RU2821523C1 - Method for preventing radiation injury of glands in person - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: group of inventions relates to medicine and can be used to prevent radiation damage of glands in radiation therapy in oncology. Presented is the use of botulinum toxin in a combination with an anticholinergic agent for preventing radiation damage of glands in a patient in need thereof, where the radiation damage is caused by radioligands. Also disclosed is a method for preventing radiation damage to parotid, submandibular, sublingual, small salivary and lachrymal glands, involving the introduction of botulinum toxin type B from opposite sides into the corresponding parotid gland or submandibular gland, and a method for preventing radiation injury of glands, comprising administering to a patient in need thereof, a botulinum toxin type A from opposite sides into a corresponding parotid gland or submandibular gland.

EFFECT: group of inventions provides effective protection of glands during radiation therapy and enables to prevent radiation damage of parotid, submandibular, sublingual, small salivary and lachrymal glands.

29 cl, 3 dwg, 18 ex

Description

Technical field

The present invention relates to the field of application of radiation therapy in oncology. The use of botulinum toxin and an anticholinergic agent allows one to avoid radiation damage to human glands from radioligands. An optimized therapy regimen may provide additional advantageous properties to the method, including both diagnostic imaging procedures and therapeutic procedures.

State of the art

A radioligand is a substance labeled with a radionuclide that can bind as a ligand to a protein target, such as a receptor. These radioligands are used, for example, both for diagnosis and therapy of oncological diseases. A striking example is PSMA radionuclides used in the diagnosis and treatment of prostate carcinoma.

PSMA (prostate specific membrane antigen (protein)) is a transmembrane protein that is expressed by prostate carcinoma cells in amounts up to 1000 times greater than that expressed by normal prostate cells. PSMA is therefore an ideal protein target for diagnosis and at the same time for targeted therapy of prostate cancer. PSMA is also expressed in other carcinomas, although at lower levels compared to prostate carcinoma. PSMA is also expressed by the salivary glands and lacrimal glands. Irreversible damage to these glands leads to severe xerostomia with a number of complications such as dental damage and chronic dry eyes, which can lead to visual impairment.

PSMA radionuclides are used both in diagnosis and therapy.

PSMA radioligands ⁶⁸ Ga-PSMA and ¹⁸ F-PSMA are used to diagnose primary and recurrent prostate cancer and search for metastases. Diagnostic ligands accumulate in prostate carcinoma cells and other organs/tumors mentioned above, and diagnostic PSMA radioligands can damage the lacrimal and salivary glands.

PSMA radioligands used in therapy always cause damage to the salivary glands of varying severity, which often persists for an extended period of time depending on the ligand, resulting in significant health problems and reduced quality of life (xerostomia, ulcers throughout the mouth, dysphagia, risk of aspiration, dental damage, etc.). Another related problem is that PSMA radioligands are often administered in repeated courses, causing the damage to the glands to accumulate. PSMA radioligands also cause lacrimal gland damage of varying severity depending on the radioligand, with health consequences such as 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 associated complications often mean that life-prolonging therapy may no longer be beneficial in patients with prostate cancer.

Presumably, different PSMA radioligands have different affinities for individual salivary glands and thus different toxicities. Various radionuclides are agents that emit alpha, beta or gamma particles. For example, the nuclides currently used are ¹⁷⁷ Lu (a source of beta radiation with a range of 2 mm) and 225Ac (a source of alpha radiation with a range of 50-90 μm). It is expected that even more highly active PSMA radioligands will be available for therapeutic use in the future, which will provide stronger radiation with a very short path (50-90 μm). There is increasing evidence that ²²⁵ Ac is more damaging to the salivary glands than ¹⁷⁷ Lu.

When using even more active radioligands, such as alpha radiation sources, the risk of gland damage increases even further.

Glands perform various functions in the human body. Among other aspects, glands are divided into endocrine and exocrine. If the target is expressed not only in the tumor but also in the glands, such as PSMA, which is expressed in the salivary glands and also in the lacrimal glands, then damage to healthy glands will also occur.

This is also where botulinum toxin can be useful: Botulinum toxin injections can protect the glands as part of an agreed procedure. Botulinum toxin is the common name for a family of toxins produced by the bacterium Clostridium botulinum . Currently, seven different botulinum toxins are known (A, B, C, D, E, F and G), having different properties. The mechanisms of action of different types of botulinum toxins also differ: for example, the main effect of type A is based on the cleavage of intracellular SNAP-25, while type B cleaves mainly “vesicle-associated membrane protein” (=VAMP). Botulinum toxin type B also has other differences compared to type A: Type B presynaptically binds the Syt II protein, there is also a partial presynaptic interaction between type B and tetanus toxin residues, as well as neurotoxin-ganglioside interaction with the gangliosides GD1a, GD1b and GM1a. Local injections of botulinum toxin result in a dose-dependent decrease in saliva production after a few days, so the onset of action is several days. Efficacy, duration of action and side effects depend mainly on the dose administered. In general, the duration of action is between four and 16 weeks, with the duration of action depending on the type used: types E and F have a significantly shorter duration of action of approximately three to six weeks. Botulinum toxin does not cause long-term or permanent damage to the salivary glands. The function of the salivary glands is completely restored from the action of botulinum toxin over time. Injections can be repeated as often as necessary without causing organ damage.

The mechanism of action of botulinum toxin on the salivary glands is known and has been described in detail previously. All drugs and types (A-G) of botulinum toxin induce dose-dependent changes in the glands within 1-10 days, i.e. for different periods of time after injection and thus lead to a temporary dose-dependent decrease in salivary secretion. Type B starts working relatively quickly in about three days, while type A starts working in about six days. A decrease in salivary secretion affects both the serous and mucous sections of the corresponding salivary glands. Decreased gland function reduces saliva production and blood flow to the glands. Both mechanisms (individually and in combination) result in reduced long-term uptake of harmful radionuclides by reducing glandular activity during PSMA radionuclide therapy, thereby preventing irreversible glandular damage. In this case, there are also differences between botulinum toxin type B and type A: Type B has a higher affinity for autonomic nerve endings compared to type A. This is especially important since the salivary glands (unlike muscles) are innervated exclusively by autonomic nerve cells . Thus, botulinum toxin type B has a stronger and longer-lasting effect on the salivary glands compared to type A. Compared with type A, local injection of type B results in increased distribution in the body with a higher affinity for autonomic structures. Accordingly, when injected into distant glands, type B may provide effects on the autonomic system in glands such as the lacrimal glands, which are not injected. This provides a certain protective effect in the lacrimal glands when botulinum toxin type B is injected into the salivary glands. This means that injection of botulinum toxin type B into the salivary gland may have some protective function due to increased affinity for autonomic structures and increased distribution in glands that are otherwise inaccessible to direct injection of botulinum toxin, such as the sublingual salivary gland, minor salivary glands and lacrimal glands. glands. This mechanism of action applies to all glands treated with BTX, even though the degree of denervation and reduction in salivary production may vary in individual glands.

The salivary glands also contain androgen receptors. Most patients with advanced prostate carcinoma receive androgen deprivation therapy. Antiandrogens markedly increase the uptake of PSMA, which leads to increased damage to the salivary glands by PSMA radioligands. Thus, the present invention is particularly suitable for patients who have already received antiandrogen therapy or are currently undergoing radioligand therapy, since they are particularly susceptible to glandular damage from PSMA radioligands.

In addition, all salivary glands express numerous α-1 adrenergic receptors. Stimulation of α-1 receptors leads to significant activation of the salivary glands and saliva secretion. Botulinum toxin type A causes down-regulation of α-1 adrenergic receptors and also reduces salivary gland activation and PSMA radioligand binding to salivary glands injected with botulinum toxin.

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. Most radionuclides are metalloids. In the submandibular gland in particular, large numbers of aquaporins (AQPs) are expressed in the apical membrane of the acinar cells of the salivary glands and in the submandibular gland in particular. Over approximately one to two weeks, botulinum toxins type A and type B significantly reduce the level of aquaporin (eg, AQP 5) mRNA in the submandibular gland and the distribution of AQP in the apical membrane. In addition, botulinum toxins type A and type B induce apoptosis of acinar cells. Thus, botulinum toxin injections into the submandibular gland result in a significant reduction in aquaporin-mediated cellular uptake of radionuclides and thus protect the salivary glands, particularly the submandibular gland, from long-term damage. After the cessation of the action of botulinum toxin, the mentioned changes in aquaporins completely disappear.

In particular, the often required repeated courses of PSMA radionuclide therapy (usually up to four cycles in six months) lead to the accumulation of long-term severe damage to the salivary glands. The botulinum toxin wears off after a period of approximately six to sixteen weeks without any consequences, and the salivary gland begins to function again.

Not only botulinum toxin, but also anticholinergics can protect the salivary and lacrimal glands. Anticholinergics, also called parasympatholytics, inhibit the effects of acetylcholine by competitively inhibiting the acetylcholine receptor. This blocks nerve stimuli that lead to increased secretion in the glands. Thus, the protective actions of botulinum toxin and anticholinergic drugs complement and enhance each other: botulinum toxin inhibits the release of acetylcholine into the synaptic cleft (presynaptically), and anticholinergic drugs block acetylcholine receptors (postsynaptically). Only combined pre- and postsynaptic blocking by both substances (botulinum toxin and anticholinergic agent) allows optimal protection of the salivary and lacrimal glands during radioligand therapy. During radioligand therapy or the use of radioligands for diagnosis, salivary production is increased in the parasympathetic fibers, and serous saliva is produced mainly in the parotid gland, for this reason its function is specifically protected by the use of systemically effective anticholinergics during PSMA radionuclide therapy. This effect is used in the present invention to provide a protective effect in the glands. Anticholinergics act in a dose-dependent manner and have systemic effectiveness, and thus can reach glands that are not directly treated by botulinum toxin injections, including the sublingual gland, minor salivary glands, and lacrimal glands. Due to the anatomical location and the risk of side effects, botulinum toxin cannot be injected directly into these glands. Thus, these glands, such as the lacrimal glands, are protected by anticholinergics so that they are not susceptible to long-term damage from the radioligand, and thus ocular dehydration and chronic severe inflammation of the eyes and eyelid margins, which greatly impair quality of life, are prevented. In addition, anticholinergics enhance the action of botulinum toxin, for example in the parotid and submandibular glands.

In particular, combined treatment with botulinum toxin and an anticholinergic agent has a beneficial effect in the submandibular gland, since this gland is seromucous. The double protective effect allows patients to mechanically prepare food in the oral cavity during the chewing process, as a result of which the chewed food moves painlessly through the digestive tract and digestion is not disturbed. In addition, saliva contains antimicrobial components and thereby ensures the remineralization of teeth, thus providing a double protective effect against tooth damage.

The protective effect in the glands can be further enhanced by a combination of botulinum toxin and an anticholinergic agent. Combination with an anticholinergic agent also results in increased action of botulinum toxin in the parotid gland and submandibular gland and partial effects on other salivary glands and lacrimal glands during the period of effectiveness of the corresponding anticholinergic agent. Thus, the combination of botulinum toxin and an anticholinergic agent is most effective in terms of salivary gland secretion, followed by botulinum toxin monotherapy and then anticholinergic monotherapy.

However, combination treatment including botulinum toxin and an anticholinergic agent does not benefit all patients: Patients with cognitive impairment, including cognitive impairment of all severity (mild to moderate to severe cognitive impairment), should not take anticholinergics. as they may experience mind-altering effects. In other words, they have contraindications. Likewise, patients with cardiac arrhythmia should not be treated with anticholinergics, as anticholinergics aggravate cardiac arrhythmia and conduction disturbances, and tachyarrhythmia, heart failure, and angina may also occur. And in this case there are contraindications. Thus, these groups of patients undergoing diagnosis or radioligand therapy are treated with botulinum toxin without an anticholinergic agent. In this case, botulinum toxin A acts both directly in the injected gland and through passive diffusion into neighboring glands. For example, if botulinum toxin type A is injected into the submandibular glands on either side of the face, the sublingual gland is also protected by diffusion. Botulinum toxin B acts both directly in the injected gland and through passive diffusion into other glands, with a larger diffusion radius compared to botulinum toxin type A. In addition, botulinum toxin type B has a higher affinity for autonomous structures, including As a result, botulinum toxin type B also acts on distant glands that are not injected with botulinum toxin type B, such as the lacrimal glands, sublingual gland and minor salivary glands.

In general, there is a pressing need for a method of protecting, in particular, the vital lacrimal and salivary glands, which are not target structures for radioligand diagnosis or radioligand therapy in the context of diagnosis or therapy.

The proposed method according to the invention provides a preventive solution to prevent irreversible damage to the glands by diagnostic or therapeutic radioligands.

Brief description of the invention

The present invention relates to botulinum toxin in combination with an anticholinergic agent for use in a method of preventing radiation damage to glands where radiation damage is caused by radioligands. In addition, the present invention also includes botulinum toxin for use in a method of preventing radiation damage to glands where radiation damage is caused by radioligands.

In some embodiments, botulinum toxin is used in combination with an anticholinergic agent for use in a method where radiation damage is caused by PSMA radioligands.

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

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, the botulinum toxin is botulinum toxin type A.

In some embodiments, the botulinum toxin contains from 1 to 10,000 units.

In some embodiments, the botulinum toxin contains from 1 unit to 1500 units of type A.

In some embodiments, the botulinum toxin is botulinum toxin type B.

In some embodiments, the botulinum toxin contains from 100 to 10,000 units of type B.

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

In some embodiments, the botulinum toxin contains from 1 to 10,000 units of type E or type F.

In some embodiments, the anticholinergic agent is selected from the group consisting of tropicamide, atropine, scopolamine, glycopyrrolate, amitriptyline, clonidine, ipratropium bromide, and trihexylphenidyl. Also included are all other pharmaceutical agents that act as an anticholinergic or parasympatholytic agent.

In some embodiments, the anticholinergic agent is for transdermal, oral, or intravenous administration.

In some embodiments, the anticholinergic agent is scopolamine, wherein the scopolamine is for transdermal administration.

In some embodiments, the botulinum toxin is botulinum toxin type B to prevent radiation damage to the parotid, submandibular, sublingual, minor salivary, and lacrimal glands where radiation damage is caused by radioligands.

In some embodiments, the botulinum toxin is botulinum toxin type A for reducing aquaporin-mediated uptake of radionuclides into submandibular and salivary gland cells.

In some embodiments, the botulinum toxin is botulinum toxin type A, wherein the botulinum toxin type A is intended to be administered in doses of 2/3 to the parotid glands and 1/3 to the submandibular glands.

In some embodiments, the botulinum toxin is botulinum toxin type B, wherein the botulinum toxin type B is intended to be administered in doses of 2/3 to the parotid glands and 1/3 to the submandibular glands.

In some embodiments, the use includes administering botulinum toxin one day to eight weeks before an imaging procedure or radiological treatment involving one or more radionuclides.

In some embodiments, the use includes administering the anticholinergic agent three days, two days, the day, or the same day before a diagnostic imaging procedure or radiological treatment using one or more radionuclides, and from about 7 to 30 days after the diagnostic imaging procedure or radiological treatment.

In some embodiments, the use includes administering botulinum toxin one day to eight weeks and an anticholinergic agent three days, two days, one day, and the same day before a diagnostic imaging procedure or radiological treatment using one or more radionuclides, and from about 7 to 30 days after a diagnostic imaging procedure or radiological treatment.

In some embodiments, the glands are exocrine and/or endocrine glands.

In some embodiments, the gland is a seromucous gland.

In some embodiments, botulinum toxin type A acts by downregulating α-1 adrenergic receptors in the glands.

In some embodiments, use is preferably administered to a group of patients who have already received antiandrogen therapy or are undergoing antiandrogen therapy during radionuclide therapy.

Advantages of the invention

Thanks to the use of botulinum toxin and an anticholinergic agent in the method according to the present invention, the salivary and lacrimal glands are protected. This means that long-term and irreversible side effects such as xerostomia, ulcers throughout the mouth, dysphagia, risk of aspiration, dental damage are prevented and thus the need for additional treatment for these side effects is prevented. This reduces the burden on the healthcare system. In a worst-case scenario, severe side effects may lead to dose adjustments or even discontinuation of radioligand therapy. The present invention also makes it possible to prevent these scenarios.

In some embodiments, the method includes the use of botulinum toxin and an anticholinergic agent. This further enhances the protective effect in the glands. Combination with an anticholinergic also results in enhanced botulinum toxin action in the parotid and submandibular glands and additional protective effects in other salivary and lacrimal glands as long as the corresponding anticholinergic remains effective. This means that long-term and irreversible side effects such as dry eyes, recurrent ocular inflammation, blurred vision, decreased visual acuity, as well as xerostomia, ulcers throughout the mouth, dysphagia, risk of aspiration and dental damage are prevented, and thus, the need for additional treatment of these side effects.

Figures

The following figures show examples of preferred treatment regimens. This means that other treatment regimens are also valid and included in the present invention. This means that monotherapies using botulinum toxin type A or type B are also examples of treatment regimens.

Figure 1: Treatment regimen for preventing radiation injury by using botulinum toxin type A or type B during radioligand therapy (every eight weeks, in this example, four radioligand administrations are indicated as part of the therapeutic procedure, and administration can be performed more frequently than four times ).

Figure 2: Treatment regimen for preventing radiation injury by using botulinum toxin type A or B and an anticholinergic agent in diagnostic and initial therapeutic use of radioligands.

Figure 3: Treatment regimen for the prevention of radiation injury using botulinum toxin type A or type B and an anticholinergic agent during radioligand therapy (every 56 days, in this example, three of the four radioligand administration procedures are indicated as part of the therapeutic procedure).

Detailed Description of the Invention

Definitions:

"Botulinum toxin" is the common name for a family of toxins produced by the bacterium Clostridium botulinum . Currently, seven different botulinum toxins are known (A, B, C, D, E, F and G), having different properties. As used herein, botulinum toxin is intended to include all different types. Currently, three preparations of botulinum toxin type A and one preparation of botulinum toxin type B are known for clinical use.

“Anticholinergics” is a general term to describe active ingredients that inhibit the action of the neurotransmitter acetylcholine in effector cells, leaving the initial release of acetylcholine unaffected.

“Prevention,” also called prophylaxis, refers to measures to prevent unwanted events or conditions that are likely to occur if no action is taken. In the context of the present application, prevention means preventing damage or side effects in human glands and other parts of the body that may occur as a result of diagnosis or radioligand therapy. Said damage includes, for example, xerostomia, ulcers throughout the mouth, dysphagia, risk of aspiration, dental damage, dry eyes, blurred vision and (chronic) ocular inflammation and decreased visual acuity.

“Radiation damage” is damage caused by ionizing radiation in the body. The effects of ionizing radiation on the body can involve a number of physical, chemical, biochemical and biological processes. In the context of the present invention, this means damage or side effects caused by the use of radioligands for diagnosis and/or therapy. Said damage or side effects include, for example, xerostomia, ulcers throughout the mouth, dysphagia, risk of aspiration, dental damage, dry eyes, blurred vision and (chronic) ocular inflammation and decreased visual acuity.

"Radionuclide" is a nuclide that is unstable and thus radioactive. The radionuclides according to the present invention are radionuclides that are used for medical purposes, in particular in diagnostics, for example, in imaging procedures, or in therapy.

A "radioligand" is a substance labeled with a radionuclide that is capable of binding as a ligand to a protein target, such as a receptor. These radioligands are used, for example, both in diagnosis and in therapy, for example, of cancer.

“Glands” are organs, and in a broader sense, individual cells that can synthesize and secrete specific substances. The glands can have both serous and mucous sections, which affect the substance produced. Non-limiting examples of these substances are saliva or tears. According to another classification of glands, they are divided into exocrine and endocrine glands.

"Dose ratio". The amount of pharmaceutical active ingredient or drug intended to be administered, in this case the amount of botulinum toxin, is generally called a dose. Dose ratios can be expressed as fractions (eg, 1/3) or ratios such as 1:1, 1:2, etc.

“Cognitive disorders” are memory disorders of any kind and include mild, moderate and severe cognitive impairment. Mild cognitive impairment or mild cognitive impairment (MCI) is an impairment in thinking compared to the norm for a person of the same age and education, but does not indicate a significant limitation in activities of daily living.

"Reduced life expectancy." The reduced life expectancy is six to eighteen months, preferably six months from diagnosis.

"High-dose therapy." By high-dose therapy is meant the administration of a total of 100 to 300 units of botulinum toxin type A, particularly preferably a total of 150 units of botulinum toxin type A. In this case, 75 to 150 units, particularly preferably 100 units, are injected into the parotid gland and 25 to 75 units more preferably 50 units, injected into the submandibular gland. The high dose of botulinum toxin type A is particularly preferably administered asymmetrically (from opposite sides).

“Asymmetrical insertion (from opposite sides).” In the case of asymmetrical administration (from opposite sides), botulinum toxin is injected into one gland and into the second gland, which is located on the opposite side of the body. For example, botulinum toxin is injected into the right parotid gland and into the (opposite) left submandibular gland (50 units). This means, for example, that the right parotid gland and the left submandibular gland can be selected for injection, and vice versa.

"Dementia". Dementia is a collection of symptoms of various diseases, the main distinguishing feature of which is the weakening of certain cognitive abilities compared to the state in previous periods. Dementia can result from a variety of degenerative and non-degenerative brain diseases.

A patient's "comorbid" or "multimorbid" status means that he suffers from another pathology or syndrome in addition to the main disease or from several different diseases at the same time.

Embodiments of the invention

The method according to the present invention is suitable for a variety of applications. It is suitable not only for the diagnosis of diseases in which radionuclides or radioligands are used, but also for the treatment of diseases in which radionuclides or radioligands are used. Examples of 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 cancers such as bronchial carcinomas, 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, genitourinary cancers systems, adrenal cortex cancer (pheochromocytoma), brain cancer, stomach cancer, kidney cancer, uterine cancer, bone cancer, esophageal cancer, oropharyngeal cancer, testicular cancer, thyroid cancer, adrenal cortex cancer, gall bladder cancer, small intestine cancer , anal cancer, pancreatic cancer, bile duct cancer, cervical cancer, uterine cancer, urethral cancer, laryngeal cancer, bone cancer, Wilms tumor, plasmacytoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma or retinoblastoma. Other diseases that require diagnosis or therapy using radioligands are also included.

The present invention relates to botulinum toxin in combination with an anticholinergic agent for use in a method of preventing radiation damage to glands where radiation damage is caused by radioligands. Radioligands as used herein include all radionuclides that are bound to a ligand.

In some embodiments, botulinum toxin is used in combination with an anticholinergic agent for use in a method where radiation damage is caused by PSMA radioligands. A particularly preferred PSMA radioligand is PSMA-617.

In some embodiments, botulinum toxin is used in combination with an anticholinergic agent for use in a method wherein the radiation damage is caused by ²²⁵ Ac-PSMA-617, ⁶⁸ Ga-PSMA, ¹⁸ F-PSMA, or ¹⁷⁷ Lu-PSMA. In some embodiments, PSMA is associated with other diagnostic or therapeutically useful radionuclides, such as ¹¹¹ In.

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 additional embodiments The preferred implementation is a combination of botulinum toxins of different types, such as type A and type B, type A and E, type A and F, type B and E, type 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 the polynucleotide, which, in turn, encodes the modified polypeptide. Chemical modifications such as pegylation of botulinum toxin or phosphorylation of amino acids are also included. Recombinant botulinum toxins are botulinum toxins produced by recombinant methods; Recombinant DNA technology methods for producing said recombinant botulinum toxins are well known. Synthetic botulinum toxins are polypeptides with a specific sequence. Synthetic botulinum toxins can be an exact copy of natural botulinum toxin or can be produced with various modifications. For example, synthetic botulinum toxins may contain unnatural amino acids or modification of the peptide backbone.

In some embodiments, the botulinum toxin contains from 1 to 10,000 units, preferably from 10 to 5,000 units, and most preferably from 20 to 4,000 units.

In some embodiments, the botulinum toxin contains from 1 to 1500 units, preferably from 10 to 1000 units, and most preferably from 20 to 900 units of type A.

In some embodiments, the botulinum toxin contains from 100 to 10,000 units, preferably from 250 to 5,000 units, and most preferably from 500 to 4,000 units of type B.

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

In some embodiments, the botulinum toxin contains from 1 unit to 10,000 units of type E or type F.

In some embodiments, the anticholinergic agent is selected from the group consisting of tropicamide, atropine, scopolamine, glycopyrrolate, amitriptyline, clonidine, ipratropium bromide, and trihexylphenidyl. Scopolamine is particularly preferred for the present invention. In some embodiments, the anticholinergic agent is administered transdermally, orally, or intravenously. Preferably, the anticholinergic agent is administered transdermally. Most preferably, scopolamine is administered transdermally.

In some embodiments, the botulinum toxin is botulinum toxin type B to prevent radiation damage to the parotid, submandibular, sublingual, minor salivary, and lacrimal glands where radiation damage is caused by radioligands. In some embodiments, botulinum toxin type B is used in a method in which patients being diagnosed or treated with radionuclides suffer from cognitive impairment. In some embodiments, botulinum toxin type B is used in a method in which patients being diagnosed or treated with radionuclides suffer from cardiac arrhythmia. In a preferred embodiment, botulinum toxin type B is used in a method in which patients being diagnosed or treated with radionuclides suffer from cognitive impairment and cardiac arrhythmia.

In some embodiments, the botulinum toxin is botulinum toxin type A for reducing aquaporin-mediated uptake of radionuclides into submandibular and salivary gland cells. In some embodiments, botulinum toxin type A is used in a method in which patients being diagnosed or treated with radionuclides suffer from cognitive impairment. In some embodiments, botulinum toxin type A is used in a method in which patients being diagnosed or treated with radionuclides suffer from cardiac arrhythmia. In another embodiment, botulinum toxin type A is used in a method in which patients being diagnosed or treated with radionuclides suffer from cognitive impairment and cardiac arrhythmia.

In one embodiment, the botulinum toxin is botulinum toxin type A, wherein the botulinum toxin type A is intended to be administered in dosage ratios of 1:1, 2:1, 3:1, 4:1, 5:1 to the parotid glands and submandibular glands. In a particularly preferred embodiment, the botulinum toxin is botulinum toxin type A, where the botulinum toxin type A is intended to be administered in doses of 2/3 to the parotid glands and 1/3 to the submandibular glands, in other words, a 2:1 ratio. In a particularly preferred embodiment, botulinum toxin type A is administered in high doses or, in other words, as part of "high dose therapy". A total of 100 to 300 units of botulinum toxin type A is administered, particularly preferably 150 units of botulinum toxin type A. 75 to 150 units, particularly preferably 100 units, are injected into the parotid gland and 25 to 75 units, especially preferably 50 units, are injected into the submandibular gland . The high dose of botulinum toxin type A is particularly preferably administered from opposite sides (asymmetrically). Botulinum toxin type A was injected asymmetrically (100 units) into the right parotid gland and into the opposite left submandibular gland (50 units). This means, for example, that the right parotid gland and the left submandibular gland can be selected for injection, and vice versa.

In one embodiment, the botulinum toxin is botulinum toxin type B, wherein the botulinum toxin type B is intended to be administered in dosage ratios of 1:1, 2:1, 3:1, 4:1, 5:1 to the parotid glands and submandibular glands. In a particularly preferred embodiment, the botulinum toxin is botulinum toxin type B, wherein the botulinum toxin type B is intended to be administered in doses of 2/3 to the parotid glands and 1/3 to the submandibular glands, i.e. in a ratio of 2:1.

In some embodiments, the use includes administering botulinum toxin one day to sixteen weeks before an imaging procedure or radiological treatment using one or more radionuclides. In preferred embodiments, the use includes administration of botulinum toxin one day to eight weeks before an imaging procedure or radiological treatment using one or more radionuclides. In this case, the duration of administration depends on the type of botulinum toxin used: Type E and type F are administered one day to eight weeks before the imaging procedure or radiological treatment, more preferably one day to four weeks, even more preferably one day to two weeks, most preferably 1 day to 7 days before an imaging procedure or before radiological treatment using one or more radionuclides. Types A and B are administered three days to twelve weeks before an imaging procedure or radiological treatment, preferably three days to four weeks before an imaging procedure or radiological treatment using one or more radionuclides, also preferably two to four weeks, most preferably two weeks before imaging or radiological treatment.

In some embodiments, the use includes administering an anticholinergic agent seven days, six days, five days, four days, three days, two days, one day, or the same day before a diagnostic imaging procedure or radiological treatment using one or more radionuclides , and up to approximately 14-28 days after the diagnostic imaging procedure or radiological treatment. In some embodiments, the use includes administering an anticholinergic agent seven days, six days, five days, four days, three days, two days, one day, or the same day before a diagnostic imaging procedure or radiological treatment using one or more radionuclides , and up to approximately 14-28 days after the diagnostic imaging procedure or radiological treatment. As noted above, the anticholinergic agent may be present in different dosage forms. If the anticholinergic agent in the present invention is administered transdermally, it can be administered every day, every other day, every other day, or even every four days.

In some embodiments, the use includes administering botulinum toxin four weeks and an anticholinergic seven days, six days, five days, four days, three days, two days, the day, or the same day before a diagnostic imaging procedure or radiologic treatment with exposure to one or more radionuclides, and up to 28 days after a diagnostic imaging procedure or radiological treatment. In preferred embodiments, the administration includes administering botulinum toxin two weeks and an anticholinergic seven days, six days, five days, four days, three days, two days, the day, or the same day before the diagnostic imaging procedure or radiological treatment with exposure to one or more radionuclides, and up to 28 days after a diagnostic imaging procedure or radiological treatment. As noted above, the anticholinergic agent may be present in different dosage forms. If the anticholinergic agent in the present invention is administered transdermally, it can be administered every day, every other day, every other day, or even every four days. In a preferred embodiment, the average age of patients treated with both botulinum toxin and an anticholinergic agent is between 50 and 75 years.

In some embodiments, the glands are exocrine and/or endocrine glands.

In some embodiments, the glands are selected from the group consisting of the parotid, submandibular, sublingual, minor salivary, and lacrimal glands. According to this list, it can be assumed that the glands can be selected either individually or in any combination. In addition, one skilled in the art will know that some glands are present on one or both sides of the body and can be combined accordingly. Thus, different, for example asymmetrical (opposite) glands can also be selected, that is, for example, the right parotid gland and the left submandibular gland can be selected, and vice versa. In one embodiment, the botulinum toxin may be botulinum toxin type A or type B.

In a particularly preferred embodiment, botulinum toxin type A is administered in high doses or, in other words, as part of "high dose therapy". In this case, a total of 100 to 300 units of botulinum toxin type A are administered, 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, for example, an anticholinergic means. In a particularly preferred embodiment, botulinum toxin type A is administered separately. 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. The high dose of botulinum toxin type A is particularly preferably administered asymmetrically (from opposite sides). Botulinum toxin type A was injected asymmetrically (100 units) into the right parotid gland and into the opposite left submandibular gland (50 units). The advantage of this route of administration is that two of the four major salivary glands are maximally protected without any side effects, and the patient continues to have sufficient salivary production in the other two glands during the initial administration of the radioligand until irreversible damage occurs to the two untreated glands. glands, which often occurs completely only during the second or subsequent course of radioligand administration. However, high-dose therapy in all four glands is excluded due to the risk of side effects such as dysphagia.

This method of selecting and combining salivary glands on one or both sides of the face is particularly preferred for comorbid or multimorbid patients, patients aged >75 years, patients suffering from mild cognitive impairment (MCI) or dementia, or patients with reduced life expectancy. These patient groups can be combined and rearranged, for example, a patient may be over 75 years of age, suffer from mild cognitive impairment and, due to illness, require diagnostic or radioligand therapy. It should also be emphasized that in these patient groups, the use of anticholinergics should ideally be avoided to avoid side effects of anticholinergics. The reduced life expectancy according to the invention is from six to eighteen months, preferably six months. For this group of patients, therapy using fewer injections using a higher dose is particularly preferred. Any side effects in all patients can also be prevented by selecting and merging the salivary glands on one or both sides of the face.

In some embodiments, the gland is a submandibular gland.

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

In some embodiments, botulinum toxin type A acts by downregulating α-1 adrenergic receptors in the glands. In some embodiments, botulinum toxin also acts by downregulating α-1 adrenergic receptors in glands, while other mechanisms are also effective.

In some embodiments, use is preferably administered to a group of patients who have already received antiandrogen therapy. In some embodiments, administration is administered to a group of patients who have not received antiandrogen therapy. In additional embodiments, administration is administered to a group of patients receiving antiandrogen therapy at the time of diagnosis or radioligand therapy.

In some embodiments, botulinum toxin type A acts by downregulating aquaporin-mediated uptake of radionuclides in the parotid and submandibular glands.

Examples:

The present invention is described in detail in the following non-limiting examples:

Example 1: Prevention of Radiation Damage by Using Botulinum Toxin Type A and an Anticholinergic Agent in Diagnostic Radioligand Applications Using, for example, ⁶⁸ Ga-PSMA

Two weeks before the diagnostic use of ⁶⁸ Ga-PSMA in an imaging procedure, a total of 20 to 900 units of botulinum toxin type A were injected, 150 units in the case of Xeomin® or BOTOX®, for example, depending on the specific preparation of botulinum toxin type A, into the corresponding glands, such as the submandibular glands on one or both sides of the face and/or the parotid glands on one or both sides of the face. Three days before the ⁶⁸ Ga-PSMA imaging procedure, additional anticholinergic administration was started. An anticholinergic drug, in this case scopolamine, was administered 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 an almost constant rate over 72 hours. Alternatively, the anticholinergic agent was administered orally every day (two days before the diagnostic procedure, the day before the diagnostic procedure, on the day of the diagnostic procedure) and up to 21 days after the diagnostic procedure. This approach also provides protection to the sublingual gland, minor salivary glands, and lacrimal glands. Two weeks later (day 0), an imaging procedure using ⁶⁸ Ga-PSMA was performed, for example, to image the patient's prostate carcinoma during follow-up. The uptake of ⁶⁸ Ga-PSMA in the glands into which botulinum toxin was injected is significantly reduced, in contrast to, for example, the brain parenchyma. This reduced uptake protects the respective glands and ensures their normal functioning, thereby avoiding long-term side effects such as xerostomia, dry eyes and similar symptoms.

Example 2: Prevention of Radiation Damage by Using Botulinum Toxin Type B and an Anticholinergic Agent in Diagnostic Radioligand Applications Using, for example, ⁶⁸ Ga-PSMA

Two weeks prior to the diagnostic use of ⁶⁸ Ga-PSMA in an imaging procedure, a total of 3000 units of botulinum toxin type B, such as MYOBLOC®, was injected into the target glands, such as the submandibular glands on one or both sides of the face and/or the parotid glands on one or both sides faces. Three days before the ⁶⁸ Ga-PSMA imaging procedure, additional anticholinergic administration was started. The anticholinergic drug, in this case scopolamine, was administered as one or two transdermal patches every three days. In this case, approximately 1 mg of scopolamine is released into the systemic circulation at an almost constant rate over 72 hours. Alternatively, the anticholinergic agent was administered orally every day (two days before the diagnostic procedure, the day before the diagnostic procedure, on the day of the diagnostic procedure) and up to 14 days after the diagnostic procedure. This approach provides additional protection to the sublingual gland, minor salivary glands, and lacrimal glands. Two weeks later (day 0), an imaging procedure using ⁶⁸ Ga-PSMA was performed, for example, to image the patient's prostate carcinoma during follow-up. The uptake of ⁶⁸ Ga-PSMA in the glands into which botulinum toxin was injected is significantly reduced, in contrast to, for example, the brain parenchyma. This reduced uptake protects the respective glands and ensures their normal functioning, thereby avoiding long-term side effects such as xerostomia, dry eyes and similar symptoms.

Example 3: Prevention of Radiation Damage by Use of Botulinum Toxin and Anticholinergic Agent in Diagnostic Radioligand Applications Using, for example, ¹⁸ F-PSMA and Botulinum Toxin Type A

Two weeks before the diagnostic use of ¹⁸ F-PSMA in an imaging procedure, a total of 20 to 900 units of botulinum toxin type A, 150 units in the case of Xeomin® or BOTOX®, for example, depending on the specific preparation of botulinum toxin type A, were injected into the target glands, such as the submandibular glands on one or both sides of the face and/or the parotid glands on one or both sides of the face. Three days before the ¹⁸ F-PSMA imaging procedure, additional anticholinergic administration was started. The anticholinergic drug, in this case scopolamine, was administered as one or two transdermal patches every three days. In this case, approximately 1 mg of scopolamine is released into the systemic circulation at an almost constant rate over 72 hours. Alternatively, the anticholinergic agent was administered orally every day (two days before the diagnostic procedure, the day before the diagnostic procedure, on the day of the diagnostic procedure) and up to 21 days after the diagnostic procedure. This approach also provides protection to the sublingual gland, minor salivary glands, and lacrimal glands. Two weeks later (day 0), an imaging procedure using ¹⁸ F-PSMA was performed, for example, to image the patient's prostate carcinoma during follow-up. The uptake of ¹⁸ F-PSMA in treated glands is significantly reduced, in contrast to, for example, the brain parenchyma. This reduced uptake protects the respective glands and ensures their normal functioning, thus avoiding side effects such as xerostomia, dry eyes and similar symptoms.

Example 4: Prevention of Radiation Damage by Use of Botulinum Toxin and Anticholinergic Agent in Diagnostic Radioligand Applications Using, for example, ¹⁸ F-PSMA and Botulinum Toxin Type B

Two weeks prior to the diagnostic use of ⁶⁸ Ga-PSMA in an imaging procedure, a total of 3000 units of botulinum toxin type B, such as MYOBLOC®, was injected into the target glands, such as the submandibular glands on one or both sides of the face and/or the parotid glands on one or both sides faces. Three days before the ¹⁸ F-PSMA imaging procedure, additional anticholinergic administration was started. The anticholinergic drug, in this case scopolamine, was administered as one or two transdermal patches every three days. In this case, approximately 1 mg of scopolamine is released into the systemic circulation at an almost constant rate over 72 hours. Alternatively, the anticholinergic agent was administered orally every day (two days before the diagnostic procedure, the day before the diagnostic procedure, on the day of the diagnostic procedure) and up to 21 days after the diagnostic procedure. This approach provides additional protection to the sublingual gland, minor salivary glands, and lacrimal glands. Two weeks later (day 0), an imaging procedure using ¹⁸ F-PSMA was performed, for example, to image the patient's prostate carcinoma during follow-up. The uptake of ¹⁸ F-PSMA in treated glands is significantly reduced, in contrast to, for example, the brain parenchyma. This reduced uptake protects the respective glands and ensures their normal functioning, thus avoiding side effects such as xerostomia, dry eyes and similar symptoms.

Example 5: Prevention of Radiation Damage by Use of Botulinum Toxin Type A and Anticholinergic in Radioligand Therapeutics Using, for example, ²²⁵ Ac-PSMA-617

Two weeks before the first therapeutic application of ²²⁵ Ac-PSMA-617, a total of 20 to 900 units of botulinum toxin type A, 150 units in the case of Xeomin® or BOTOX®, for example, depending on the specific preparation of botulinum toxin type A, were injected into the target glands, such as the submandibular glands on one or both sides of the face and/or the parotid glands on one or both sides of the face. Three days before therapy using ²²⁵ Ac-PSMA-617, an additional anticholinergic drug was started. The anticholinergic drug, in this case scopolamine, was administered as one or two transdermal patches every three days. In this case, approximately 1 mg of scopolamine is released into the systemic circulation at an almost constant rate. Alternatively, the anticholinergic agent was administered orally every day (two days before the therapeutic procedure, the day before the therapeutic procedure, on the day of the therapeutic procedure) and up to 21 days after the therapeutic procedure. This approach also provides protection to the sublingual gland, minor salivary glands, and lacrimal glands. Two weeks later (day 0), the first dose of ²²⁵ Ac-PSMA-617 (100 kBq/kg) was administered to initiate treatment of the patient's prostate carcinoma. The uptake of ²²⁵ Ac-PSMA-617 in treated glands is significantly reduced compared to, for example, brain parenchyma. This reduced uptake protects the respective glands and ensures their normal functioning, thus avoiding severe, long-term and irreversible side effects, such as, for example, dehydration of the eyes, which significantly impairs the quality of life, and chronic severe inflammation of the eyes and eyelid margins, Dysphagia, concomitant weight loss and inflammation of the oral mucosa, and dental damage and similar symptoms are prevented. After approximately eight weeks, another dose of ²²⁵ Ac-PSMA-617 (100 kBq/kg) was administered. Two weeks before a new therapeutic procedure, during an additional course of therapy ²²⁵ Ac-PSMA-617, a total of 20 to 900 units of botulinum toxin type A were administered, from 50 to 150 units in the case of Xeomin® or BOTOX®, for example, depending on the specific botulinum toxin type A preparation and the severity of the effect of the previous botulinum toxin injection. An additional anticholinergic drug was started three days before therapy using ²²⁵ Ac-PSMA-617. The agent was administered every day (two days before the therapeutic procedure, the day before the therapeutic procedure, on the day of the therapeutic procedure) and up to 21 days after the therapeutic procedure. At the same time, cycles of therapy with ²²⁵ Ac-PSMA-617 were carried out, which were repeated every eight weeks. Approximately four cycles of ²²⁵ Ac-PSMA-617 therapy were expected to be required.

Example 6: Prevention of Radiation Damage by Use of Botulinum Toxin Type B and Anticholinergic in Radioligand Therapeutics Using, for example, ²²⁵ Ac-PSMA-617

Two weeks before the first therapeutic application of ²²⁵ Ac-PSMA-617, a total of 3000 units of botulinum toxin type B, such as MYOBLOC®, was injected into the target glands, such as the submandibular glands on one or both sides of the face and/or the parotid glands on one or both sides faces. Three days before therapy using ²²⁵ Ac-PSMA-617, an additional anticholinergic drug was started. The anticholinergic drug, in this case scopolamine, was administered as one or two transdermal patches every three days. Approximately 1 mg of scopolamine is released into the systemic circulation at an almost constant rate. Alternatively, the anticholinergic agent was administered orally every day (two days before the therapeutic procedure, the day before the therapeutic procedure, on the day of the therapeutic procedure) and up to 21 days after the therapeutic procedure. This approach provides additional protection to the sublingual gland, minor salivary glands, and lacrimal glands. Two weeks later (day 0), the first dose of ²²⁵ Ac-PSMA-617 (100 kBq/kg) was administered to initiate treatment of the patient's prostate carcinoma. The uptake of ²²⁵ Ac-PSMA-617 in treated glands is significantly reduced compared to, for example, brain parenchyma. Said reduced uptake protects the respective glands and ensures their normal functioning, thus avoiding severe, long-term and irreversible side effects, such as, for example, dehydration of the eyes, which significantly impairs the quality of life, and chronic severe inflammation of the eyes and eyelid margins, Dysphagia, concomitant weight loss and inflammation of the oral mucosa, and dental damage and similar symptoms are prevented. After approximately eight weeks, another dose of ²²⁵ Ac-PSMA-617 (100 kBq/kg) was administered. Two weeks before the therapeutic procedure, during an additional course of therapy with ²²⁵ Ac-PSMA-617, a total of 1000 to 3000 units of botulinum toxin type B were injected into the target glands, depending on the severity of the effect of the previous botulinum toxin injection. An additional anticholinergic drug was started three days before therapy using ²²⁵ Ac-PSMA-617. The agent was administered every day (two days before the therapeutic procedure, the day before the therapeutic procedure, on the day of the therapeutic procedure) and up to 21 days after the therapeutic procedure. At the same time, cycles of therapy with ²²⁵ Ac-PSMA-617 were carried out, which were repeated every eight weeks. Approximately four cycles of ²²⁵ Ac-PSMA-617 therapy were expected to be required.

Example 7: Prevention of Radiation Damage by Use of Botulinum Toxin Type A and Anticholinergic Agent in Radioligand Therapeutics Using, for example, ¹⁷⁷ Lu-PSMA

A total of 20 to 900 units of botulinum toxin type A were injected, 150 units in the case of Xeomin® or BOTOX®, for example, depending on the specific botulinum toxin type A preparation, into the target glands, such as the submandibular glands on one or both sides of the face and/or parotid glands on one or both sides of the face. Three days before therapy using ¹⁷⁷ Lu-PSMA, an additional anticholinergic drug was administered. The anticholinergic drug, in this case scopolamine, was administered as one or two transdermal patches every three days. In this case, approximately 1 mg of scopolamine is released into the systemic circulation at an almost constant rate over 72 hours. Alternatively, the anticholinergic agent was administered orally every day (two days before the therapeutic procedure, the day before the therapeutic procedure, on the day of the therapeutic procedure) and up to 21 days after the therapeutic procedure. This approach provides additional protection to the sublingual gland, minor salivary glands, and lacrimal glands. Two weeks later (day 0), the first dose of ¹⁷⁷ Lu-PSMA (6 GBq/kg) was administered to initiate treatment of the patient's prostate carcinoma. The uptake of ¹⁷⁷ Lu-PSMA in treated glands is significantly reduced, in contrast to, for example, the brain parenchyma. This reduced uptake protects the respective glands and ensures their normal functioning, which thus avoids severe, long-term and irreversible side effects such as dry eyes, which significantly impairs the quality of life, and chronic severe inflammation of the eyes and eyelid margins, dysphagia is prevented, concomitant weight loss, inflammation of the oral mucosa, and dental damage and similar symptoms. After approximately eight weeks, another dose of ¹⁷⁷ Lu-PSMA (100 kBq/kg) was administered. One day to eight weeks before the therapeutic procedure, during an additional course of ¹⁷⁷ Lu-PSMA therapy, a total of 20 to 900 units of botulinum toxin type A were administered, from 50 to 150 units in the case of Xeomin® or BOTOX®, for example, depending on the specific botulinum toxin type A preparation and the severity of the effect of the previous botulinum toxin injection into the target glands, such as the submandibular glands on one or both sides of the face and/or the parotid glands on one or both sides of the face. An additional anticholinergic agent was administered three days before therapy using ¹⁷⁷ Lu-PSMA. The agent was administered every day (two days before the therapeutic procedure, the day before the therapeutic procedure, on the day of the therapeutic procedure) and up to 21 days after the therapeutic procedure. At the same time, cycles of ¹⁷⁷ Lu-PSMA therapy were carried out every eight weeks. Approximately four cycles of ¹⁷⁷ Lu-PSMA therapy were expected to be required.

Example 8: Prevention of Radiation Damage by Use of Botulinum Toxin Type B and Anticholinergic in Radioligand Therapeutics Using, for example, ¹⁷⁷ Lu-PSMA

Two weeks before the first therapeutic application of ¹⁷⁷ Lu-PSMA, a total of 3000 units of botulinum toxin type B, such as MYOBLOC®, was injected into the target glands, such as the submandibular glands on one or both sides of the face and/or the parotid glands on one or both sides of the face. Three days before therapy using ¹⁷⁷ Lu-PSMA, an additional anticholinergic drug was administered. The anticholinergic drug, in this case scopolamine, was administered as one or two transdermal patches every three days. Approximately 1 mg of scopolamine is released into the systemic circulation at an almost constant rate over 72 hours. Alternatively, the anticholinergic agent was administered orally every day (two days before the therapeutic procedure, the day before the therapeutic procedure, on the day of the therapeutic procedure) and up to 21 days after the therapeutic procedure. This approach provides additional protection to the sublingual gland, minor salivary glands, and lacrimal glands. Two weeks later (day 0), the first dose of ¹⁷⁷ Lu-PSMA (6 GBq/kg) was administered to initiate treatment of the patient's prostate carcinoma. The uptake of ¹⁷⁷ Lu-PSMA in treated glands is significantly reduced, in contrast to, for example, the brain parenchyma. Said reduced uptake protects the respective glands and ensures their normal functioning, thus avoiding severe, long-term and irreversible side effects, such as, for example, dehydration of the eyes, which significantly impairs the quality of life, and chronic severe inflammation of the eyes and eyelid margins, Dysphagia, concomitant weight loss and inflammation of the oral mucosa, and dental damage and similar symptoms are prevented. After approximately eight weeks, another dose of ¹⁷⁷ Lu-PSMA (100 kBq/kg) was administered. Two weeks before the therapeutic procedure, during an additional course of ¹⁷⁷ Lu-PSMA therapy, a total of 1000 to 3000 units of botulinum toxin type B were injected, depending on the specific botulinum toxin type A preparation and the severity of the effect of the previous botulinum toxin injection, into the target glands, such as the submandibular glands. glands on one or both sides of the face and/or parotid glands on one or both sides of the face. An additional anticholinergic agent was administered three days before therapy using ¹⁷⁷ Lu-PSMA. The agent was administered every day (two days before the therapeutic procedure, the day before the therapeutic procedure, on the day of the therapeutic procedure) and up to 21 days after the therapeutic procedure. At the same time, cycles of ¹⁷⁷ Lu-PSMA therapy were carried out every eight weeks. Approximately four cycles of ¹⁷⁷ Lu-PSMA therapy were expected to be required.

Example 9: Prevention of Radiation Damage by Use of Botulinum Toxin Type A in Diagnostic Radioligand Applications Using, for example, ⁶⁸ Ga-PSMA

Two weeks before the diagnostic use of ⁶⁸ Ga-PSMA in an imaging procedure, a total of 20 to 900 units of botulinum toxin type A were administered, a total of 150 units in the case of Xeomin® or BOTOX®, for example, depending on the specific preparation of botulinum toxin type A. Botulinum toxin type A were administered at a fixed dose ratio of 2/3 (into the parotid gland) to 1/3 (into the submandibular gland), i.e. 50 units of botulinum toxin type A were injected into each of the two parotid glands and 25 units of botulinum toxin type A into each of the two submandibular glands. Two weeks later (day 0), an imaging procedure using ⁶⁸ Ga-PSMA was performed, for example, to image the patient's prostate carcinoma during follow-up. The uptake of ⁶⁸ Ga-PSMA in the glands into which botulinum toxin was injected is significantly reduced, in contrast to, for example, the brain parenchyma. This reduced uptake protects the respective glands and ensures their normal functioning, thereby avoiding long-term side effects such as xerostomia, dry eyes and similar symptoms.

Example 10: Prevention of Radiation Damage by Use of Botulinum Toxin Type B in Diagnostic Radioligand Applications Using, for example, ⁶⁸ Ga-PSMA

Two weeks prior to the diagnostic use of ⁶⁸ Ga-PSMA, a total of 3000 units of botulinum toxin type B, such as MYOBLOC®, was administered in the imaging procedure. Botulinum toxin type B was administered at a fixed dose ratio of 2/3 (to the parotid gland) to 1/3 (to the submandibular gland). Given a total dose of 3000 units, this means that 1000 units of botulinum toxin type B were injected into each of the two parotid glands and 500 units of botulinum toxin type B were injected into each of the two submandibular glands. Two weeks later (day 0), an imaging procedure using ⁶⁸ Ga-PSMA was performed, for example, to image the patient's prostate carcinoma during follow-up. The uptake of ⁶⁸ Ga-PSMA in the glands into which botulinum toxin was injected is significantly reduced, in contrast to, for example, the brain parenchyma. This reduced uptake protects the respective glands and ensures their normal functioning, thereby avoiding long-term side effects such as xerostomia, dry eyes and similar symptoms.

Example 11: Prevention of Radiation Damage by Use of Botulinum Toxin Type A in Radioligand Therapeutics Using, for example, ²²⁵ Ac-PSMA-617

Two weeks before the therapeutic use of ²²⁵ Ac-PSMA-617 in the imaging procedure, a total of 20 to 900 units of botulinum toxin type A were administered, 150 units in the case of using, for example, Xeomin® or BOTOX®, depending on the specific preparation of botulinum toxin type A. Botulinum toxin type A (Xeomin® or BOTOX®) was administered at a fixed dose ratio of 2/3 (into the parotid gland) to 1/3 (into the submandibular gland), i.e. injected 50 units of botulinum toxin type A into each of the two parotid glands and 25 units of botulinum toxin type A into each of the two submandibular glands. Two weeks later (day 0), the first dose of ²²⁵ Ac-PSMA-617 (100 kBq/kg) was administered to initiate treatment of the patient's prostate carcinoma. The uptake of ²²⁵ Ac-PSMA-617 in treated glands is significantly reduced compared to, for example, brain parenchyma. This reduced uptake protects the respective glands and ensures their normal functioning, which thus avoids severe, long-term and irreversible side effects such as dry eyes, which significantly impairs the quality of life, and chronic severe inflammation of the eyes and eyelid margins, dysphagia is prevented, concomitant weight loss and inflammation of the oral mucosa, and dental damage and similar symptoms. After approximately eight weeks, another dose of ²²⁵ Ac-PSMA-617 (100 kBq/kg) was administered. During an additional course of therapy with ²²⁵ Ac-PSMA-617, a total of 20 to 900 units of botulinum toxin type A were administered two weeks before the therapeutic procedure, a total of 50 to 150 units in the case of Xeomin® or BOTOX®, for example, depending on the severity effect of a previous botulinum toxin injection. Botulinum toxin type A (Xeomin® or BOTOX®) was administered at a fixed dose ratio of 2/3 (to the parotid gland) to 1/3 (to the submandibular gland). At the same time, cycles of therapy with ²²⁵ Ac-PSMA-617 were carried out every eight weeks. Approximately four cycles of ²²⁵ Ac-PSMA-617 therapy were expected to be required.

Example 12: Prevention of Radiation Damage by Use of Botulinum Toxin Type B in Radioligand Therapeutics Using, for example, ²²⁵ Ac-PSMA-617

Two weeks prior to therapeutic use of ²²⁵ Ac-PSMA-617, a total of 3000 units of botulinum toxin type B, such as MYOBLOC®, was administered in the imaging procedure. Botulinum toxin type B was administered at a fixed dose ratio of 2/3 (to the parotid gland) to 1/3 (to the submandibular gland). Given a total dose of 3000 units, this means that 1000 units of botulinum toxin type B were injected into each of the two parotid glands and 500 units of botulinum toxin type B were injected into each of the two submandibular glands. Two weeks later (day 0), the first dose of ²²⁵ Ac-PSMA-617 (100 kBq/kg) was administered to initiate treatment of the patient's prostate carcinoma. The uptake of ²²⁵ Ac-PSMA-617 in treated glands is significantly reduced compared to, for example, brain parenchyma. This reduced uptake protects the respective glands and ensures their normal functioning, which thus avoids severe, long-term and irreversible side effects such as dry eyes, which significantly impairs the quality of life, and chronic severe inflammation of the eyes and eyelid margins, dysphagia is prevented, concomitant weight loss and inflammation of the oral mucosa, and dental damage and similar symptoms. After approximately eight weeks, another dose of ²²⁵ Ac-PSMA-617 (100 kBq/kg) was administered. Two weeks before the therapeutic procedure, during an additional course of therapy with ²²⁵ Ac-PSMA-617, a total of 1000 to 3000 units of botulinum toxin type B were administered, depending on the severity of the effect of the previous botulinum toxin injection. In parallel, cycles of therapy with ²²⁵ Ac-PSMA-617 were carried out every eight weeks. Approximately four cycles of ²²⁵ Ac-PSMA-617 therapy were expected to be required.

Example 13: Prevention of Radiation Damage by Use of Botulinum Toxin Type A and Anticholinergic Agent in Therapeutic Application ¹⁷⁷ Lu-PSMA-617

Two weeks (14 days) before therapeutic use of ¹⁷⁷ Lu-PSMA-617, a total of 120 units of botulinum toxin type A (Xeomin®) were administered. Botulinum toxin type A was injected into the parotid glands on both sides (40 units each) and into the submandibular glands (20 units each).

An additional anticholinergic agent was administered three days before therapy using ¹⁷⁷ Lu-PSMA-617. An anticholinergic drug, in this case scopolamine, was administered as a transdermal patch every three days. In this method, approximately 1 mg of scopolamine is released into the systemic circulation at an almost constant rate over 72 hours. The scopolamine patch was replaced on day 0 and day 3 of ¹⁷⁷ Lu-PSMA-617 therapy, such that the patient received an additional dose of scopolamine for up to six days after therapy. This provides additional protection to the sublingual gland, minor salivary glands and lacrimal glands.

Immediately before starting ¹⁷⁷ Lu-PSMA-617/day 0 therapy, saliva production was normal. In this case, the amount of saliva was 5.7 grams in the Saxon test, with the normal range being ≥2.75 grams of saliva produced in two minutes of chewing. Two weeks later (day 0), the first dose ^{of 177} Lu-PSMA-617 (6 GBq/kg) was administered to initiate treatment of the patient's prostate carcinoma.

Approximately eight weeks later (day 56), another dose ^{of 177} Lu-PSMA-617 (6 GBq/kg) was administered. After completion of treatment (two cycles of therapy on days 0 and 56) and a follow-up period of approximately eight weeks, saliva production remained at normal, unchanged levels on day 108. In this case, the amount of saliva in the Saxon test was 5.5 grams, while the norm is ≥ 2.75 grams of saliva produced in two minutes of chewing. There were no difficulties with swallowing. No dry eyes were noted.

Example 14: Prevention of Radiation Damage by Use of Botulinum Toxin Type A in Therapeutic Use ¹⁷⁷ Lu-PSMA-617

Two and a half weeks (18 days) before therapeutic use of ¹⁷⁷ Lu-PSMA-617, a total of 150 units of botulinum toxin type A (Xeomin®) was administered. Botulinum toxin type A was injected asymmetrically (100 units) into the right parotid gland and into the opposite left submandibular gland (50 units).

Immediately before starting ¹⁷⁷ Lu-PSMA-617/day 0 therapy, saliva production was normal. In this case, the amount of saliva in the Saxon test was 4.6 grams, with the norm being ≥ 2.75 grams of saliva produced in two minutes of chewing. Two and a half weeks later (day 0), the first dose ^{of 177} Lu-PSMA-617 (6 GBq/kg) was administered to initiate treatment of the patient's prostate carcinoma.

Approximately eight weeks later (day 56), another dose ^{of 177} Lu-PSMA-617 (6 GBq/kg) was administered. After completion of treatment (two cycles of therapy on days 0 and 56) and a follow-up period of approximately eight weeks, saliva production remained at normal, unchanged levels on day 116. In this case, the amount of saliva in the Saxon test was 4.3 grams, with the standard value being ≥2.75 grams of saliva produced in two minutes of chewing. Dysphagia did not occur. No dry eyes were noted.

Example 15: Prevention of Radiation Damage by Use of Botulinum Toxin Type B in Therapeutic Use ¹⁷⁷ Lu-PSMA-617

Two weeks (13 days) before therapeutic use of ¹⁷⁷ Lu-PSMA-617, a total of 6000 units of botulinum toxin type B (Neurobloc®) was administered. Botulinum toxin type B was injected asymmetrically (4000 units) into the right parotid gland and into the opposite left submandibular gland (2000 units).

Immediately before starting ¹⁷⁷ Lu-PSMA-617/day 0 therapy, saliva production was normal. Two and a half weeks later (day 0), the first dose ^{of 177} Lu-PSMA-617 (6 GBq/kg) was administered to initiate treatment of the patient's prostate carcinoma.

Approximately eight weeks later (day 56), another dose ^{of 177} Lu-PSMA-617 (6 GBq/kg) was administered. After completion of treatment (two cycles of therapy on days 0 and 56) and a follow-up period of approximately eight weeks, saliva production remained at normal, unchanged levels on day 116. Dysphagia did not occur. No dry eyes were noted.

Based on Examples 13-15, the following additional treatments are planned for the following four patient groups:

1) Middle-aged patients 50-75 years old

2) Elderly patients >75 years old

3) Multimorbid patients and/or patients with mild cognitive impairment (MCI)

4) Patients with short life expectancy < 1.5 years

Example 16: Treatment Plan for Group 1 Patients (Middle Age, 50-75 Years): Prevention of Radiation Damage with Botulinum Toxin Type A and Anticholinergic Therapeutic Use ²²⁵ Ac-PSMA-617

Three weeks (21 days) before therapeutic use of ²²⁵ Ac-PSMA-617, a total of 150 units of botulinum toxin type A (Xeomin®) is administered. Botulinum toxin type A is injected on both sides into the parotid glands (50 units each) or submandibular glands (25 units each) (i.e., at a ratio of 2/3 to the parotid glands to 1/3 to the submandibular glands).

Additionally, an anticholinergic agent is administered three days before therapy using ²²⁵ Ac-PSMA-617. An anticholinergic drug, in this case scopolamine, is administered as a transdermal patch every three days. In this case, approximately 1 mg of scopolamine is released into the systemic circulation at an almost constant rate over 72 hours. Replace the indicated scopolamine patch on day 0 and day 3 and day 6 of ²²⁵ Ac-PSMA-617 therapy, so that the patient receives an additional dose of scopolamine for up to nine days after therapy. This approach also provides protection to the sublingual salivary gland, minor salivary glands, and lacrimal glands.

Example 17: Treatment Plan for Group 2 Patients (Age 75 Years or Older): Prevention of Radiation Damage with Botulinum Toxin Type B in Therapeutic Use ²²⁵ Ac-PSMA-617

Two weeks (14 days) before the therapeutic use of ²²⁵ Ac-PSMA-617, a total of 6000 units of botulinum toxin type B (Neurobloc®) is administered. Botulinum toxin type A is injected into the parotid glands (2000 units each) or submandibular glands (1000 units each) on both sides (i.e., at a ratio of 2/3 to the parotid glands to 1/3 to the submandibular salivary glands).

Example 18: Treatment Plan for Patients in Groups 3+4 (Multimorbid Patients/Patients with MCI/Patients with Reduced Life Expectancy): Prevention of Radiation Damage by Using Botulinum Toxin Type A in Therapeutic Use ²²⁵ Ac-PSMA-617

Three weeks (21 days) before the therapeutic use of ²²⁵ Ac-PSMA-617, a total of 150 units of botulinum toxin type A (Xeomin®) is planned to be administered. It is planned to inject botulinum toxin type A asymmetrically as part of high-dose monotherapy (100 units) on one side into the right parotid gland or on one side into the left submandibular gland (50 units) (i.e., at a ratio of 2/3 in the parotid gland to 1/3 into the submandibular gland).

The term “high-dose botulinum toxin A (Xeomin®) monotherapy” refers to the appropriate administration of a single dose to two glands, which corresponds to a previously unpublished dose range for each gland, but is well tolerated, as can be seen in patients who have already received treatment. High-dose glandular monotherapy should not be administered to all four glands in this patient population to prevent dysphagia. Asymmetric monotherapy with botulinum toxin type A into only one parotid and one contralateral submandibular gland also avoids anticholinergic-related side effects in patients in group 3. The two initially unchanged glands that were not injected, which had initial salivary production, were reduced (to their complete damage in the second, third or fourth course of treatment ²²⁵ Ac-PSMA-617) duration of xerostomia during therapy due to the complete destruction of two of the four salivary glands caused by repeated courses of treatment ²²⁵ Ac-PSMA-617, and thus indicated The method is particularly suitable for patients in group 4 with a short life expectancy in terms of quality of life.

Claims (29)

1. Use of botulinum toxin in combination with an anticholinergic agent to prevent radiation damage to glands in a patient in need where radiation damage is caused by radioligands. 2. Use according to claim 1, characterized in that said radiation damage is caused by a PSMA radioligand. 3. Application according to claim 1 or 2, characterized in that said radiation damage is selected from the group consisting of damage ²²⁵ Ac-PSMA, ⁶⁸ Ga-PSMA, ¹⁸ F-PSMA or ¹⁷⁷ Lu-PSMA. 4. Use according to claim 1, characterized in that said botulinum toxin is selected from the group consisting of botulinum toxins types A, B, C, D, E, F and G. 5. Use according to any of the preceding paragraphs, characterized in that said botulinum toxin contains from 1 to 10,000 units. 6. Use according to any of the preceding claims, characterized in that said botulinum toxin is botulinum toxin type A. 7. Use according to any of the preceding paragraphs, where the amount of botulinum toxin type A is from 1 to 1500 units. 8. Application according to any one of paragraphs. 1-5, characterized in that said botulinum toxin is botulinum toxin type B. 9. Application according to any one of paragraphs. 1-5, 8, where the amount of botulinum toxin type B is from 100 to 10,000 units. 10. Application according to any one of paragraphs. 1-5, characterized in that said botulinum toxin is botulinum toxin type E or type F. 11. Application according to any one of paragraphs. 1-5, 10, where the amount of botulinum toxin type E or type F is from 1 to 10,000 units. 12. Use according to any of the preceding claims, characterized in that said anticholinergic agent is selected from the group consisting of tropicamide, atropine, scopolamine, glycopyrrolate, amitriptyline, clonidine, ipratropium bromide and trihexylphenidyl. 13. Use according to any of the preceding claims, characterized in that said anticholinergic agent is administered transdermally, orally or intravenously. 14. Use according to any of the preceding claims, characterized in that said anticholinergic agent is scopolamine, and wherein the scopolamine is administered transdermally. 15. The use of any of the preceding claims, wherein the prevention includes administration of botulinum toxin one day to eight weeks before a diagnostic imaging procedure or before radiological treatment using one or more radioligands. 16. The use of any of the preceding claims, wherein the prevention includes the administration of an anticholinergic agent three days, two days, the day, or the same day before a diagnostic imaging procedure or radiological treatment using one or more radionuclides, and from approximately 7 to 30 days after a diagnostic imaging procedure or radiological treatment. 17. The use of any of the preceding claims, wherein the prevention includes the administration of botulinum toxin one day to eight weeks, and the administration of said anticholinergic agent three days, two days, the day or the same day before the diagnostic imaging procedure or radiological treatment using one or more radionuclides, and from about 7 to 30 days after the diagnostic imaging procedure or radiological treatment. 18. Use according to any of the preceding claims, characterized in that said glands are exocrine and/or endocrine glands. 19. Use according to any of the preceding claims, characterized in that said gland is a seromucous gland. 20. Use according to any of the preceding claims, characterized in that the patients have already received antiandrogen therapy or are undergoing antiandrogen therapy. 21. A method of preventing radiation damage to the parotid, submandibular, sublingual, minor salivary and lacrimal glands, comprising introducing botulinum toxin type B from opposite sides into the corresponding parotid gland or submandibular gland, wherein the radiation damage is caused by radioligands. 22. The method according to claim 21, characterized in that said botulinum toxin type B is administered in doses of 2/3 to the parotid glands and 1/3 to the submandibular glands. 23. A method of preventing radiation damage to glands, comprising administering botulinum toxin type A to a patient in need thereof from opposite sides into the corresponding parotid gland or submandibular gland. 24. The method according to claim 23, characterized in that botulinum toxin type A is injected into the parotid gland in an amount of 100 units, and botulinum toxin type A is injected into the corresponding opposite submandibular gland in an amount of 50 units. 25. The method according to claim 23, characterized in that said botulinum toxin type A is administered in doses of 2/3 to the parotid glands and 1/3 to the submandibular glands. 26. The method of claim 23, wherein said patient has a life expectancy of six to twelve months. 27. The method according to claim 23, characterized in that the age of said patient is 75 years or more. 28. The method according to claim 23, characterized in that said patient suffers from mild cognitive impairment or dementia. 29. The method according to claim 23, characterized in that said patient is co- or multimorbid.