Method for preventing radiation damage to human glands

Abstract

The present invention relates to the field of radiation oncology. Methods according to the present invention include using botulinum toxin and an anticholinergic drug to protect the gland from radiation damage and side effects caused by a radioligand. Methods according to the present invention also include using botulinum toxin to protect the gland from radiation damage caused by the radioligand. By using the methods according to the present invention, the present invention can provide effective protection of the gland from 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 to human glands caused by radioligands. Optimized treatment protocols can further enhance the method's effectiveness. This includes both diagnostic imaging procedures and therapeutic procedures. Background of the Invention

[0003] Radioligands are substances labeled with a radionuclide that can act as ligands and bind to target proteins, such as receptors. For example, such radioligands are used in the diagnosis and treatment of tumors. A prominent example is the PSMA radionuclide in the diagnosis and treatment of prostate cancer.

[0004] PSMA (prostate-specific membrane protein) is a transmembrane protein expressed by prostate cancer cells at up to 1,000 times the level expressed by normal prostate cells. Therefore, PSMA is an ideal target protein for both the diagnosis of prostate cancer and its targeted therapy. PSMA is also expressed by other cancers, albeit at lower levels compared to prostate cancer. PSMA is also expressed by the salivary and ocular glands. Permanent damage to these glands can lead to severe dry mouth and various complications, such as tooth damage and chronic dry eyes, which can lead to vision impairment.

[0005] PSMA radionuclides are used diagnostically and therapeutically.

[0006] PSMA radioligand 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 as mentioned above, and the diagnostic PSMA radioligand can damage the ocular and salivary glands.

[0007] The PSMA radioligands used therapeutically always cause damage to the salivary glands, the severity of which varies and often persists depending on the radioligand, leading to serious health problems and reduced quality of life (dry mouth, ulcers throughout the oral area, difficulty swallowing, risk of aspiration, tooth damage, etc.). Another related problem is that PSMA radioligands are often administered repeatedly, resulting in cumulative glandular damage. PSMA radioligands also cause ocular gland damage, the severity of which varies depending on the radioligand, with health consequences: dry eyes, recurrent ocular inflammation, chronic ocular inflammation, and visual impairment. This damage caused by PSMA therapy is often irreversible. In addition, this damage and complications often mean that prostate cancer patients can no longer take advantage of life-prolonging therapies.

[0008] It is hypothesized that different PSMA radioligands have different affinities for individual salivary glands and, therefore, different toxicities. The various radionuclides are alpha, beta, or gamma emitters. For example, radionuclides are currently being used. 177 Lu (a beta emitter with a range of 2 mm) and 225Ac (an alpha emitter with a range of 50-90 μm). In the future, it is expected that even more potent PSMA radioligands that emit strongly at very short distances (50-90 μm) will be used for therapeutic purposes. There is increasing evidence that 225 Ac ratio 177 Lu causes greater damage to the salivary glands.

[0009] With the use of even more potent radioligands such as alpha emitters, the risk of glandular damage is greater.

[0010] Glands perform a variety of tasks in the human body. In particular, a distinction is made between endocrine and exocrine glands. For example, if a target is expressed not only in tumors but also in glands, such as PSMA in salivary and ocular glands, healthy glands will also be targeted.

[0011] This is where botulinum toxin can help: as part of a coordinated procedure, botulinum toxin injections can protect the glands. Botulinum toxin is the general name 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), each with different properties. The mechanisms of action of the various botulinum toxin types also differ: for example, the primary action of type A is based on the cleavage of intracellular SNAP-25, while type B primarily cleaves "vehicle associated membrane protein" (=VAMP). Botulinum toxin type B has other differences compared to type A: type B binds presynaptically to the Syt II protein, and there is also a partial presynaptic interaction between type B and tetanus toxin residues, as well as a neurotoxin-ganglioside interaction with the gangliosides GD1a, GD1b, and GM1a. Local botulinum toxin injections lead to a dose-dependent reduction in saliva production after a few days, so the onset of action is several days. The effectiveness, duration of action, and side effects depend primarily on the dose administered. Generally, the duration of action ranges from 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 fully recovers with botulinum toxin. Injections can be repeated as often as needed without damaging the organ.

[0012] The mechanism of action of botulinum toxin on the salivary glands is known and has been described in detail previously. All botulinum toxin preparations and types (AG) induce dose-dependent denervation of the glands within 1-10 days after injection (i.e., with variable timing), and thus induce a temporary, dose-dependent reduction in salivary secretion. Type B has a relatively rapid onset of action, approximately 3 days, while type A has an onset of action of approximately 6 days. The reduction in salivary secretion affects both the serous and mucous portions of the relevant salivary glands. This decrease in glandular function reduces saliva production and blood flow to the glands. Because glandular activity in the glands is permanently reduced during radionuclide-PSMA treatment, both mechanisms (alone or in combination) lead to reduced uptake of harmful radionuclides, thereby preventing irreversible damage to the glands. A key difference between botulinum toxin types B and A is that type B has a higher affinity for autonomic nerve endings than type A. This is particularly important because salivary glands (in contrast to muscles) are completely innervated by the autonomic nervous system. Therefore, the effects of botulinum toxin type B on the salivary glands are stronger and longer-lasting than those of type A. Compared to type A, local injection with type B results in greater diffusion within the body and a higher affinity for autonomic nervous structures. Therefore, when injected into distant glands, type B can have an autonomic effect on glands that have not been injected, such as the ocular glands. This can have a certain protective effect on the ocular glands by injecting botulinum toxin type B into the salivary glands. This means that salivary gland injections of botulinum toxin type B can have a certain protective function due to the higher affinity for autonomic structures and diffusion to a larger area of ​​the glands, which otherwise the botulinum toxin injection cannot directly enter, such as the sublingual salivary glands, minor salivary glands, and ocular glands. This mechanism of action applies to all glands treated with BTX, even though the degree of denervation that reduces saliva production may vary among individual glands.

[0013] Salivary glands also possess androgen receptors. Most patients with advanced prostate cancer receive anti-androgen therapy. Anti-androgens significantly increase PSMA uptake, leading to enhanced salivary gland damage by PSMA radioligands. Therefore, the present invention is particularly suitable for patients who have already received anti-androgen therapy or are currently receiving radioligand therapy, as they are particularly susceptible to glandular damage by PSMA radioligands.

[0014] Furthermore, all salivary glands express a high number of alpha-1 adrenergic receptors. Stimulation of alpha-1 receptors results in significant salivary gland activation and saliva secretion. Botulinum toxin type A leads to downregulation of alpha-1 adrenergic receptors and also reduces salivary gland activation and binding of the PSMA radioligand to salivary glands injected with botulinum toxin.

[0015] In addition, aquaporins lead to a significant increase in PSMA radioligand binding, particularly in the submandibular gland. Aquaporins are proteins that form channels in the cell membrane to facilitate the passage of water and other molecules (such as metalloids). The radionuclides are primarily metalloids. In particular, the submandibular gland expresses high levels of aquaporins (AQPs) in the apical membrane of the salivary glands, and in particular, the acinar cells of the submandibular gland. 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, injection of botulinum toxin into the submandibular gland results in a significant reduction in the uptake of radionuclides mediated by aquaporins into the cells, and thereby protects the salivary glands, particularly the submandibular gland, from permanent damage. When the effect of botulinum toxin subsides, the above-mentioned aquaporin changes completely disappear.

[0016] In particular, the frequent need for repeated radionuclide PSMA therapy (usually up to four treatments within six months) results in cumulative, permanent, and substantial damage to the salivary glands. The effects of botulinum toxin subside without consequence after approximately six to 16 weeks, and salivary gland function resumes.

[0017] Not only botulinum toxin, but also anticholinergics can protect the salivary and ocular glands. Anticholinergics (also known as parasympatholytics) inhibit the effects of acetylcholine by competitively inhibiting acetylcholine receptors. This blocks the neural stimulation that leads to increased glandular secretion. Therefore, the protective effects of botulinum toxin and anticholinergics complement and enhance each other: botulinum toxin inhibits the release of acetylcholine into the synaptic cleft (presynaptic), and anticholinergics block acetylcholine receptors (postsynaptic). Only the combined presynaptic and postsynaptic blockade of either agent (botulinum toxin and anticholinergics) can produce the best protective effect of the salivary and ocular glands during radioligand therapy. During radioligand therapy or diagnostic use of radioligands, parasympathetic nerve fibers increase saliva production, and serous saliva is primarily produced in the parotid gland, which is why systemically effective anticholinergics specifically protect this function during PSMA radionuclide therapy. This effect serves as the gland's protective effect in the present invention. Anticholinergics are dose-dependent and systemically effective and are therefore able to reach glands that botulinum toxin injections cannot directly treat, including the sublingual glands, minor salivary glands, and eye glands. Due to their anatomical location and the risk of side effects, these glands cannot be treated directly with botulinum toxin. Therefore, these glands (such as the eye glands) are protected by anticholinergics so that they are not permanently damaged by the radioligand and thus avoid eye dehydration and chronic severe inflammation of the eyes and eyelid margins that seriously limit quality of life. In addition, anticholinergics enhance the effects of botulinum toxin on, for example, the parotid and submandibular glands.

[0018] The submandibular gland, in particular, benefits from combined treatment with botulinum toxin and anticholinergics, as this gland is seromucous. This dual protection ensures that the patient's food is mechanically prepared in the mouth during chewing, allowing the food pulp to continue to glide smoothly and not hindering digestion. Furthermore, saliva contains antimicrobial components, thereby ensuring the remineralization of teeth, thus preventing tooth damage through this dual protection.

[0019] Combining botulinum toxin with an anticholinergic drug further enhances glandular protection. Combining botulinum toxin with an anticholinergic drug resulted in enhanced effects on the parotid and submandibular glands, as well as partial effects on other salivary and ocular glands, for a duration of effect not seen with the corresponding anticholinergic drug. Thus, the combination of botulinum toxin and an anticholinergic drug was most effective in improving salivary gland secretion, followed by botulinum toxin monotherapy, and then anticholinergic monotherapy.

[0020] However, not all patients benefit from the combination of botulinum toxin and anticholinergics: patients with cognitive impairment, including all degrees of cognitive impairment (from mild to moderate to severe), should not take anticholinergics because cognitive-altering effects may occur. In other words, there are contraindications. Similarly, patients with cardiac arrhythmias should not be treated with anticholinergics because they increase heart rate and conduction disturbances, and tachyarrhythmias, heart failure, and angina attacks may also occur. There are contraindications here as well. Therefore, these patient groups exposed to radioligand diagnosis or therapy are treated with botulinum toxins instead of anticholinergics. Here, botulinum toxin A exerts its effects directly in the injected gland and in adjacent glands by passive diffusion. For example, if botulinum toxin type A is injected into both sides of the submandibular gland, the sublingual gland is also protected by diffusion. Botulinum toxin type B exerts its effects directly in the injected gland and in other glands by passive diffusion, with a larger diffusion radius than botulinum toxin type A. In addition, botulinum toxin type B has a higher affinity for autonomic nervous structures, resulting in botulinum toxin type B also acting on distant glands that have not been injected with botulinum toxin type B, such as the ocular glands, sublingual glands, and minor salivary glands.

[0021] In conclusion, there is an urgent need for a method for protecting, in particular, the important ocular and salivary glands, which are not target structures for radioligand diagnostics or radioligand therapeutics, in the context of diagnosis or therapy.

[0022] The present method of the invention provides a prophylactic solution to prevent irreversible damage to the gland by diagnostic or therapeutic radioligands. Summary of the Invention

[0023] The present invention relates to a botulinum toxin in combination with an anticholinergic drug for use in a method for preventing radiation damage to a gland, wherein the radiation damage is caused by a radioligand. Furthermore, the present invention also encompasses a botulinum toxin for use in a method for preventing radiation damage to a gland, wherein the radiation damage is caused by a radioligand.

[0024] In some embodiments, botulinum toxin is used in combination with an anticholinergic drug in methods wherein the radiation damage is caused by a PSMA radioligand.

[0025] In some embodiments, botulinum toxin is used in combination with an anticholinergic drug in methods wherein radiation damage is caused by 225 Ac-PSMA-617, 68 Ga-PSMA, 18 F-PSMA or 177 Lu-PSMA caused.

[0026] In some embodiments, the botulinum toxin is selected from the group consisting of type A, type B, type C, type D, type E, type F, and type G botulinum toxin.

[0027] In some embodiments, the botulinum toxin is botulinum toxin type A.

[0028] In some embodiments, the botulinum toxin comprises between 1 and 10,000 units.

[0029] In some embodiments, the botulinum toxin comprises between 1 Unit and 1,500 Units of Type A.

[0030] In some embodiments, the botulinum toxin is botulinum toxin type B.

[0031] In some embodiments, the botulinum toxin comprises between 100 and 10,000 type B units.

[0032] In some embodiments, the botulinum toxin is botulinum toxin type E or type F.

[0033] In some embodiments, the botulinum toxin comprises between 1 and 10,000 units of type E or type F.

[0034] In some embodiments, the anticholinergic drug is selected from the group consisting of: tropicamide, atropine, scopolamine, glycopyrrolate, amitriptyline, clonidine, ipratropium bromide, and trihexyphenidyl. All other drugs that act as anticholinergics or antiparasympathetic agents are also contemplated.

[0035] In some embodiments, the anticholinergic drug is administered transdermally, orally, or intravenously.

[0036] In some embodiments, the anticholinergic drug is scopolamine, wherein the scopolamine is administered transdermally.

[0037] In some embodiments, the botulinum toxin is botulinum toxin type B and is used to prevent radiation damage to the parotid, submandibular, sublingual, minor salivary, and ocular glands, wherein the radiation damage is caused by a radioligand.

[0038] In some embodiments, the botulinum toxin is botulinum toxin type A and is used to reduce aquaporin-mediated radionuclide uptake in submandibular and salivary gland cells.

[0039] In some embodiments, the botulinum toxin is botulinum toxin type A, wherein the botulinum toxin type A is administered into the parotid gland at a dose ratio of 2 / 3 and into the submandibular gland at a dose ratio of 1 / 3.

[0040] In some embodiments, the botulinum toxin is botulinum toxin type B, wherein the botulinum toxin type B is administered to the parotid gland at a dose ratio of 2 / 3 and to the submandibular gland at a dose ratio of 1 / 3.

[0041] In some embodiments, the use comprises administering the botulinum toxin one day to eight weeks prior to an imaging procedure or radiation therapy with one or more radionuclides.

[0042] In some embodiments, the use comprises administering the anticholinergic drug three days, two days, one day, and the same day before a diagnostic imaging procedure or radiation therapy with one or more radionuclides and about 7 to 30 days after the diagnostic imaging procedure or radiation therapy.

[0043] In some embodiments, the use comprises administering a botulinum toxin one day to eight weeks prior to a diagnostic imaging procedure or prior to radiation therapy with one or more radionuclides, and administering an anticholinergic drug three days, two days, one day, and the same day prior to a diagnostic imaging procedure or prior to radiation therapy with one or more radionuclides, and about 7 to 30 days after the diagnostic imaging procedure or radiation therapy.

[0044] In some embodiments, the gland is an exocrine gland and / or an endocrine gland.

[0045] In some embodiments, the gland is a seromucous gland.

[0046] In some embodiments, botulinum toxin type A acts by downregulating alpha-1 adrenergic receptors in the gland.

[0047] In some embodiments, the use is preferably performed in a group of patients who have undergone or are undergoing anti-androgen therapy, preferably during radionuclide therapy.

[0048] Advantages of the present invention

[0049] By using botulinum toxin and anticholinergic drugs in the methods of the present invention, salivary and ocular glands are protected. This means that permanent and irreversible side effects such as dry mouth, ulcers throughout the oral cavity, difficulty swallowing, the risk of aspiration, and tooth damage are prevented, and thus, further treatment for these side effects is also avoided. This relieves the burden on the healthcare system. In the worst case, severe side effects can lead to dose adjustments or even cessation of radioligand therapy. The present invention also prevents these situations.

[0050] In some embodiments, the method comprises the use of botulinum toxin and an anticholinergic drug. This further increases the protective effect on the glands. The combination with the anticholinergic drug results in an enhanced effect of the botulinum toxin on the parotid and submandibular glands, as well as additional protective effects on other salivary and ocular glands, as long as the corresponding anticholinergic drug remains effective. This means that in addition to dry mouth, ulcers in the entire oral area, difficulty swallowing, risk of aspiration, and tooth damage, permanent and irreversible side effects such as dry eyes, recurrent eye inflammation, visual impairment, and loss of visual acuity can also be prevented, and thus further treatment of these side effects is also prevented. BRIEF DESCRIPTION OF THE DRAWINGS

[0051] The following figures illustrate examples of preferred treatment regimens. This means that other treatment regimens are possible and encompassed by the present invention. This means that monotherapy with botulinum toxin type A or type B also represents an exemplary treatment regimen.

[0052] Figure 1 : Treatment regimen for preventing radiation damage by the use of botulinum toxin type A or type B in therapeutic use of radioligands (in this example, four administrations of radioligand every eight weeks are shown as part of the treatment program, where administration may occur more than four times)

[0053] Figure 2 : A treatment regimen for preventing radiation injury by using botulinum toxin type A or type B and anticholinergic drugs during the diagnostic and initial therapeutic use of radioligands.

[0054] Figure 3 : A treatment regimen for preventing radiation damage in therapeutic use of radioligands by using botulinum toxin type A or type B and anticholinergic drugs (every 56 days, in this example, three of four radioligand administrations are shown as part of the treatment program). DETAILED DESCRIPTION

[0055] definition:

[0056] "Botulinum toxin" is the general name for a family of toxins produced by the bacterium Clostridium botulinum.

[0057] There are currently seven different known botulinum toxins (A, B, C, D, E, F, and G), each of which differs in its properties. In this application, botulinum toxin is intended to encompass all different types. Currently, there are three botulinum toxin type A preparations and one botulinum toxin type B preparation in clinical use.

[0058] "Anticholinergics" is a general term for active ingredients that antagonize the effects of the neurotransmitter acetylcholine on effector cells, wherein the initial release of acetylcholine is not affected.

[0059] "Prevention" is also called prophylaxis and refers to measures to avoid adverse events or conditions that might occur if no measures are taken. In the context of this application, prevention refers to avoiding damage to glands and other parts of the body or side effects that might occur as a result of diagnosis or treatment with radioligands. Such damage includes, for example, dry mouth, ulcers in the entire oral area, difficulty swallowing, risk of aspiration, dental damage, dry eyes, visual impairment and (chronic) eye inflammation and loss of visual acuity.

[0060] "Radiation damage" is damage caused to an organism by ionizing radiation. The effects of ionizing radiation on an organism may include a variety of physical, chemical, biochemical, and biological processes. In the context of the present invention, it refers to 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, visual impairment and (chronic) eye inflammation, and loss of visual acuity.

[0061] A "radionuclide" is a nuclide that is unstable and therefore radioactive. The radionuclides of the present invention are radionuclides that are used for medical purposes, in particular for diagnostics such as imaging procedures or for therapy.

[0062] A "radioactive ligand" is a substance labeled with a radionuclide that can bind to a target protein (eg, a receptor) as a ligand. Such radioactive ligands are used, for example, in the diagnosis and treatment of tumor diseases.

[0063] A "gland" is an organ, and by extension, a single cell, that synthesizes and secretes specific substances. Glands can have both serous and mucous parts, which influence the substances produced. Non-limiting examples of such substances are saliva or tears. Another classification of glands is to divide them into exocrine and endocrine glands.

[0064] The amount of a pharmaceutical active ingredient or drug (here, the amount of botulinum toxin) to be administered is often referred to as a "dose ratio." A dose ratio can be expressed as a fraction (e.g., 1 / 3) or a ratio such as 1:1, 1:2, etc.

[0065] "Cognitive impairment" is any type of memory impairment and includes mild, moderate, and severe cognitive impairment. Mild cognitive impairment or mild cognitive impairment (MCI) is an impairment in thinking ability that is beyond normal for a person's age and education, but does not represent a serious disability in daily life.

[0066] "Reduced life expectancy"Reduced life expectancy is between 6 and 18 months, preferably 6 months from diagnosis.

[0067] "High-dose therapy" is understood to mean the administration of a total of between 100 and 300 units of botulinum toxin type A, particularly preferably a total of 150 units of botulinum toxin type A. In this case, between 75 and 150 units, particularly preferably 100 units, are administered to the parotid gland, and between 25 and 75 units, more preferably 50 units, are administered to the submandibular gland. The high-dose botulinum toxin type A is particularly preferably administered asymmetrically (contralaterally).

[0068] "Asymmetric (contralateral) administration" In the case of asymmetric (contralateral) administration, botulinum toxin is injected into a gland on the opposite side of the body. For example, botulinum toxin is administered to the right parotid gland and the (contralateral) left submandibular gland (50 units). This means, for example, that the right parotid gland and the left submandibular gland can be injected, or vice versa.

[0069] Dementia is a collection of symptoms from various disorders characterized by a decline in several cognitive abilities compared to earlier states. Dementia can be caused by a variety of degenerative and nondegenerative diseases of the brain.

[0070] "Comorbidity" or "multimorbidity" means that a patient suffers from another pathology or syndrome in addition to the underlying disease, or suffers from several different diseases at the same time.

[0071] Embodiments of the present invention

[0072] The method of the present invention is suitable for a variety of uses. It is suitable for diagnosis of disease, for which radionuclides or radioligands are used, and for treatment of disease, 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 Ra. Diseases include tumor diseases such as bronchial cancer (such as small cell or large cell bronchial cancer), colon cancer, breast cancer, prostate cancer, liver cancer, pancreatic cancer, bladder cancer, skin cancer, ovarian cancer, genitourinary tract cancer, adrenocortical cancer (pheochromocytoma), brain cancer, stomach cancer, kidney cancer, uterine cancer, bone cancer, esophageal cancer, oropharyngeal cancer, testicular cancer, thyroid cancer, adrenocortical cancer, gallbladder cancer, small intestine cancer, anal cancer, pancreatic cancer, bile duct cancer, cervical cancer, uterine body cancer, urethra cancer, laryngeal cancer, bone cancer, Wilms' tumor, plasma cell tumor, Hodgkin's lymphoma, non-Hodgkin's lymphoma or retinoblastoma. Other diseases that require diagnosis or treatment by radioligands are also included.

[0073] The present invention relates to a botulinum toxin in combination with an anticholinergic drug for use in a method for preventing radiation damage to a gland, wherein the radiation damage is caused by a radioligand. Radioligands within the meaning of the present invention include all radionuclides coupled to a ligand.

[0074] In some embodiments, botulinum toxin is used in combination with an anticholinergic drug in methods wherein the radiation damage is caused by a PSMA radioligand. A particularly preferred PSMA radioligand is PSMA-617.

[0075] In some embodiments, botulinum toxin is used in combination with an anticholinergic drug in methods wherein radiation damage is caused by 225 Ac-PSMA-617, 68 Ga-PSMA, 18 F-PSMA or 177 In some embodiments, PSMA is combined with other diagnostically or therapeutically suitable radionuclides such as 111 In coupling.

[0076] 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 other embodiments, combinations of different botulinum toxin types are preferred, such as types A and B, A and E, A and F, B and E, and B and F. Modified, recombinant, and synthetic botulinum toxins are also included. Modified botulinum toxins include amino acid substitutions, deletions, or insertions in the codons of a polynucleotide that, in turn, encodes a modified polypeptide. Chemical modifications, such as pegylation of botulinum toxins or phosphorylation of amino acids, are also included. Recombinant botulinum toxins are recombinantly produced botulinum toxins; recombinant DNA technology methods for producing such recombinant botulinum toxins are well known. Synthetic botulinum toxins are polypeptides with defined sequences. Synthetic botulinum toxins may represent exact copies of naturally occurring botulinum toxins or may be produced with various modifications. For example, synthetic botulinum toxins may contain unnatural amino acids or modifications to the peptide backbone.

[0077] In some embodiments, the botulinum toxin comprises between 1 and 10,000 units, preferably between 10 and 5,000 units, and most preferably between 20 and 4,000 units.

[0078] In some embodiments, the botulinum toxin comprises between 1 and 1,500 units of type A, preferably between 10 and 1,000 units, and most preferably between 20 and 900 units.

[0079] In some embodiments, the botulinum toxin comprises between 100 and 10,000 units, preferably between 250 and 5,000 units, and most preferably between 500 and 4,000 units of type B.

[0080] In some embodiments, the botulinum toxin is botulinum toxin type E or type F.

[0081] In some embodiments, the botulinum toxin comprises between 1 Unit and 10,000 Units of type E or type F.

[0082] In some embodiments, the anticholinergic drug is selected from the group consisting of tropicamide, atropine, scopolamine, glycopyrrolate, amitriptyline, clonidine, ipratropium bromide, and trihexyphenidyl. Scopolamine is particularly preferred. In some embodiments, the anticholinergic drug is administered transdermally, orally, or intravenously. Preferably, the anticholinergic drug is administered transdermally. Most preferably, scopolamine is administered transdermally.

[0083] In some embodiments, the botulinum toxin is botulinum toxin type B and is used to prevent radiation damage to the parotid, submandibular, sublingual, minor salivary, and ocular glands, wherein the radiation damage is caused by a radioligand. In some embodiments, botulinum toxin type B is used in methods wherein a patient undergoing radionuclide diagnosis or therapy suffers from cognitive impairment. In some embodiments, botulinum toxin type B is used in methods wherein a patient undergoing radionuclide diagnosis or therapy suffers from cardiac arrhythmias. In preferred embodiments, botulinum toxin type B is used in methods wherein a patient undergoing radionuclide diagnosis or therapy suffers from both cognitive impairment and cardiac arrhythmias.

[0084] In some embodiments, the botulinum toxin is botulinum toxin type A and is used to reduce aquaporin-mediated radionuclide uptake in submandibular and salivary gland cells. In some embodiments, botulinum toxin type A is used in a method wherein the patient undergoing radionuclide diagnosis or therapy suffers from cognitive impairment. In some embodiments, botulinum toxin type A is used in a method wherein the patient undergoing radionuclide diagnosis or therapy suffers from a cardiac arrhythmia. In another embodiment, botulinum toxin type A is used in a method wherein the patient undergoing radionuclide diagnosis or therapy suffers from both cognitive impairment and a cardiac arrhythmia.

[0085] In one embodiment, the botulinum toxin is botulinum toxin type A, wherein the botulinum toxin type A is administered to the parotid and submandibular glands at a dose 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, wherein the botulinum toxin type A is administered to the parotid glands at a dose ratio of 2 / 3 and to the submandibular glands at a dose ratio of 1 / 3, in other words, at a ratio of 2:1. 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 between 100 and 300 units of botulinum toxin type A is administered, particularly preferably 150 units of botulinum toxin type A. Between 75 and 150 units, particularly preferably 100 units, are administered to the parotid glands, and between 25 and 75 units, particularly preferably 50 units, are administered to the submandibular glands. The high-dose botulinum toxin type A is particularly preferably administered contralaterally (asymmetrically). Botulinum toxin type A is applied asymmetrically to the right parotid gland (100 units) and to the contralateral left submandibular gland (50 units). This means, for example, that the right parotid gland and the left submandibular gland can be injected, or vice versa.

[0086] In one embodiment, the botulinum toxin is botulinum toxin type B, wherein the botulinum toxin type B is administered to the parotid gland and the submandibular gland at a dose 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, wherein the botulinum toxin type B is administered to the parotid gland at a dose ratio of 2 / 3 and to the submandibular gland at a dose ratio of 1 / 3, i.e., at a ratio of 2: 1.

[0087] In some embodiments, the use comprises administering the botulinum toxin one day to sixteen weeks prior to an imaging procedure or radiation therapy with one or more radionuclides. In a preferred embodiment, the use comprises administering the botulinum toxin one day to eight weeks prior to an imaging procedure or radiation therapy with one or more radionuclides. In this case, the timing of administration depends on the type of botulinum toxin used: Type E and Type F are administered one day to eight weeks prior to the imaging procedure or radiation therapy, more preferably one day to four weeks prior to the imaging procedure or radiation therapy with one or more radionuclides, even more preferably one day to two weeks prior to the imaging procedure or radiation therapy with one or more radionuclides, and most preferably one day to seven days prior to the imaging procedure or radiation therapy. Type A and Type B are administered three days to twelve weeks prior to the imaging procedure or radiation therapy, preferably three days to four weeks prior to the imaging procedure or radiation therapy with one or more radionuclides, further preferably between two and four weeks prior to the imaging procedure or radiation therapy, and most preferably two weeks prior to the imaging procedure or radiation therapy.

[0088] In some embodiments, the use comprises administering the anticholinergic drug seven, six, five, four, three, two, one, and the same day prior to a diagnostic imaging procedure or prior to radiation therapy with one or more radionuclides, and up to about 14 to 28 days after the diagnostic imaging procedure or after radiation therapy. In some embodiments, the use comprises administering the anticholinergic drug seven, six, five, four, three, two, one, and the same day prior to a diagnostic imaging procedure or prior to radiation therapy with one or more radionuclides, and up to about 14 to 28 days after the diagnostic imaging procedure or after radiation therapy. As previously described, the anticholinergic drug can have a variety of dosage forms. If the anticholinergic drug of the present invention is administered transdermally, it can be administered every day, every other day, every three days, or even every four days.

[0089] In some embodiments, the use comprises administering botulinum toxin four weeks prior to a diagnostic imaging procedure or prior to radiation therapy with one or more radionuclides, and administering the anticholinergic drug seven, six, five, four, three, two, one, and the same day prior to the diagnostic imaging procedure or prior to radiation therapy with one or more radionuclides, and up to 28 days after the diagnostic imaging procedure or after radiation therapy. In a preferred embodiment, the use comprises administering botulinum toxin two weeks prior to a diagnostic imaging procedure or prior to radiation therapy with one or more radionuclides, and administering the anticholinergic drug seven, six, five, four, three, two, one, and the same day prior to the diagnostic imaging procedure or prior to radiation therapy with one or more radionuclides, and up to 28 days after the diagnostic imaging procedure or after radiation therapy. As previously mentioned, the anticholinergic drug can have a variety of dosage forms. If the anticholinergic drug of the present invention is administered transdermally, it can be administered every day, every other day, every three days, or even every four days. In a preferred embodiment, the average age of patients treated with both botulinum toxin and the anticholinergic drug is between 50 and 75 years old.

[0090] In some embodiments, the gland is an exocrine gland and / or an endocrine gland.

[0091] In some embodiments, the gland is selected from the group consisting of the parotid gland, submandibular gland, sublingual gland, minor salivary gland, and ocular gland. As shown in the list, the glands can be selected individually or in any combination. In addition, those skilled in the art will appreciate that some glands are present on one side or both sides and can be combined accordingly. Thus, various glands can also be selected, for example asymmetrically (contralaterally), i.e., for example, the right parotid gland and the left submandibular gland can be selected, or vice versa. In one embodiment, the botulinum toxin can be botulinum toxin type A or type B.

[0092] In a particularly preferred embodiment, botulinum toxin type A is administered in high doses, or in other words, as a "high-dose therapy". In this case, a total of between 100 and 300 units of botulinum toxin type A is applied, particularly preferably 150 units of botulinum toxin type A. In this embodiment, botulinum toxin type A can be administered alone (monotherapy) or in combination with other agents, such as anticholinergics. In a particularly preferred embodiment, botulinum toxin type A is applied alone. In one embodiment, between one and four glands are injected, and in a preferred embodiment, two glands are injected. Between 75 and 150 units, particularly preferably 100 units, are applied to the parotid gland, and between 25 and 75 units, particularly preferably 50 units are applied to the submandibular gland. High-dose botulinum toxin type A is particularly preferably applied asymmetrically (contralaterally). Botulinum toxin type A is applied asymmetrically (100 units) to the right parotid gland and to 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 during the initial radioligand administration, the patient initially still maintains adequate saliva production through the other two glands until the two untreated glands are irreversibly damaged, which usually 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.

[0093] This type of selection and combination of salivary glands on one or both sides is particularly beneficial for patients with comorbidities and multiple diseases, patients aged >75 years, patients with mild cognitive impairment (MCI) or dementia, or patients with a shortened life expectancy. These patient groups can be freely combined and permuted. For example, the patient may be >75 years old, suffer from mild cognitive impairment, and require the use of radioligands for diagnosis or treatment due to the disease. It should also be emphasized that in these patient groups, anticholinergic drugs should ideally be avoided to avoid anticholinergic side effects. The life expectancy shortened according to the present invention is six to eighteen months, preferably six months. Despite the higher dosage, the treatment with fewer injections is particularly beneficial for this group of patients. By selecting and combining the salivary glands on one or both sides, any side effects can also be avoided for all patients.

[0094] In some embodiments, the gland is the submandibular gland.

[0095] In some embodiments, the gland is a seromucous gland. In other embodiments, the gland is a mucous gland or a serous gland.

[0096] In some embodiments, botulinum toxin type A acts by downregulating alpha-1 adrenergic receptors in the gland. In some embodiments, botulinum toxin also acts by downregulating alpha-1 adrenergic receptors in the gland, although other mechanisms are also effective.

[0097] In some embodiments, it is preferred to use it in a group of patients who have already been treated with anti-androgen therapy. In some embodiments, it is used in a group of patients who have not yet been treated with anti-androgen therapy. In other embodiments, it is used in a group of patients who are undergoing anti-androgen therapy during radioligand diagnosis or treatment.

[0098] In some embodiments, botulinum toxin type A acts to downregulate aquaporin-mediated radionuclide uptake in the parotid and submandibular glands.

[0099] Example:

[0100] The present invention is described in more detail by the following non-limiting examples.

[0101] Example 1: Use 68 An example of Ga-PSMA is the use of radioligands in diagnostic applications using botulinum toxin type A. Bacillary toxins and anticholinergic drugs for preventing radiation injury

[0102] During the imaging procedure 68 Two weeks before the diagnostic use of Ga-PSMA, a total of between 20 and 900 units of botulinum toxin type A, depending on the specific botulinum toxin type A preparation, should be administered. or For example, 150 units are applied to the relevant glands, such as one or both mandibular glands and / or one or both parotid glands. 68 Three days before the imaging procedure of Ga-PSMA, an additional administration of an anticholinergic drug was started. The anticholinergic drug (in this case, scopolamine) was administered in the form of one to two transdermal patches every three days. In this case, about 1 mg of scopolamine was released into the systemic circulation at an almost constant rate over 72 hours. Alternatively, the anticholinergic drug was administered orally daily (two days before the diagnostic procedure, one day before the diagnostic procedure, on the day of the diagnostic procedure) and for up to 21 days after the diagnostic procedure. This approach also protects the sublingual glands, minor salivary glands, and ocular glands. Two weeks later (Day 0), the use 68 Imaging procedures using Ga-PSMA, for example, to obtain follow-up images of patients with prostate cancer. In contrast to, for example, the brain parenchyma, the glands treated with botulinum toxin 68 The uptake of Ga-PSMA is significantly reduced. This reduced uptake protects the corresponding glands and allows them to function normally, thus avoiding persistent side effects such as dry mouth, dry eyes, and similar symptoms.

[0103] Example 2: Use 68 An example of Ga-PSMA is the use of radioligands in diagnostic applications using botulinum toxin type B. Bacillary toxins and anticholinergic drugs for preventing radiation injury

[0104] During the imaging procedure 68 Two weeks before the diagnostic use of Ga-PSMA, a total of 3,000 units of botulinum toxin type B (eg ) is applied to the desired glands, such as the submandibular glands on one or both sides, and / or to the parotid glands on one or both sides. 68 Three days before the imaging procedure of Ga-PSMA, an additional administration of an anticholinergic drug was started. The anticholinergic drug (here scopolamine) was applied in the form of one to two transdermal patches every three days. In this case, about 1 mg of scopolamine was released into the systemic circulation at an almost constant rate over 72 hours. Alternatively, the anticholinergic drug was administered orally every day (two days before the diagnostic procedure, one day before the diagnostic procedure, on the day of the diagnostic procedure) and 14 days after the diagnostic procedure. This method also protects the sublingual glands, minor salivary glands and eye glands. Two weeks later (day 0), the use 68 Imaging procedures using Ga-PSMA, for example, to obtain follow-up images of patients with prostate cancer. 68 The uptake of Ga-PSMA is significantly reduced. This reduced uptake protects the corresponding glands and allows them to function normally, thus avoiding persistent side effects such as dry mouth, dry eyes, and similar symptoms.

[0105] Example 3: Use 18 Examples of F-PSMA and botulinum toxin type A in diagnostic uses of radioligands Prevention of radiation injury through the use of botulinum toxin and anticholinergic drugs

[0106] During the imaging procedure 18 Two weeks before the diagnostic use of F-PSMA, a total of between 20 and 900 units of botulinum toxin type A, depending on the specific botulinum toxin type A preparation, should be administered. or For example, 150 units are applied to the desired glands, such as one or both submandibular glands and / or one or both parotid glands. 18 Three days before the imaging procedure of F-PSMA, an anticholinergic drug is also started. The anticholinergic drug (here scopolamine) is applied in the form of one to two transdermal patches every three days. In this case, about 1 mg of scopolamine is released into the systemic circulation at an almost constant rate over 72 hours. Alternatively, the anticholinergic drug is administered orally every day (two days before the diagnostic procedure, one day before the diagnostic procedure, on the day of the diagnostic procedure) and for up to 21 days after the diagnostic procedure. This method also protects the sublingual glands, minor salivary glands and eye glands. Two weeks later (day 0), the anticholinergic drug is used 18 Imaging procedures using F-PSMA, for example, to obtain follow-up images of patients with prostate cancer. In the treated gland compared to, for example, the brain parenchyma 18 The uptake of F-PSMA is significantly reduced. This reduced uptake protects the corresponding glands and allows them to function normally, thus avoiding side effects such as dry mouth, dry eyes, and similar symptoms.

[0107] Example 4: Use 18 Examples of F-PSMA and botulinum toxin type B in diagnostic uses of radioligands Prevention of radiation injury through the use of botulinum toxin and anticholinergic drugs

[0108] During the imaging procedure 68 Two weeks before the diagnostic use of Ga-PSMA, a total of 3,000 units of botulinum toxin type B (eg ) is applied to the desired glands, such as the submandibular glands on one or both sides, and / or to the parotid glands on one or both sides. 18 Three days before the imaging procedure of F-PSMA, anticholinergic drugs are also started. Anticholinergic drugs (here scopolamine) are applied in the form of one to two transdermal patches every three days. In this case, about 1 mg of scopolamine is released into the systemic circulation at an almost constant rate over 72 hours. Alternatively, anticholinergic drugs are administered orally every day (two days before the diagnostic procedure, one day before the diagnostic procedure, on the day of the diagnostic procedure) and for up to 21 days after the diagnostic procedure. This method also protects the sublingual glands, minor salivary glands and eye glands. Two weeks later (day 0), the use 18 Imaging procedures using F-PSMA, for example, to obtain follow-up images of patients with prostate cancer. In the treated gland compared to, for example, the brain parenchyma 18 The uptake of F-PSMA is significantly reduced. This reduced uptake protects the corresponding glands and allows them to function normally, thus avoiding side effects such as dry mouth, dry eyes, and similar symptoms.

[0109] Example 5: Use 225 In the case of Ac-PSMA-617, therapeutic use of radioligands is achieved by using A-type Botulinum toxin and anticholinergic drugs for preventing radiation injury

[0110] exist 225 Two weeks before the first therapeutic use of Ac-PSMA-617, a total of between 20 and 900 units of botulinum toxin type A, depending on the specific botulinum toxin type A preparation, should be administered. or For example, 150 units are applied to the desired glands, such as one or both submandibular glands and / or one or both parotid glands. 225 Three days before the treatment with Ac-PSMA-617, an anticholinergic drug is also started. The anticholinergic drug (here scopolamine) is applied every three days in the form of one to two transdermal patches. In this case, about 1 mg of scopolamine is released into the systemic circulation at an almost constant rate. Alternatively, the anticholinergic drug is administered orally every day (two days before the treatment procedure, one day before the treatment procedure, on the day of the treatment procedure) and for up to 21 days after the treatment procedure. This method also protects the sublingual glands, minor salivary glands and eye glands. Two weeks later (day 0), the anticholinergic drug is administered orally. 225 First administration of Ac-PSMA-617 (100 kBq / kg) to initiate treatment of prostate cancer patients. In the treated gland, compared to, for example, the brain parenchyma 225The uptake of Ac-PSMA-617 was significantly reduced. This reduced uptake protected the corresponding glands and allowed them to function normally, thus avoiding serious, persistent and irreversible side effects such as eye dehydration and chronic severe inflammation of the eyes and eyelid margins that severely limited the quality of life, and preventing dysphagia, associated weight loss and inflammation of the oral mucosa, as well as tooth damage and similar symptoms. After about eight weeks, 225 Another administration of Ac-PSMA-617 (100 kBq / kg) was performed two weeks before the other treatment procedure. 225 During further treatment with Ac-PSMA-617, a total of between 20 and 900 units of botulinum toxin type A is administered, depending on the specific botulinum toxin type A preparation and the degree of effectiveness of previous botulinum toxin injections. or For example, it is between 50 and 150 units. 225 Anticholinergic medication was also started three days prior to the treatment with Ac-PSMA-617. This dose was administered daily (two days prior to the treatment procedure, one day prior to the treatment procedure, on the day of the treatment procedure) and for up to 21 days after the treatment procedure. 225 Treatment cycles of Ac-PSMA-617 are administered every eight weeks. Approximately four cycles of Ac-PSMA-617 are expected to be required. 225 Ac-PSMA-617 therapy.

[0111] Example 6: Use 225 In the case of Ac-PSMA-617, therapeutic use of radioligands is achieved by using type B Botulinum toxin and anticholinergic drugs for preventing radiation injury

[0112] exist 225 Two weeks before the first therapeutic use of Ac-PSMA-617, a total of 3,000 units of botulinum toxin type B (e.g. ) is applied to the desired glands, such as one or both submandibular glands, and / or one or both parotid glands. 225 Three days before the treatment with Ac-PSMA-617, an anticholinergic drug is additionally started. The anticholinergic drug (here scopolamine) is applied every three days in the form of one to two transdermal patches. Approximately 1 mg of scopolamine is released into the systemic circulation at an almost constant rate. Alternatively, the anticholinergic drug is administered orally daily (two days before the treatment procedure, one day before the treatment procedure, on the day of the treatment procedure) and for up to 21 days after the treatment procedure. This approach additionally protects the sublingual glands, minor salivary glands, and ocular glands. Two weeks later (Day 0), the 225 First administration of Ac-PSMA-617 (100 kBq / kg) to initiate treatment of prostate cancer patients. In the treated gland, compared to, for example, the brain parenchyma 225The uptake of Ac-PSMA-617 was significantly reduced. This reduced uptake protected the corresponding glands and allowed them to function normally, thus avoiding serious, persistent and irreversible side effects such as eye dehydration that severely limited the quality of life and chronic severe inflammation of the eyes and eyelid margins, and preventing dysphagia, associated weight loss and inflammation of the oral mucosa, as well as tooth damage and similar symptoms. After about eight weeks, 225 Another administration of Ac-PSMA-617 (100 kBq / kg) was performed two weeks before the treatment procedure. 225 During further treatment with Ac-PSMA-617, a total of between 1,000 and 3,000 units of botulinum toxin type B is injected into the desired glands, depending on the effectiveness of the previous botulinum toxin injections. 225 Anticholinergic medication was also started three days prior to the treatment with Ac-PSMA-617. This dose was administered daily (two days prior to the treatment procedure, one day prior to the treatment procedure, on the day of the treatment procedure) and for up to 21 days after the treatment procedure. 225 Treatment cycles of Ac-PSMA-617 are administered every eight weeks. Approximately four cycles of Ac-PSMA-617 are expected to be required. 225 Ac-PSMA-617 therapy.

[0113] Example 7: Use 177 Examples of Lu-PSMA in therapeutic use of radioligands include the use of botulinum toxin type A. Bacillary toxins and anticholinergic drugs for preventing radiation injury

[0114] Depending on the specific botulinum toxin type A preparation, a total of between 20 and 900 units of botulinum toxin type A is used. or For example, 150 units are applied to the desired glands, such as one or both submandibular glands and / or one or both parotid glands. 177 Three days before the Lu-PSMA treatment, an anticholinergic drug is additionally administered. The anticholinergic drug (here scopolamine) is applied every three days in the form of one to two transdermal patches. In this case, about 1 mg of scopolamine is released into the systemic circulation at an almost constant rate over 72 hours. Alternatively, the anticholinergic drug is orally administered daily (two days before the treatment procedure, one day before the treatment procedure, on the day of the treatment procedure) and for up to 21 days after the treatment procedure. This method also protects the sublingual glands, minor salivary glands and eye glands. Two weeks later (Day 0), a 177 First administration of LU-PSMA (6 GBq / kg) to start treatment of prostate cancer patients. In the treated gland compared to, for example, the brain parenchyma 177The uptake of Lu-PSMA was significantly reduced. This reduced uptake protected the corresponding glands and enabled them to function normally, thus avoiding serious, persistent and irreversible side effects such as dry eyes that severely limited the quality of life and chronic severe inflammation of the eyes and eyelid margins, and preventing dysphagia, associated weight loss, inflammation of the oral mucosa, and tooth damage and similar symptoms. After about eight weeks, 177 Another administration of Lu-PSMA (100 kBq / kg) was performed one day to eight weeks before the treatment procedure. 177 During further Lu-PSMA treatment, depending on the specific botulinum toxin type A preparation and the degree of effectiveness of previous botulinum toxin injections, a total of between 20 and 900 units of botulinum toxin type A is administered. or For example, between 50 and 150 units are applied to the desired glands, such as one or both submandibular glands and / or one or both parotid glands. 177 An anticholinergic drug was additionally administered three days prior to Lu-PSMA therapy. This dose was administered daily (two days prior to the procedure, one day prior to the procedure, and on the day of the procedure) and for up to 21 days after the procedure. 177 Lu-PSMA treatment cycles are expected to take approximately four 177 Lu-PSMA treatment cycles.

[0115] Example 8: Use 177 Examples of Lu-PSMA in therapeutic use of radioligands include the use of botulinum toxin type B. Bacillary toxins and anticholinergic drugs for preventing radiation injury

[0116] exist 177 Two weeks before the first therapeutic use of Lu-PSMA, a total of 3,000 units of botulinum toxin type B (e.g. ) is applied to the desired glands, such as one or both submandibular glands, and / or one or both parotid glands. 177 Three days before the LU-PSMA treatment, an anticholinergic drug is additionally administered. The anticholinergic drug (here, scopolamine) is applied every three days in the form of one to two transdermal patches. Approximately 1 mg of scopolamine is released into the systemic circulation at an almost constant rate over 72 hours. Alternatively, the anticholinergic drug is administered orally daily (two days before the treatment procedure, one day before the treatment procedure, on the day of the treatment procedure) and for up to 21 days after the treatment procedure. This approach additionally protects the sublingual glands, minor salivary glands, and ocular glands. Two weeks later (Day 0), a 177 First administration of Lu-PSMA (6 GBq / kg) to start treatment of prostate cancer patients. In the treated gland compared to, for example, the brain parenchyma 177The uptake of Lu-PSMA was significantly reduced. This reduced uptake protected the corresponding glands and allowed them to function normally, thus avoiding serious, persistent and irreversible side effects such as eye dehydration and chronic severe inflammation of the eyes and eyelid margins that severely limited the quality of life, and preventing dysphagia, the associated weight loss and inflammation of the oral mucosa, as well as tooth damage and similar symptoms. About eight weeks later, another dose of 177 Lu-PMSA (100kBq / kg). Two weeks after the treatment, 177 During further Lu-PSMA treatment, a total of between 1,000 and 3,000 units of botulinum toxin type B is administered 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 injections. 177 An anticholinergic drug was additionally administered three days prior to Lu-PSMA therapy. This dose was administered daily (two days prior to the procedure, one day prior to the procedure, and on the day of the procedure) and for up to 21 days after the procedure. 177 Lu-PSMA treatment cycles are expected to take approximately four 177 Lu-PSMA treatment cycles.

[0117] Example 9: Use 68 An example of Ga-PSMA is the use of radioligands in diagnostic applications using botulinum toxin type A. Bacitracin to prevent radiation damage

[0118] During the imaging procedure 68 Two weeks prior to the diagnostic use of Ga-PSMA, a total of between 20 and 900 units of botulinum toxin type A was administered, depending on the specific botulinum toxin type A preparation. or For example, a total of 150 units is used. 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 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), the 68 Ga-PSMA is used in imaging procedures, for example, to obtain follow-up images of patients with prostate cancer. 68 The uptake of Ga-PSMA is significantly reduced. This reduced uptake protects the corresponding glands and allows them to function normally, thus avoiding persistent side effects such as dry mouth, dry eyes, and similar symptoms.

[0119] Example 10: Use 68 An example of Ga-PSMA is the use of radioligands in diagnostic applications using botulinum toxin type B. Bacitracin to prevent radiation damage

[0120] During the imaging procedure 68Two weeks before the diagnostic use of Ga-PSMA, a total of 3,000 units of botulinum toxin type B was administered, e.g. Botulinum toxin type B was administered in a fixed dose ratio of 2 / 3 (parotid gland) to 1 / 3 (submandibular gland). Assuming a total of 3,000 units, this means 1,000 units of botulinum toxin type B was administered to each of the two parotid glands and 500 units of botulinum toxin type B was administered to each of the two submandibular glands. Two weeks later (Day 0), the 68 Ga-PSMA is used in imaging procedures, for example, to obtain follow-up images of patients with prostate cancer. 68 The uptake of Ga-PSMA is significantly reduced. This reduced uptake protects the corresponding glands and allows them to function normally, thus avoiding persistent side effects such as dry mouth, dry eyes, and similar symptoms.

[0121] Example 11: Use 225 In the case of Ac-PSMA-617, therapeutic use of radioligands is achieved by using A Botulinum toxin type 2 to prevent radiation damage

[0122] During the imaging procedure 225 Two weeks prior to therapeutic use of Ac-PSMA-617, a total of between 20 and 900 units of botulinum toxin type A was administered, depending on the specific botulinum toxin type A formulation. or For example, 150 units of botulinum toxin type A ( or ) was 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 was applied to each of the two parotid glands and 25 units of botulinum toxin type A was applied to each of the two submandibular glands. Two weeks later (day 0), 225 First administration of Ac-PSMA-617 (100 kBq / kg) to initiate treatment of prostate cancer patients. In the treated gland, compared to, for example, the brain parenchyma 225 The uptake of Ac-PSMA-617 was significantly reduced. This reduced uptake protected the corresponding glands and allowed them to function normally, thus avoiding serious, persistent and irreversible side effects such as dry eyes and chronic severe inflammation of the eyes and eyelid margins that severely limited the quality of life, and preventing dysphagia, the associated weight loss and inflammation of the oral mucosa, as well as tooth damage and similar symptoms. After about eight weeks, 225 Another administration of Ac-PSMA-617 (100 kBq / kg). 225During further treatment with Ac-PSMA-617, a total of 20 to 900 units of botulinum toxin type A was administered two weeks before the treatment procedure, depending on the degree of effect of the previous botulinum toxin injection. or For example, a total of 50 to 150 units. Botulinum toxin type A ( or ) was administered at a fixed dose ratio of 2 / 3 (parotid gland) to 1 / 3 (submandibular gland). 225 Treatment cycles of Ac-PSMA-617 are expected to require approximately four cycles of 225 Ac-PSMA-617 therapy.

[0123] Example 12: Use 225 In the case of Ac-PSMA-617, therapeutic use of radioligands is achieved by using B Botulinum toxin type 2 to prevent radiation damage

[0124] During the imaging procedure 225 Two weeks prior to therapeutic use of Ac-PSMA-617, a total of between 3,000 units of botulinum toxin type B was administered, e.g. Botulinum toxin type B was administered in a fixed dose ratio of 2 / 3 (parotid gland) to 1 / 3 (submandibular gland). Assuming a total of 3,000 units, this means 1,000 units of botulinum toxin type B were administered to each of the two parotid glands and 500 units of botulinum toxin type B were administered to each of the two submandibular glands. Two weeks later (Day 0), 225 First administration of Ac-PSMA-617 (100 kBq / kg) to initiate treatment of prostate cancer patients. In the treated gland, compared to, for example, the brain parenchyma 225 The uptake of Ac-PSMA-617 was significantly reduced. This reduced uptake protected the corresponding glands and allowed them to function normally, thus avoiding serious, persistent and irreversible side effects such as dry eyes and chronic severe inflammation of the eyes and eyelid margins that severely limited the quality of life, and preventing dysphagia, the associated weight loss and inflammation of the oral mucosa, as well as tooth damage and similar symptoms. After about eight weeks, 225 Another administration of Ac-PSMA-617 (100 kBq / kg). 225 During further treatment with Ac-PSMA-617, a total of between 1,000 and 3,000 units of botulinum toxin type B was administered two weeks prior to the treatment procedure, depending on the degree of effectiveness of the previous botulinum toxin injections. 225 Treatment cycles of Ac-PSMA-617 are expected to require approximately four cycles of 225 Ac-PSMA-617 therapy.

[0125] Example 13: 177 The therapeutic use of Lu-PSMA-617 is achieved through the use of botulinum toxin type A and anticholinergics Drugs that can prevent radiation damage

[0126] exist 177 Two weeks (14 days) before the therapeutic use of Lu-PSMA-617, a total of 120 units of botulinum toxin type A was administered. Botulinum toxin type A (40 units each) was applied to the parotid and submandibular glands (20 units each) bilaterally.

[0127] In use 177 An anticholinergic drug was additionally administered three days prior to the Lu-PSMA-617 therapy. The anticholinergic drug (here, scopolamine) was applied every three days in the form of a transdermal patch. During this procedure, approximately 1 mg of scopolamine was released into the systemic circulation at a nearly constant rate over 72 hours. The scopolamine patch was applied to the skin. 177 The Lu-PSMA-617 therapy was switched on days 0 and 3, allowing patients to receive additional scopolamine for up to six days after therapy. This additionally protected the sublingual, minor salivary, and ocular glands.

[0128] Immediately for the first time 177 Before Lu-PSMA-617 treatment / Day 0, saliva production was normal. In this case, the saliva was 5.7 g in the Saxon test, and the normal value is 2.75 g saliva production after two minutes of chewing. 177 First administration of Lu-PSMA-617 (6 GBq / kg) to initiate treatment of prostate cancer patients.

[0129] About eight weeks later (day 56), 177 Another administration of Lu-PSMA-617 (6 GBq / kg) was administered. Following completion of treatment (two treatment cycles on days 0 and 56) and an approximately eight-week follow-up period, normal saliva production remained unchanged on day 108. Here, the Saxon test showed 5.5 grams of saliva, with a normal value of 2.75 grams of saliva produced after 2 minutes of chewing. No dysphagia was observed. No dry eyes were reported.

[0130] Example 14: 177 Therapeutic use of Lu-PSMA-617 by preventing radiation with botulinum toxin type A damage

[0131] exist 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 was administered. Botulinum toxin type A was administered asymmetrically (100 units) into the right parotid gland and contralaterally into the left submandibular gland (50 units).

[0132] Immediately for the first time 177Before Lu-PSMA-617 treatment / Day 0, saliva production was normal. In this case, the saliva in the Saxon test was 4.6 g, and the normal value is saliva production ≥ 2.75 g after 2 minutes of chewing. 177 First administration of Lu-PSMA-617 (6 GBq / kg) to initiate treatment of prostate cancer patients.

[0133] About eight weeks later (day 56), 177 Another administration of Lu-PSMA-617 (6 GBq / kg) was performed. After completing treatment (two treatment cycles on days 0 and 56) and an approximately eight-week follow-up period, normal saliva production remained unchanged on day 116. Here, the Saxon test showed 4.3 grams of saliva, with the standard value being 2.75 grams or more of saliva after 2 minutes of chewing. No dysphagia occurred. No dry eyes were reported.

[0134] Example 15: 177 Therapeutic use of Lu-PSMA-617 by preventing radiation with botulinum toxin type B damage

[0135] exist 177 Two weeks (13 days) before the therapeutic use of Lu-PSMA-617, a total of 6,000 units of botulinum toxin type B was administered. Botulinum toxin type B was applied asymmetrically to the right parotid gland (4,000 units) and the contralateral left submandibular gland (2,000 units).

[0136] Immediately for the first time 177 Before Lu-PSMA-617 treatment / Day 0, saliva production was normal. 177 First administration of Lu-PSMA-617 (6 GBq / kg) to initiate treatment of prostate cancer patients.

[0137] About eight weeks later (day 56), 177 Another administration of Lu-PSMA-617 (6 GBq / kg) was administered. Following completion of treatment (two treatment cycles on Days 0 and 56) and an approximately eight-week follow-up period, normal saliva production remained unchanged on Day 116. Dysphagia did not occur. No dry eyes were reported.

[0138] Based on Examples 13-15, the following further treatments are planned for the following four patient groups:

[0139] 1) Middle-aged patients aged 50-75

[0140] 2) Elderly patients >75 years old

[0141] 3) Patients with multiple illnesses and / or mild cognitive impairment (MCI)

[0142] 4) Patients with an expected short survival time of <1.5 years

[0143] Example 16: Planned treatment of patients in patient group 1 (middle-aged, 50-75 years old): 225 Treatment with Ac-PSMA-617 Prevention of radiation damage during sexual use by using botulinum toxin type A and anticholinergic drugs

[0144] exist 225 Three weeks (21 days) before the therapeutic use of Ac-PSMA-617, a total of 150 units of botulinum toxin type A was administered. Botulinum toxin type A was applied bilaterally to the parotid glands (50 units each) or the submandibular glands (25 units each) (ie, in a ratio of 2 / 3 parotid glands to 1 / 3 submandibular glands).

[0145] In use 225 An anticholinergic drug was additionally administered three days prior to the Ac-PSMA-617 therapy. The anticholinergic drug (here, scopolamine) was applied every three days in the form of a transdermal patch. In this case, approximately 1 mg of scopolamine was released into the systemic circulation at an almost constant rate over 72 hours. The scopolamine patch was applied to the skin every three days. 225 The Ac-PSMA-617 regimen was switched on days 0, 3, and 6, allowing patients to receive additional scopolamine for up to nine days after treatment. This approach also protected the sublingual salivary glands, minor salivary glands, and ocular glands.

[0146] Example 17: Planned treatment of patients in patient group 2 (aged 75 years or older): 225 Ac-PSMA-617 Prevention of radiation damage by therapeutic use of botulinum toxin type B

[0147] exist 225 Two weeks (14 days) prior to the therapeutic use of Ac-PSMA-617, a total of 6,000 units of botulinum toxin type B was administered. Botulinum toxin type B was applied to the parotid glands (2,000 units each) or the submandibular glands (1,000 units each) bilaterally (ie, in a ratio of 2 / 3 parotid glands to 1 / 3 mandibular salivary glands).

[0148] Example 18: Patients in Patient Group 3+4 (Multimorbid Patients / Patients with MCI / Patients with Shortened Life Expectancy) Planned treatment: 225 Therapeutic use of Ac-PSMA-617 by preventing radiation damage with botulinum toxin type A

[0149] exist 225 Three weeks (21 days) prior to the therapeutic use of Ac-PSMA-617, a total of 150 units of botulinum toxin type A will be administered. Botulinum toxin type A will be administered as a high-dose monotherapy (100 units) asymmetrically to the right parotid gland on one side or to the left submandibular gland on one side (50 units) (ie, in a ratio of 2 / 3 parotid gland to 1 / 3 submandibular gland).

[0150] Term Botulinum toxin A High-dose monotherapy refers to corresponding single doses in both glands, with dose ranges for each gland not previously published but well tolerated, as can be seen in patients already treated. In order to avoid dysphagia, glandular high-dose monotherapy should never be applied to all four glands in this patient group. Asymmetric monotherapy with botulinum toxin type A only in one contralateral parotid and submandibular gland was also used to avoid side effects associated with anticholinergic drugs in group 3 patients. Initial saliva production in the two initially non-injected glands was shortened during the treatment period (until they were injected for the second, third or fourth time). 225 Ac-PSMA-617 treatment of complete lesions) duration of dry mouth, at the expense of repeated 225 Ac-PSMA-617 treatment results in the complete destruction of two of the four salivary glands and is therefore particularly suitable for patient group 4, who are expected to have a short survival time in terms of quality of life.

Claims

1. Use of a combination of botulinum toxin and an anticholinergic drug in the preparation of a medicament for preventing radiation damage to a gland, wherein the radiation damage is caused by a radioligand and wherein the anticholinergic drug is selected from the group consisting of tropicamide, atropine, scopolamine, glycopyrrolate, amitriptyline, clonidine, ipratropium bromide and trihexyphenidyl.

2. The use according to claim 1, wherein the radiation damage is caused by a PSMA radioligand.

3. The method according to claim 1, wherein the radioligand is selected from the group consisting of: 225 Ac-PSMA, 68 Ga-PSMA, 18 F-PSMA or 177 Lu-PSMA.

4. The use according to claim 1, wherein the botulinum toxin is selected from the group consisting of botulinum toxin type A, type B, type C, type D, type E, type F and type G.

5. The use according to any one of claims 1 to 4, wherein the botulinum toxin comprises between 1 and 10,000 units.

6. The use according to any one of claims 1 to 4, wherein the botulinum toxin is botulinum toxin type A.

7. The use according to any one of claims 1 to 4, wherein the botulinum toxin comprises between 1 and 1,500 units of botulinum toxin type A.

8. The use according to any one of claims 1 to 4, wherein the botulinum toxin is botulinum toxin type B.

9. The use according to any one of claims 1 to 4, wherein the botulinum toxin comprises between 100 and 10,000 units of botulinum toxin type B.

10. The use according to any one of claims 1 to 4, wherein the botulinum toxin is botulinum toxin type E or type F.

11. The use according to any one of claims 1 to 4, wherein the botulinum toxin comprises between 1 and 10,000 units of botulinum toxin type E or type F.

12. The use according to any one of claims 1 to 4, wherein the anticholinergic drug is administered transdermally, orally or intravenously.

13. The use according to any one of claims 1 to 4, wherein the anticholinergic drug is scopolamine, wherein the scopolamine is administered transdermally.

14. The use according to claim 4, wherein the botulinum toxin type B is administered contralaterally to the right parotid gland and the left submandibular gland; or the left parotid gland and the right submandibular gland.

15. The use according to claim 8, wherein the botulinum toxin type B is administered contralaterally to the right parotid gland and the left submandibular gland; or the left parotid gland and the right submandibular gland.

16. The use according to claim 9, wherein the botulinum toxin type B is administered contralaterally to the right parotid gland and the left submandibular gland; or the left parotid gland and the right submandibular gland.

17. The use according to claim 4, wherein the botulinum toxin type A is administered contralaterally to the right parotid gland and the left submandibular gland; or the left parotid gland and the right submandibular gland.

18. The use according to claim 6, wherein the botulinum toxin type A is administered contralaterally to the right parotid gland and the left submandibular gland; or the left parotid gland and the right submandibular gland.

19. The use according to claim 7, wherein the botulinum toxin type A is administered contralaterally to the right parotid gland and the left submandibular gland; or the left parotid gland and the right submandibular gland.

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