10 units and 1,000 units, and most preferably between 20 units and 900 units.

[0072] In some embodiments, the botulinum toxin comprises type B at 100 units to 10,000 units, preferably 250 units to 5,000 units, and most preferably 500 units to 4,000 units.

[0073] In some embodiments, the botulinum toxin is botulinum toxin type E or F.

[0074] In some embodiments, the botulinum toxin comprises between 1 unit and 10,000 units of type E or F.

[0075] In some embodiments, the anticholinergic is selected from the group consisting of tropicamide, atropine, scopolamine, glycopyrrolate, amitriptyline, clonidine, ipratropium bromide, and trihexyphenidyl. Here, scopolamine is particularly preferred. In some embodiments, the anticholinergic is administered transdermally, orally, or intravenously. Preferably, the anticholinergic is administered transdermally. Most preferably, scopolamine is administered transdermally.

[0076] In some embodiments, the botulinum toxin is botulinum toxin type B for the prevention of radiation damage to the parotid gland, submandibular gland, sublingual gland, minor salivary gland, and ocular gland, where the radiation damage is caused by a radioligand. In some embodiments, botulinum toxin type B is used in methods in which patients undergoing radionuclide diagnosis or treatment suffer from cognitive impairment. In some embodiments, botulinum toxin type B is used in methods in which patients undergoing radionuclide diagnosis or treatment suffer from cardiac arrhythmia. In a preferred embodiment, botulinum toxin type B is used in methods in which patients undergoing radionuclide diagnosis or treatment suffer from cognitive impairment and cardiac arrhythmia.

[0077] In some embodiments, the botulinum toxin is botulinum toxin type A to reduce aquaporin-mediated radionuclide uptake in submandibular gland and salivary gland cells.In some embodiments, botulinum toxin type A is used in methods in which patients undergoing radionuclide diagnosis or treatment suffer from cognitive dysfunction.In some embodiments, botulinum toxin type A is used in methods in which patients undergoing radionuclide diagnosis or treatment suffer from cardiac arrhythmia.In another embodiment, botulinum toxin type A is used in methods in which patients undergoing radionuclide diagnosis or treatment suffer from cognitive dysfunction and cardiac arrhythmia.

[0078] In one embodiment, the botulinum toxin is botulinum toxin type A, and the botulinum toxin type A is administered to the parotid and submandibular glands in a dosage ratio of 1:1, 2:1, 3:1, 4:1, or 5:1. In a particularly preferred embodiment, the botulinum toxin is botulinum toxin type A, and the botulinum toxin type A is administered in a dosage ratio of 2 / 3 in the parotid gland and 1 / 3 in the submandibular gland, in other words, a 2:1 ratio. In a particularly preferred embodiment, the botulinum toxin type A is administered in a high dose, or in other words, as a "high dose therapy." A total of 100 to 300 units of botulinum toxin type A, with 150 units being particularly preferred, are applied. 75 to 150 units, with 100 units being particularly preferred, are applied to the parotid gland, and 25 to 75 units, with 50 units being particularly preferred, are applied to the submandibular gland. High-dose botulinum toxin type A is particularly preferably applied contralaterally (asymmetrically). Botulinum toxin type A was applied asymmetrically to the right parotid gland (100 units) and the contralateral left submandibular gland (50 units). This means, for example, that the right parotid gland and the left submandibular gland, or vice versa, can be selected for injection.

[0079] In one embodiment, the botulinum toxin is botulinum toxin type B and is administered to the parotid and submandibular glands in a dosage ratio of 1:1, 2:1, 3:1, 4:1, 5:1. In a particularly preferred embodiment, the botulinum toxin is botulinum toxin type B and is administered in a dosage ratio of 2 / 3 in the parotid gland and 1 / 3 in the submandibular gland, i.e., a 2:1 ratio.

[0080] In some embodiments, the use involves administering the botulinum toxin 1 day to 16 weeks prior to imaging or radiation therapy using one or more radionuclides. In preferred embodiments, the use involves administering the botulinum toxin 1 day to 8 weeks prior to imaging or radiation therapy using one or more radionuclides. In this case, the administration time depends on the type of botulinum toxin used: Types E and F are administered 1 day to 8 weeks, more preferably 1 day to 4 weeks, even more preferably 1 day to 2 weeks, and most preferably 1 day to 7 days prior to imaging or radiation therapy using one or more radionuclides. Types A and B are administered 3 days to 12 weeks, preferably 3 days to 4 weeks, and also preferably 2 weeks to 4 weeks, most preferably 2 weeks, prior to imaging or radiation therapy using one or more radionuclides.

[0081] In some embodiments, the use involves administering an anticholinergic agent 7, 6, 5, 4, 3, 2, 1, and the same day as a diagnostic imaging procedure or radiation therapy using one or more radionuclides, and up to about 14 to 28 days after the diagnostic imaging procedure or radiation therapy. In some embodiments, the use involves administering an anticholinergic agent 7, 6, 5, 4, 3, 2, 1, and the same day as a diagnostic imaging procedure or radiation therapy using one or more radionuclides, and up to about 14 to 28 days after the diagnostic imaging procedure or radiation therapy. As mentioned above, anticholinergic agents can have various dosage forms. When the anticholinergic agent of the present invention is applied transdermally, it can be administered daily, every other day, every third day, or even every third day.

[0082] In some embodiments, the use includes administering a botulinum toxin 4 weeks before a diagnostic imaging procedure or radiation therapy using one or more radionuclides, and an anticholinergic agent 7, 6, 5, 4, 3, 2, 1 day before, and on the same day, up to 28 days after the diagnostic imaging procedure or radiation therapy. In a preferred embodiment, the use includes administering a botulinum toxin 2 weeks before a diagnostic imaging procedure or radiation therapy using one or more radionuclides, and an anticholinergic agent 7, 6, 5, 4, 3, 2, 1 day before, and on the same day, up to 28 days after the diagnostic imaging procedure or radiation therapy. As mentioned above, the anticholinergic agent may have various dosage forms. When the anticholinergic agent in the present invention is applied transdermally, it can be administered every day, every other day, every third day, or even every third day. In a preferred embodiment, patients treated with both a botulinum toxin and an anticholinergic have an average age of 50 to 75 years.

[0083] In some embodiments, the gland is an exocrine gland and / or an endocrine gland.

[0084] In some embodiments, the glands are selected from the group consisting of parotid glands, submandibular glands, sublingual glands, minor salivary glands, and ocular glands. As the list suggests, the glands may be selected individually or in any combination. Furthermore, those skilled in the art will recognize that some glands may be present on one side or both sides and may be combined accordingly. Therefore, various glands may also be selected asymmetrically (contralaterally), for example, the right parotid gland and the left submandibular gland, or vice versa. In one embodiment, the botulinum toxin may be botulinum toxin type A or type B.

[0085] In a particularly preferred embodiment, botulinum toxin type A is administered in high doses, or in other words, as "high-dose therapy." In this case, a total of 100 to 300 units of botulinum toxin type A, particularly preferably 150 units, are administered. In this embodiment, botulinum toxin type A can be administered alone ("monotherapy") or in combination with other agents, such as, for example, anticholinergics. In a particularly preferred embodiment, botulinum toxin type A is administered alone. In one embodiment, one to four glands are injected, and in a preferred embodiment, two glands are injected. 75 to 150 units, particularly preferably 100 units, are administered to the parotid gland, and 25 to 75 units, particularly preferably 50 units, are administered to the submandibular gland. High-dose botulinum toxin type A is particularly preferably administered asymmetrically (contralaterally). Botulinum toxin type A was applied asymmetrically to the right parotid gland (100 units) and the contralateral left submandibular gland (50 units). The advantage of this application is that two of the four major salivary glands are maximally protected without any side effects, and the patient still maintains sufficient saliva production through the other two glands initially during the initial radioligand administration until the two untreated glands are irreversibly damaged, which often occurs completely only with the second or subsequent radioligand administration. However, high-dose therapy of all four glands is excluded due to the risk of side effects in the form of dysphagia.

[0086] This type of selective combination of unilateral or bilateral salivary glands is particularly advantageous for patients with comorbidities and multimorbid conditions, patients over 75 years of age, patients suffering from mild cognitive impairment (MCI) or dementia, or patients with a short life expectancy. These patient groups can be freely combined and in any order. For example, a patient may be over 75 years of age, suffer from mild cognitive impairment, and require diagnosis or treatment with a radioligand for a disease. It should also be emphasized that anticholinergic drugs should ideally be avoided in these patient groups to avoid their side effects. The reduced life expectancy achieved by this method is 6 to 8 months, preferably 6 months. Treatment with higher doses but fewer injections is particularly advantageous for this group of patients. Any side effects in all patients can also be avoided by selective combination of unilateral or bilateral salivary glands.

[0087] In some embodiments, the gland is a submandibular gland.

[0088] In some embodiments, the gland is a serous mucus gland. In other embodiments, the gland is a mucus gland or a serous gland.

[0089] In some embodiments, botulinum toxin type A acts by downregulating alpha-1 adrenergic receptors in the gland, hi some embodiments, botulinum toxin also acts by downregulating alpha-1 adrenergic receptors in the gland, although other mechanisms are also effective.

[0090] In some embodiments, the use is preferably carried out in a group of patients already undergoing antiandrogen therapy. In some embodiments, the use is carried out in a group of patients not undergoing antiandrogen therapy. In further embodiments, the application is carried out in a group of patients undergoing antiandrogen therapy during radioligand diagnosis or treatment.

[0091] In some embodiments, botulinum toxin type A acts to downregulate aquaporin-mediated radionuclide uptake in the parotid and submandibular glands.

[0092] Example The present invention is further illustrated by the following non-limiting examples:

[0093] Example 1: 68 Prevention of radiation damage from the use of botulinum toxin type A and anticholinergic drugs in diagnostic use of radioligands using the example of Ga-PSMA In imaging 68 Two weeks prior to diagnostic use of Ga-PSMA, a total of 20 units to 900 units of botulinum toxin type A, depending on the particular botulinum toxin type A formulation, e.g., 150 units when using Xeomin® or BOTOX®, is applied to the involved glands, such as one or both mandibular glands and / or one or both parotid glands. 68 Three days before the imaging procedure using Ga-PSMA, additional administration of an anticholinergic drug is initiated. The anticholinergic drug, in this case scopolamine, is applied every three days in the form of one or two transdermal patches. In this case, approximately 1 mg of scopolamine is released into the systemic circulation at a fairly constant rate within 72 hours. Alternatively, the anticholinergic drug is administered orally daily (two days before the diagnostic procedure, one day before the diagnostic procedure, and the same day as the diagnostic procedure) and for up to 21 days after the diagnostic procedure. This approach also protects the sublingual gland, minor salivary glands, and ocular glands. Two weeks later (day 0), 68 Imaging with Ga-PSMA is performed, for example, to obtain follow-up images of prostate cancer patients. 68 Uptake of Ga-PSMA is significantly reduced in contrast to, for example, the brain parenchyma. This reduced uptake protects the glands and allows them to function normally, thus avoiding persistent side effects such as dry mouth, dry eyes, and similar symptoms.

[0094] Example 2: 68Prevention of radiation damage from the use of botulinum toxin type B and anticholinergic drugs in diagnostic use of radioligands using the example of Ga-PSMA In imaging 68 Two weeks prior to diagnostic use of Ga-PSMA, a total of 3,000 units of botulinum toxin type B, e.g., MYOBLOC®, is applied to the desired glands, such as one or both submandibular glands and / or one or both parotid glands. 68 Three days before the imaging procedure using Ga-PSMA, additional administration of an anticholinergic drug is initiated. The anticholinergic drug, here scopolamine, is applied every three days in the form of one or two transdermal patches. In this case, approximately 1 mg of scopolamine is released into the systemic circulation at a fairly constant rate within 72 hours. Alternatively, the anticholinergic drug is administered orally daily (two days before the diagnostic procedure, one day before the diagnostic procedure, and the same day as the diagnostic procedure) and for 14 days after the diagnostic procedure. This approach also protects the sublingual gland, minor salivary glands, and ocular glands. Two weeks later (day 0), 68 Imaging with Ga-PSMA is performed, for example, to obtain follow-up images of prostate cancer patients. 68 Uptake of Ga-PSMA is significantly reduced in contrast to, for example, the brain parenchyma. This reduced uptake protects the glands and allows them to function normally, thus avoiding persistent side effects such as dry mouth, dry eyes, and similar symptoms.

[0095] Example 3: 18 Prevention of radiation damage from the use of botulinum toxin and anticholinergic drugs in diagnostic use of radioligands using the example of F-PSMA and botulinum toxin type A In imaging 18 Two weeks prior to diagnostic use of F-PSMA, a total of 20 units to 900 units of botulinum toxin type A, depending on the particular botulinum toxin type A formulation, e.g., 150 units when using Xeomin® or BOTOX®, is applied to the desired glands, such as one or both submandibular glands and / or one or both parotid glands. 18Anticholinergic medication is additionally initiated three days before imaging using F-PSMA. The anticholinergic, here scopolamine, is applied every three days in the form of one or two transdermal patches. In this case, approximately 1 mg of scopolamine is released into the systemic circulation at a fairly constant rate within 72 hours. Alternatively, the anticholinergic is administered orally daily (two days before the diagnostic procedure, one day before the diagnostic procedure, and the same day as the diagnostic procedure) and up to 21 days after the diagnostic procedure. This approach also protects the sublingual gland, minor salivary glands, and ocular glands. Two weeks later (day 0), 18 Imaging with F-PSMA is performed, for example, to obtain follow-up images of prostate cancer patients. 18 Uptake of F-PSMA is significantly reduced in contrast to, for example, the brain parenchyma. This reduced uptake protects the glands and allows them to function normally, thus avoiding side effects such as dry mouth, dry eyes, and similar symptoms.

[0096] Example 4: 18 Prevention of radiation damage from the use of botulinum toxin and anticholinergic drugs in diagnostic use of radioligands using the example of F-PSMA and botulinum toxin type B In imaging 68 Two weeks prior to diagnostic use of Ga-PSMA, a total of 3,000 units of botulinum toxin type B, e.g., MYOBLOC®, is applied to the desired glands, such as one or both submandibular glands and / or one or both parotid glands. 18 Anticholinergic medication is additionally initiated three days before imaging using F-PSMA. The anticholinergic, here scopolamine, is applied in the form of one or two transdermal patches every three days. In this case, approximately 1 mg of scopolamine is released into the systemic circulation at a fairly constant rate within 72 hours. Alternatively, the anticholinergic is administered orally daily (two days before the diagnostic procedure, one day before the diagnostic procedure, and the same day as the diagnostic procedure) and up to 21 days after the diagnostic procedure. This approach also protects the sublingual gland, minor salivary glands, and ocular glands. Two weeks later (day 0), 18 Imaging with F-PSMA is performed, for example, to obtain follow-up images of prostate cancer patients.18 Uptake of F-PSMA is significantly reduced in contrast to, for example, the brain parenchyma. This reduced uptake protects the glands and allows them to function normally, thus avoiding side effects such as dry mouth, dry eyes, and similar symptoms.

[0097] Example 5: 225 Prevention of radiation damage from the use of botulinum toxin type A and anticholinergic drugs in the therapeutic use of radioligands using the example of Ac-PSMA-617 225 Two weeks prior to the first therapeutic use of Ac-PSMA-617, a total of 20 units to 900 units of botulinum toxin type A, depending on the particular botulinum toxin type A formulation, e.g., 150 units when using Xeomin® or BOTOX®, is applied to the desired glands, such as one or both submandibular glands and / or one or both parotid glands. 225 Three days before treatment with Ac-PSMA-617, an anticholinergic drug is additionally initiated. The anticholinergic drug, here scopolamine, is applied every three days in the form of one or two transdermal patches. In this case, approximately 1 mg of scopolamine is released into the systemic circulation at a fairly constant rate. Alternatively, the anticholinergic drug is administered orally every day (two days before the treatment procedure, one day before the treatment procedure, and the same day of the treatment procedure) and up to 21 days after the treatment procedure. This approach also protects the sublingual gland, minor salivary glands, and ocular glands. Two weeks later (day 0), to begin treatment of prostate cancer patients, 225 The first dose of Ac-PSMA-617 (100 kBq / kg) was administered. 225 The uptake of Ac-PSMA-617 is significantly reduced compared to, for example, the brain parenchyma. This reduced uptake protects the glands and allows them to function normally, thus avoiding severe, persistent, and irreversible side effects such as dry eyes, chronic severe inflammation of the eyes and eyelid margins, and swallowing disorders, which significantly limit quality of life, and associated weight loss, inflammation of the oral mucosa, dental damage, and similar symptoms. After about 8 weeks, 225Another administration of Ac-PSMA-617 (100 kBq / kg) was administered 2 weeks before another treatment procedure. 225 During further courses of treatment with Ac-PSMA-617, a total of 20 units to 900 units of botulinum toxin type A, e.g., 50 units to 150 units when using Xeomin® or BOTOX®, is administered depending on the particular botulinum toxin type A formulation and the degree of effectiveness of the previous botulinum toxin injection. 225 Anticholinergic medication will be additionally initiated 3 days before treatment with Ac-PSMA-617. This medication will be administered daily (2 days before the treatment procedure, 1 day before the treatment procedure, and the same day of the treatment procedure) and up to 21 days after the treatment procedure. Concurrently, every 8 weeks. 225 A treatment cycle with Ac-PSMA-617 is performed. 225 Approximately four cycles of treatment with Ac-PSMA-617 are expected to be required.

[0098] Example 6: 225 Prevention of radiation damage from the use of botulinum toxin type B and anticholinergic drugs in the therapeutic use of radioligands using the example of Ac-PSMA-617 225 Two weeks prior to the first therapeutic use of Ac-PSMA-617, a total of 3,000 units of botulinum toxin type B, e.g., MYOBLOC®, is applied to the desired glands, such as one or both submandibular glands and / or one or both parotid glands. 225 Anticholinergic drugs are additionally initiated three days before treatment with Ac-PSMA-617. The anticholinergic drug, here scopolamine, is applied every three days in the form of one or two transdermal patches. Approximately 1 mg of scopolamine is released into the systemic circulation at a fairly constant rate. Alternatively, the anticholinergic drug is administered orally every day (two days before the treatment procedure, one day before the treatment procedure, and the same day of the treatment procedure) and up to 21 days after the treatment procedure. This approach also protects the sublingual gland, minor salivary glands, and ocular glands. Two weeks later (day 0), to begin treatment of prostate cancer patients, 225 The first dose of Ac-PSMA-617 (100 kBq / kg) was administered.225 The uptake of Ac-PSMA-617 is significantly reduced compared to, for example, the brain parenchyma. This reduced uptake protects the glands and allows them to function normally, thus avoiding severe, persistent, and irreversible side effects such as dry eyes, chronic severe inflammation of the eyes and eyelid margins, and swallowing disorders, which significantly limit quality of life, and associated weight loss, inflammation of the oral mucosa, dental damage, and similar symptoms. After about 8 weeks, 225 Another administration of Ac-PSMA-617 (100 kBq / kg) will be administered 2 weeks before the treatment procedure. 225 During further courses of treatment with Ac-PSMA-617, a total of 1,000 units to 3,000 units of botulinum toxin type B are administered to the desired gland depending on the effectiveness of the previous botulinum toxin injection. 225 Anticholinergic medication will be additionally initiated 3 days before treatment with Ac-PSMA-617. This medication will be administered daily (2 days before the treatment procedure, 1 day before the treatment procedure, and the same day of the treatment procedure) and up to 21 days after the treatment procedure. Concurrently, every 8 weeks. 225 A treatment cycle with Ac-PSMA-617 is performed. 225 Approximately four cycles of treatment with Ac-PSMA-617 are expected to be required.

[0099] Example 7: 177 Prevention of radiation damage from the use of botulinum toxin type A and anticholinergic drugs in the therapeutic use of radioligands using the example of Lu-PSMA Depending on the particular botulinum toxin type A formulation, a total of 20 units to 900 units of botulinum toxin type A, e.g., 150 units when using Xeomin® or BOTOX®, are applied to the desired glands, such as one or both submandibular glands and / or one or both parotid glands. 177An anticholinergic drug is additionally administered three days before treatment with Lu-PSMA. The anticholinergic drug, here scopolamine, is applied every three days in the form of one or two transdermal patches. In this case, approximately 1 mg of scopolamine is released into the systemic circulation at a fairly constant rate within 72 hours. Alternatively, the anticholinergic drug is orally administered daily (two days before the treatment procedure, one day before the treatment procedure, and the same day of the treatment procedure) and up to 21 days after the treatment procedure. This approach also protects the sublingual gland, minor salivary glands, and ocular glands. Two weeks later (day 0), to begin treatment of prostate cancer patients, 177 The first dose of LU-PSMA (6GBq / kg) was administered. 177 The uptake of Lu-PSMA is significantly reduced, for example, in contrast to the brain parenchyma. This reduced uptake protects the glands and allows them to function normally, thus avoiding severe, persistent, and irreversible side effects such as dry eye, chronic severe inflammation of the eyes and eyelid margins, difficulty swallowing, and related weight loss, inflammation of the oral mucosa, dental damage, and similar symptoms, which significantly limit quality of life. After approximately 8 weeks, 177 Administer another dose of Lu-PSMA (100 kBq / kg) 1 day to 8 weeks before the treatment procedure. 177 During further courses of treatment with Lu-PSMA, a total of 20 units to 900 units of botulinum toxin type A, e.g., 50 units to 150 units when using Xeomin® or BOTOX®, are applied to the desired glands, such as one or both submandibular glands and / or one or both parotid glands, depending on the particular botulinum toxin type A formulation and the degree of effectiveness of the previous botulinum toxin injection. 177 An additional dose is administered 3 days before treatment with Lu-PSMA. This drug is administered daily (2 days before the treatment procedure, 1 day before the treatment procedure, and the same day of the treatment procedure) and up to 21 days after the treatment procedure. Concurrently, every 8 weeks 177 A treatment cycle using Lu-PSMA will be performed. 177 Approximately four treatment cycles with Lu-PSMA are expected to be required.

[0100] Example 8:177 Prevention of radiation damage from the use of botulinum toxin type B and anticholinergic drugs in the therapeutic use of radioligands using the example of Lu-PSMA 177 Two weeks prior to the first therapeutic use of Lu-PSMA, a total of 3,000 units of botulinum toxin type B, e.g., MYOBLOC®, is applied to the desired glands, such as one or both submandibular glands and / or one or both parotid glands. 177 An anticholinergic drug is additionally administered three days before treatment with LU-PSMA. The anticholinergic drug, here scopolamine, is applied every three days in the form of one or two transdermal patches. Approximately 1 mg of scopolamine is released into the systemic circulation at a fairly constant rate within 72 hours. Alternatively, the anticholinergic drug is administered orally daily (two days before the treatment procedure, one day before the treatment procedure, and the same day of the treatment procedure) and up to 21 days after the treatment procedure. This approach also protects the sublingual gland, minor salivary glands, and ocular glands. Two weeks later (day 0), to begin treatment for prostate cancer patients, 177 The first dose of Lu-PSMA (6 GBq / kg) was administered. 177 The uptake of Lu-PSMA is significantly reduced, for example, in contrast to the brain parenchyma. This reduced uptake protects the glands and allows them to function normally, thus avoiding severe, persistent, and irreversible side effects such as dry eyes, chronic severe inflammation of the eyes and eyelid margins, and swallowing disorders, which significantly limit quality of life, and associated weight loss, inflammation of the oral mucosa, dental damage, and similar symptoms. After about 8 weeks, 177 Administer another dose of Lu-PSMA (100 kBq / kg) 2 weeks prior to the treatment procedure. 177 During further courses of treatment with Lu-PSMA, a total of 1,000 to 3,000 units of botulinum toxin type B is applied to the desired glands, such as one or both submandibular glands and / or one or both parotid glands, depending on the effectiveness of the previous botulinum toxin injection. 177An additional dose is administered 3 days before treatment with Lu-PSMA. This drug is administered daily (2 days before the treatment procedure, 1 day before the treatment procedure, and the same day of the treatment procedure) and up to 21 days after the treatment procedure. Concurrently, every 8 weeks 177 A treatment cycle using Lu-PSMA will be performed. 177 Approximately four treatment cycles with Lu-PSMA are expected to be required.

[0101] Example 9: 68 Prevention of radiation damage from the use of botulinum toxin type A in diagnostic use of radioligands using the example of Ga-PSMA In imaging 68 Two weeks prior to diagnostic use of Ga-PSMA, a total of 20 units to 900 units of botulinum toxin type A is applied, depending on the specific botulinum toxin type A formulation, e.g., 150 units when using Xeomin® or BOTOX®. Botulinum toxin type A is applied in a fixed dose ratio of 2 / 3 (parotid gland) to 1 / 3 (submandibular gland), i.e., 50 units of botulinum toxin type A is applied to each of the two parotid glands and 25 units of botulinum toxin type A is applied to each of the two submandibular glands. Two weeks later (day 0), imaging is performed, e.g., to obtain follow-up images of prostate cancer patients. 68 Botulinum toxin-treated glands were used. 68 Uptake of Ga-PSMA is significantly reduced in contrast to, for example, the brain parenchyma. This reduced uptake protects the glands and allows them to function normally, thus avoiding persistent side effects such as dry mouth, dry eyes, and similar symptoms.

[0102] Example 10: 68 Prevention of radiation damage from the use of botulinum toxin type B in the therapeutic use of radioligands using the example of Ga-PSMA In imaging 68Two weeks before the diagnostic use of Ga-PSMA, a total of 3,000 units of botulinum toxin type B, such as MYOBLOC®, are applied. The botulinum toxin type B is applied in a fixed dose ratio of 2 / 3 (parotid gland) to 1 / 3 (submandibular gland). Assuming a total of 3,000 units, this means that 1,000 units of botulinum toxin type B are applied to each of the two parotid glands and 500 units of botulinum toxin type B are applied to each of the two submandibular glands. Two weeks later (day 0), imaging is performed, for example, to obtain follow-up images of prostate cancer patients. 68 Botulinum toxin-treated glands were used. 68 Uptake of Ga-PSMA is significantly reduced in contrast to, for example, the brain parenchyma. This reduced uptake protects the glands and allows them to function normally, thus avoiding persistent side effects such as dry mouth, dry eyes, and similar symptoms.

[0103] Example 11: 225 Prevention of radiation damage from the use of botulinum toxin type A in the therapeutic use of radioligands using the example of Ac-PSMA-617 In imaging 225 Two weeks prior to the therapeutic use of Ac-PSMA-617, a total of 20 units to 900 units of botulinum toxin type A, for example 150 units in the case of Xeomin® or BOTOX®, depending on the specific botulinum toxin type A formulation, are applied. Botulinum toxin type A (Xeomin® or BOTOX®) is applied in a fixed dose ratio of 2 / 3 (parotid gland) to 1 / 3 (submandibular gland), i.e., 50 units of botulinum toxin type A are applied to each of the two parotid glands and 25 units of botulinum toxin type A are applied to each of the two submandibular glands. Two weeks later (day 0), to begin treatment of prostate cancer patients, 225 The first dose of Ac-PSMA-617 (100 kBq / kg) was administered. 225The uptake of Ac-PSMA-617 is significantly reduced compared to, for example, the brain parenchyma. This reduced uptake protects the glands and allows them to function normally, thus avoiding severe, persistent, and irreversible side effects such as dry eyes, chronic severe inflammation of the eyes and eyelid margins, and swallowing difficulties, which significantly limit quality of life. The associated weight loss, inflammation of the oral mucosa, dental damage, and similar symptoms are prevented. After approximately 8 weeks, 225 Another administration of Ac-PSMA-617 (100 kBq / kg) will be administered. 225 In a further course of treatment with Ac-PSMA-617, depending on the effectiveness of the previous botulinum toxin injection, a total of 20 units to 900 units of botulinum toxin type A, e.g., 50 units to 150 units when using Xeomin® or BOTOX®, is administered two weeks prior to the treatment procedure. Botulinum toxin type A (Xeomin® or BOTOX®) is administered in a fixed dose ratio of 2 / 3 (parotid gland) to 1 / 3 (submandibular gland). At the same time, 225 Treatment cycles with Ac-PSMA-617 are performed every 8 weeks. 225 Approximately four cycles of treatment with Ac-PSMA-617 are expected to be required.

[0104] Example 12: 225 Prevention of radiation damage from the use of botulinum toxin type B in the therapeutic use of radioligands using the example of Ac-PSMA-617 In imaging 225 Two weeks before the therapeutic use of Ac-PSMA-617, a total of 3,000 units of botulinum toxin type B, such as MYOBLOC®, are applied. The botulinum toxin type B is applied in a fixed dose ratio of 2 / 3 (parotid gland) to 1 / 3 (submandibular gland). Assuming a total of 3,000 units, this means that 1,000 units of botulinum toxin type B are administered to each of the two parotid glands and 500 units of botulinum toxin type B are administered to each of the two submandibular glands. Two weeks later (day 0), to begin treatment of prostate cancer patients, 225The first dose of Ac-PSMA-617 (100 kBq / kg) was administered. 225 The uptake of Ac-PSMA-617 is significantly reduced compared to, for example, the brain parenchyma. This reduced uptake protects the glands and allows them to function normally, thus avoiding severe, persistent, and irreversible side effects such as dry eyes, chronic severe inflammation of the eyes and eyelid margins, and swallowing difficulties, which significantly limit quality of life. The associated weight loss, inflammation of the oral mucosa, dental damage, and similar symptoms are prevented. After approximately 8 weeks, 225 Another administration of Ac-PSMA-617 (100 kBq / kg) will be administered. 225 During further treatment with Ac-PSMA-617, a total of 1,000 to 3,000 units of botulinum toxin type B will be administered two weeks prior to the treatment procedure, depending on the effectiveness of the previous botulinum toxin injection. 225 Treatment cycles with Ac-PSMA-617 are performed every 8 weeks. 225 Approximately four cycles of treatment with Ac-PSMA-617 are expected to be required.

[0105] Example 13: 177 Prevention of Radiation Damage through the Use of Botulinum Toxin Type A and Anticholinergics in the Therapeutic Use of Lu-PSMA-617 177 Two weeks (14 days) before the therapeutic use of Lu-PSMA-617, a total of 120 units of botulinum toxin type A (Xeomin®) was applied to both parotid (40 units each) and submandibular (20 units each) glands.

[0106] Anticholinergic drugs, 177 An additional dose was administered three days before treatment with Lu-PSMA-617. An anticholinergic drug, here scopolamine, was applied every three days in the form of a transdermal patch. In this process, approximately 1 mg of scopolamine was released into the systemic circulation at a nearly constant rate within 72 hours. The scopolamine patch was 177Lu-PSMA-617 therapy was substituted on days 0 and 3, so patients were treated with additional scopolamine for up to 6 days after treatment, which further protected the sublingual, minor salivary, and ocular glands.

[0107] First 177 Immediately prior to Lu-PSMA-617 therapy / day 0, saliva production was normal. In this case, saliva was 5.7 grams by Saxon test, with normal values ​​being ≥ 2.75 grams of saliva production after 2 minutes of chewing. Two weeks later (day 0), 177 An initial dose of Lu-PSMA-617 (6 GBq / kg) was administered to initiate treatment in patients with prostate cancer.

[0108] Approximately 8 weeks later (56 days), 177 Another dose of Lu-PSMA-617 (6 GBq / kg) was administered. After completion of treatment (two treatment cycles on days 0 and 56) and a follow-up period of approximately 8 weeks, on day 108, normal saliva production remained unchanged. Here, the Saxon test showed a saliva volume of 5.5 grams, with a normal value of ≥ 2.75 grams of saliva produced after 2 minutes of chewing. No swallowing difficulties occurred. No dry eyes were reported.

[0109] Example 14: 177 Prevention of Radiation Damage from the Use of Botulinum Toxin Type A in the Therapeutic Use of Lu-PSMA-617 177 Two and a half weeks (18 days) before the therapeutic use of Lu-PSMA-617, a total of 150 units of botulinum toxin type A (Xeomin®) was applied asymmetrically to the right parotid gland (100 units) and the contralateral left submandibular gland (50 units).

[0110] First 177 Immediately after Lu-PSMA-617 therapy / day 0, saliva production was normal. In this case, saliva was 4.6 grams by Saxon test, with normal values ​​being ≥ 2.75 grams of saliva produced after 2 minutes of chewing. Two and a half weeks later (day 0), 177An initial dose of Lu-PSMA-617 (6 GBq / kg) was administered to initiate treatment in patients with prostate cancer.

[0111] Approximately 8 weeks later (56 days), 177 Another dose of Lu-PSMA-617 (6 GBq / kg) was administered. After completion of treatment (two treatment cycles on days 0 and 56) and a follow-up period of approximately 8 weeks, on day 116, normal saliva production remained unchanged. Here, the saliva volume in the Saxon test was 4.3 grams, with the normal value being ≥ 2.75 grams of saliva production after 2 minutes of chewing. No swallowing difficulties occurred. No dry eyes were reported.

[0112] Example 15: 177 Prevention of radiation damage by use of botulinum toxin type B in the therapeutic use of Lu-PSMA-617 177 Two weeks (13 days) before the therapeutic use of Lu-PSMA-617, a total of 6,000 units of botulinum toxin type B (Neurobloc®) was applied asymmetrically to the right parotid gland (4,000 units) and the contralateral left submandibular gland (2,000 units).

[0113] First 177 Immediately after Lu-PSMA-617 therapy / day 0, saliva production was normal. Two and a half weeks later (day 0), 177 An initial dose of Lu-PSMA-617 (6 GBq / kg) was administered to initiate treatment in patients with prostate cancer.

[0114] Approximately 8 weeks later (56 days), 177 Another dose of Lu-PSMA-617 (6 GBq / kg) was administered. After completion of treatment (two treatment cycles on days 0 and 56) and a follow-up period of approximately 8 weeks, on day 116, normal saliva production remained unchanged. No swallowing difficulties occurred. No dry eyes were reported.

[0115] Based on Examples 13-15, the following further treatments of the following four patient groups are planned: 1) Middle-aged patients 50-75 years old 2) Elderly patients >75 years old 3) Patients with multimorbidity and / or mild cognitive impairment (MCI) 4) Patients with a predicted short survival time <1.5 years

[0116] Example 16: Planned treatment of patients in Patient Group 1 (middle-aged, 50-75 years old): 225 Prevention of Radiation Damage from the Use of Botulinum Toxin Type A and Anticholinergics in the Therapeutic Use of Ac-PSMA-617 225 Three weeks (21 days) prior to therapeutic use of Ac-PSMA-617, a total of 150 units of botulinum toxin type A (Xeomin®) will be applied to both parotid (50 units each) or submandibular (25 units each) glands (i.e., a ratio of 2 / 3 parotid to 1 / 3 submandibular).

[0117] Anticholinergic drugs, 225 An additional dose is administered three days before the therapeutic use of Ac-PSMA-617. An anticholinergic drug, here scopolamine, is applied every three days in the form of a transdermal patch. In this case, approximately 1 mg of scopolamine is released into the systemic circulation at a fairly constant rate within 72 hours. The scopolamine patch is 225 Ac-PSMA-617 therapy was substituted on days 0, 3, and 6, so patients were treated with additional scopolamine for up to 9 days after treatment. This approach also protects the sublingual, minor salivary, and ocular glands.

[0118] Example 17: Planned treatment of patients in patient group 2 (age 75 years and older): 225 Prevention of radiation damage from the use of botulinum toxin type B in the therapeutic use of Ac-PSMA-617 225Two weeks (14 days) prior to therapeutic use of Ac-PSMA-617, a total of 6,000 units of botulinum toxin type B (Neurobloc®) will be applied bilaterally to the parotid (2,000 units each) or submandibular (1,000 units each) glands (i.e., a ratio of 2 / 3 parotid to 1 / 3 mandibular salivary glands).

[0119] Example 18: Planned treatment of patients in patient group 3+4 (patients with multimorbidity / MCI / short life expectancy): 225 Prevention of Radiation Damage from the Use of Botulinum Toxin Type A in the Therapeutic Use of Ac-PSMA-617 225 Three weeks (21 days) prior to therapeutic use of Ac-PSMA-617, a total of 150 units of botulinum toxin type A (Xeomin®) will be applied asymmetrically to either the right parotid gland unilaterally as high-dose monotherapy (100 units) or the left submandibular gland unilaterally (50 units) (i.e., a ratio of 2 / 3 parotid to 1 / 3 submandibular).

[0120] The term high-dose monotherapy with botulinum toxin type A (Xeomin®) refers to a single administration in each of the two glands, a previously unpublished dose range per gland, but one that is well tolerated, as confirmed by previously treated patients. High-dose glandular monotherapy should never be applied to all four glands in this patient group to avoid dysphagia. Asymmetric monotherapy with botulinum toxin type A in only one contralateral parotid and submandibular gland also helps to avoid anticholinergic-related side effects in patient group 3. The two initially unaltered, uninjected glands with initial saliva production are then administered repeatedly. 225 The Ac-PSMA-617 treatment sacrificed the complete destruction of two of the four salivary glands to reduce the duration of dry mouth during the treatment period (if they were the second, third, or fourth dose). 225until completely damaged by Ac-PSMA-617 treatment), and therefore is particularly suitable for patient group 4, who are predicted to have a short survival time from a quality of life perspective.

Claims

1. 1. A pharmaceutical composition for preventing radiation damage to salivary glands, comprising a combination of botulinum toxin type A and scopolamine, The pharmaceutical composition, wherein said radiation damage is caused by a radioligand.

2. The pharmaceutical composition of claim 1 , wherein the radiation damage is caused by a PSMA radioligand.

3. The radiation damage ２２５ Ac-PSMA, ６８ Ga-PSMA, １８ F-PSMA, or １７７ The pharmaceutical composition of claim 1 or 2, wherein the compound is selected from the group consisting of Lu-PSMA.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the botulinum toxin type A comprises 1 unit to 10,000 units.

5. The pharmaceutical composition according to any one of claims 1 to 4, comprising 1 unit to 1,500 units of botulinum toxin type A.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the scopolamine is administered transdermally, orally or intravenously.

7. The pharmaceutical composition of any one of claims 1 to 6, wherein the scopolamine is administered transdermally.

8. A pharmaceutical composition for use in a method for preventing radiation damage to salivary glands and / or lacrimal glands, comprising botulinum toxin type B, wherein the radiation damage is caused by a radioligand, and the botulinum toxin type B is administered contralaterally to a specific parotid or mandibular gland.

9. A pharmaceutical composition for use in a method for preventing radiation damage to salivary glands and / or lacrimal glands, comprising botulinum toxin type A, wherein the radiation damage is caused by a radioligand, and the botulinum toxin type A is administered contralaterally to a specific parotid or mandibular gland.

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