CN111658647A

CN111658647A - Use of thalidomide and derivatives thereof

Info

Publication number: CN111658647A
Application number: CN201910175717.2A
Authority: CN
Inventors: 张鸿祺; 于嘉兴; 洪韬; 汪一波
Original assignee: Xuanwu Hospital
Current assignee: Xuanwu Hospital
Priority date: 2019-03-08
Filing date: 2019-03-08
Publication date: 2020-09-15
Also published as: WO2020182094A1

Abstract

The present application provides the use of thalidomide or a thalidomide derivative for the manufacture of a medicament for the treatment of arteriovenous malformations. The present application also provides pharmaceutical compositions comprising thalidomide or a thalidomide derivative for use in the treatment of arteriovenous malformations. The present application also provides a method of treating arteriovenous malformations comprising administering to an individual in need thereof an effective amount of thalidomide or a thalidomide derivative.

Description

Use of thalidomide and derivatives thereof

Technical Field

The present application relates generally to the field of medicine. In particular, the present application relates to novel pharmaceutical uses of thalidomide and its derivatives, more particularly for the treatment of arteriovenous malformations.

Background

Arteriovenous malformations (AVMs) are a class of vascular dysplastic diseases consisting of a blood-supplying artery, a drainage vein and an arteriovenous short circuit therebetween. Because of the loss of capillary network, the arterial blood with extremely high pressure directly enters the venous system, so a series of pathophysiological changes such as bleeding, local venous hypertension, blood stealing, space occupying effect and the like are caused, corresponding clinical symptoms are generated, and the high lethal and disabling rate is achieved. AVM affects most tissues and organs of the human body, such as the brain, spinal cord, skin, muscle, bone and organs, and the cerebral arteriovenous malformation (BAVM) and spinal arteriovenous malformation (SAVM) are collectively called central nervous system arteriovenous malformations. The incidence rate of central nervous system arteriovenous malformation is about one hundred thousand, and the central nervous system arteriovenous malformation is one of the main diseases treated by neurosurgery. Clinically, common arteriovenous malformations are sporadic lesions and have no genetic tendency. In addition, some rare genetic diseases, such as Hereditary Hemorrhagic Telangiectasia (HHT), capillary malformation-arteriovenous malformation (CM-AVM), etc., may be manifested as multiple arteriovenous malformations throughout the body.

Current treatment modalities for AVM include surgical resection, interventional embolization, and radiation therapy. However, due to the complex lesion structure, the treatment difficulty is high, particularly, the arteriovenous malformation of the brain and the spinal cord has close anatomical relationship with the central nervous system, the treatment related risk is extremely high, most lesions can not be cured, and only partial occlusion can be realized, even the treatment can not be performed. According to literature statistics, the overall cure rate of the central nervous system AVM is less than 40%. Meanwhile, a great deal of research suggests that the AVM is a dynamically-developed lesion, the structural change or proliferation phenomenon of the lesion is not rare, and the proliferation or structural change increases the risk of a long-term clinical event. In addition, multicenter RCT studies such as ARUBA suggest that the natural medical history of unbroken BAVM is superior to clinical risk following surgical intervention. Thus, the traditional treatment modalities of AVM are not ideal and require clinicians to explore new treatment modalities.

Thalidomide (Thalidomide), also known as Thalidomide, is a glutamic acid derivative. This drug was first marketed in 1957 as a sedative hypnotic and emetic inhibitor in federal germany and was later released in 1961 because of its potent teratogenic effect. However, later researches find that one of the important teratogenesis mechanisms of thalidomide is that the drug has a strong anti-angiogenesis effect and inhibits the development of fetal limb blood vessels. In addition, thalidomide is an immunomodulator, can reduce various inflammatory factors such as TNF-alpha and IL-6, and enhance the activity of T cells. These findings have led to the reapplication of thalidomide in clinical settings, and are now useful in the treatment of immune-related diseases such as inflammatory bowel disease, systemic lupus erythematosus, ankylosing spondylitis, and type II leprosy, as well as multiple myeloma, prostate cancer, breast cancer, liver cancer, ovarian cancer, melanoma, and other malignancies.

Summary of The Invention

In a first aspect, the present application provides the use of thalidomide or a thalidomide derivative in the manufacture of a medicament for the treatment of arteriovenous malformations.

In some embodiments, the thalidomide derivative is selected from the group consisting of lenalidomide, pomalidomide and apremilast.

In some embodiments, the arteriovenous malformation is a central nervous system arteriovenous malformation. In some embodiments, the arteriovenous malformation is a cerebral arteriovenous malformation or a spinal arteriovenous malformation.

In some embodiments, the arteriovenous malformation is a non-central nervous system arteriovenous malformation.

In some embodiments, the arteriovenous malformation is a somite arteriovenous malformation.

In some embodiments, the arteriovenous malformation is a sporadic arteriovenous malformation.

In a second aspect, the present application provides a pharmaceutical composition comprising thalidomide or a thalidomide derivative for use in the treatment of arteriovenous malformations.

In some embodiments, the arteriovenous malformation is a cutaneous arteriovenous malformation.

In a third aspect, the present application provides a method of treating arteriovenous malformations comprising administering to an individual in need thereof an effective amount of thalidomide or a thalidomide derivative.

Brief description of the drawings

Fig. 1 shows images of a cranial nmr examination of a patient with arteriovenous malformations before (left panel) and 1 month (after) administration of thalidomide.

Fig. 2 shows mri images of cervical vertebrae of a patient with a somite spinal cord arteriovenous malformation before (left) and 1 month after (left) administration of thalidomide.

Figure 3 shows photographs of the appearance of the cervical cutaneous vascular malformations of patients with the somite spinal cord arteriovenous malformations of figure 2 before (left panel) and 1 month (after) dosing with thalidomide.

Detailed description of the invention

The inventors of the present application have conducted years of research and practice in the field of neurosurgery, where arteriovenous malformations are the more common type of neurosurgical disease. Because the pathological change structure of the arteriovenous malformation is more complex, the surgical treatment has higher difficulty, and particularly, the arteriovenous malformation of the brain and the spinal cord has close anatomical relationship with the central nervous system, and the surgical treatment risk is very high. Therefore, the inventors of the present application have conducted extensive research and study on the treatment of arteriovenous malformations with drugs, and have established various inventions of the present application.

The structural formula of Thalidomide (Thalidomide) is shown as follows

Thalidomide derivatives, also known as thalidomide analogs or thalidomide compounds, are compounds developed based on the core structure of thalidomide. A variety of thalidomide derivatives have been developed, including but not limited to:

lenalidomide (Lenalidomide)

Pomalidomide (Pomalidomide)

And

apremilast (Apremilast)

Compared with lenalidomide and pomalidomide which are structural analogues of thalidomide, apremilast is obtained by grafting known action structures on the basis of the structural analogues of thalidomide and optimizing the known action structures. According to the current reports, thalidomide derivatives are thought to exert biological effects in a similar manner, but the intrinsic mechanism has not been fully elucidated.

With respect to clinical phenotypes, arteriovenous malformations include sporadic arteriovenous malformations and familial arteriovenous malformations (e.g., HHT-associated arteriovenous malformations). The clinical characteristics of the two types of lesions are also obviously different, and clinical researches find that the central nervous system lesion of the familial AVM has smaller volume and lower bleeding rate than the diffused lesion. The difference in imaging performance is that sporadic arteriovenous malformations are more likely to be of a compact mass type, and familial venous malformations are mostly of a diffuse type.

Research has shown that the pathogenesis of sporadic arteriovenous malformation and familial arteriovenous malformation is different at the gene level, and the mutant gene and the genetic mechanism involved in the occurrence of the two types of pathological changes are different. More than 90% of sporadic AVMs were found to have somatic mutations in KRAS and its downstream genes, whereas familial AVMs have been clearly caused by germline mutations in the Engolin, ACVRL1, MADH4 and RASA1 genes, and the direct downstream pathways of genes involved in familial arteriovenous malformations and sporadic arteriovenous malformations do not overlap.

In terms of the diseased site, arteriovenous malformations include central nervous system arteriovenous malformations, non-central nervous system arteriovenous malformations (also referred to as "other site arteriovenous malformations"), and somite arteriovenous malformations (with central nervous system and other site arteriovenous malformations). Arteriovenous malformations of the central nervous system include cerebral arteriovenous malformations or spinal arteriovenous malformations. Non-central nervous system arteriovenous malformations may involve skin, muscle, bone, and various organs. At present, the pathogenic factors of different pathogenic parts of arteriovenous malformation are not completely clarified.

The inventors of the present application have unexpectedly found that thalidomide or a thalidomide derivative has a therapeutic effect on arteriovenous malformations, particularly sporadic arteriovenous malformations (e.g., arteriovenous malformations of the human central nervous system and somite arteriovenous malformations of the skin and muscle vessels) while not having a significant effect on normal blood vessels of patients. The prior art has certain reports on the pharmacological effects of thalidomide or thalidomide derivatives, such as angiogenesis inhibition, immunoregulation and the like, but the pharmacological effects cannot completely and reasonably explain the treatment results observed by the inventor of the application.

In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable carrier, excipient, or diluent.

The administration of thalidomide or a thalidomide derivative in pure form or in a suitable pharmaceutical composition can be carried out by any acceptable mode of administration of the agents used for a similar purpose. Pharmaceutical compositions can be prepared by mixing thalidomide or a thalidomide derivative with a suitable pharmaceutically acceptable carrier, diluent or excipient, and can be formulated into preparations in solid, semisolid, liquid or gaseous form, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols. Standard routes of administration for such pharmaceutical compositions include, without limitation, oral, topical, transdermal, inhalation, parenteral, sublingual, rectal, vaginal, and intranasal. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. The pharmaceutical compositions are formulated so that the active ingredients contained therein are biologically effective when the compositions are administered to a patient. The compositions for administration to a subject or patient are in the form of one or more dosage units, where, for example, a tablet can be one dosage unit. The actual method of preparing such dosage forms is known to those skilled in the art, see, for example, the Science and Practice of Pharmacy, 20 th edition (Philadelphia Collegeof Pharmacy and Science, 2000). In any event, the composition to be administered comprises a therapeutically effective amount of thalidomide or a thalidomide derivative for the treatment of arteriovenous malformations in accordance with the teachings herein.

The pharmaceutical compositions herein also comprise a pharmaceutically acceptable carrier comprising any suitable diluent or excipient, which comprises any agent that does not itself induce the production of antibodies harmful to the individual receiving the composition, and which may be administered without undue toxicity. Pharmaceutically acceptable carriers include, but are not limited to, liquids such as water, saline, glycerol, ethanol, and the like. A detailed discussion of pharmaceutically acceptable carriers, diluents and other excipients is provided in REMINGTON' S PHARMACEUTICAL SCIENCES (Mack pub.co., n.j. current edition).

The pharmaceutical composition may be in solid or liquid form. In one aspect, the carrier is a microparticle, such that the composition is in the form of, for example, a tablet or powder. When the composition is, for example, an oral syrup, an injectable liquid, or an aerosol useful, for example, in administration by inhalation, the carrier can be a liquid.

When intended for oral administration, the pharmaceutical composition is preferably in a solid or liquid form, wherein semi-solid, semi-liquid, suspension and gel forms are encompassed within the solid or liquid forms contemplated herein.

As a solid composition for oral administration, the pharmaceutical composition may be formulated into the form of powder, granules, compressed tablets, pills, capsules, chewables, poultices, and the like. Typically, such solid compositions comprise one or more inert diluents or edible carriers. Furthermore, one or more of the following may be present: a binder such as carboxymethyl cellulose, ethyl cellulose, microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch, lactose or dextrin, disintegrants such as alginic acid, sodium alginate, sodium starch glycolate, corn starch, etc.; lubricants such as magnesium stearate or hydrogenated vegetable oil; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; flavoring agents such as peppermint, methyl salicylate, or orange flavoring; and a colorant.

When the pharmaceutical composition is in the form of a capsule, for example a gelatin capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or an oil.

The pharmaceutical compositions may be in liquid form, such as elixirs, syrups, solutions, emulsions or suspensions. The liquid may be used in two example forms for oral administration or for delivery by injection. When intended for oral administration, the composition may also contain one or more sweetening agents, preserving agents, coloring agents/colorants and taste-enhancing agents. In compositions intended for administration by injection, one or more surfactants, preservatives, wetting agents, dispersing agents, suspending agents, buffering agents, stabilizing agents, and isotonicity agents may be included.

Whether or not the liquid pharmaceutical compositions are in the form of solutions, suspensions, etc., they may contain one or more of the following adjuvants: sterile diluents such as water for injection, saline solutions, preferably physiological saline, ringer's solution, isotonic sodium chloride, non-volatile oils such as synthetic mono-or diglycerides which may serve as a solvent or suspending medium, polyethylene glycols, glycerol, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tension such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Physiological saline is a preferred adjuvant. Preferably, the injectable pharmaceutical composition is sterile.

Liquid pharmaceutical compositions intended for parenteral or oral administration should contain thalidomide or a thalidomide derivative in an amount such that a suitable dosage is obtained. Typically, the amount is at least 0.01% thalidomide or a thalidomide derivative in the composition. When intended for oral administration, the amount may vary from 0.1% to about 70% by weight of the composition. Preferred oral pharmaceutical compositions comprise from about 4% to about 50% thalidomide or a thalidomide derivative.

Pharmaceutical compositions may comprise a variety of materials that modify the physical form of solid or liquid dosage units. For example, the composition may comprise a material that forms an envelope surrounding the active ingredient. Typically, the material forming the coating is inert and may be selected from, for example, sugars, shellac, and other enteric coating agents. Alternatively, the active ingredient may be packaged in gelatin capsules.

The pharmaceutical compositions may be prepared by methods well known in the pharmaceutical art. For example, pharmaceutical compositions intended for administration by injection are prepared by combining thalidomide or a thalidomide derivative with sterile, distilled water to form a solution. Surfactants may be added to promote the formation of a homogeneous solution or suspension. Surfactants are compounds that interact non-covalently with a compound to facilitate dissolution or uniform suspension of the compound in an aqueous delivery system.

The term "individual" herein refers to an individual, typically a mammal, suffering from an arteriovenous malformation. Examples of mammals include, but are not limited to, any member of the mammalian class, e.g., humans, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs, and the like. In one embodiment herein, the mammal is a human. It will be appreciated by those skilled in the art that thalidomide or a thalidomide derivative should be administered in a therapeutically effective amount. The therapeutically effective amount will vary depending on a variety of factors, including the activity of the particular compound employed; compound metabolic stability and duration of action; the age, weight, health, sex, and diet of the patient; the method and time of administration; the rate of drainage; a pharmaceutical composition; the severity of a particular disorder or disease state; and problems undergoing therapy. Taking the daily dosage of a human individual as an example, for an adult, the initial dosage may be 25mg (less than 30Kg), 50mg (30-60Kg), 75mg (more than 60 Kg); if no obvious adverse reaction exists, 25mg can be added every 2 weeks; the highest dose can be 50mg (less than 30Kg), 150mg (30-60Kg), 200mg (more than 60 Kg); for minors, the initial dose may be 25mg (less than 30Kg), 50mg (30-60Kg), 75mg (more than 60 Kg); if no obvious adverse reaction exists, 25mg can be added every 2 weeks; the maximum dose may be 50mg (less than 30Kg), 100mg (30-60Kg), 150mg (more than 60 Kg).

The effective dosage ranges provided herein are not intended to be limiting and represent preferred dosage ranges. However, as understood and determinable by those skilled in The relevant art, The most preferred dose is adjusted for individual individuals (see, e.g., Berkow, eds., The Merck Manual, 16 th edition, Merck and Co., Rahway, N.J., 1992; Goodmanetna, eds., Goodman and Cilman's The Pharmacological Basis of science of Goodman and Cilman, 10 th edition, Pergamon Press, Inc., Elmsord, N.Y. (2001); Avery's Treatment: Principles and clinical Practice; 3 rd edition, Principles and clinical Practice of pharmaceuticals and Therapeutics, William, Australia and biological, Australia Co., Australia, Aust, basic and Clinical Pharmacology, Mack Publishing Co., Easton, Pa. (1992)).

If necessary, the total dose required for each treatment is given in multiple doses or in one dose over the course of a day. Typically, treatment is initiated with a smaller dose than the optimal dose of the compound. Thereafter, the dose is increased by small increments until the optimum effect is achieved under the circumstances. The diagnostic pharmaceutical compound or composition can be administered alone or in combination with other diagnostic methods and/or drugs related to the pathology or to the symptoms of other pathologies.

Examples

The following examples are provided merely to illustrate some embodiments of the present application and are not intended to be limiting in any way.

This example used thalidomide to conduct a clinical trial in which 8 sporadic central nervous system arteriovenous malformations and other arteriovenous malformations were treated with thalidomide. The curative effect of thalidomide on vascular malformation of patients is observed by various means such as imaging means (deep tissue arteriovenous malformation) such as MRI or DSA, direct vision observation (skin arteriovenous malformation), pathological examination, neurology department physical examination (neurological dysfunction of patients with spinal arteriovenous malformation through mALS score or neurological dysfunction of patients with cerebral arteriovenous malformation through mRS score) and related biological marker detection.

Patients with sporadic central nervous system arteriovenous malformations and other arteriovenous malformations incorporated in this example include:

patients with cerebral arteriovenous malformations;

patients with spinal arteriovenous malformation; and

patients with segment arteriovenous malformation

The research scheme is as follows: selecting patients with arteriovenous malformation meeting the selection standard, signing an informed consent, collecting baseline information of the patients, giving thalidomide oral treatment, and evaluating the curative effect of the patients by the corresponding examination means every month after receiving the treatment.

The research results are as follows: after 8 patients take thalidomide (25mg-100mg) for 1 month, 7 patients (87.5%) were evaluated for improvement by the above-mentioned various examination measures. Adverse reactions included constipation (3 cases) and numbness of limbs (1 case), with specific results shown in table 1.

TABLE 1

- -: the failure to evaluate means that the corresponding case cannot be evaluated for the corresponding item due to objective reasons, for example, the case may have no corresponding symptoms and thus cannot be evaluated.

The following is an example of the case of two patients.

The patient female (case number 1 in Table 1) was diagnosed with cerebral arteriovenous malformation by cerebral hemorrhage by cranial NMR examination. The cerebral arteriovenous malformation embolization is performed for 2 times before, and the focus of infection cannot be embolized effectively due to large lesion volume and dispersed structure. According to the treatment protocol of this example, patients were orally administered thalidomide (50mg-75mg)1 month every night 1 hour before sleep, and review of MRI suggested a significant reduction in lesion size compared to that before dosing (see figure 1). During the administration period, the patient complains about the transient tremor of both lower limbs and relieves himself.

The patient male (case No. 3 in Table 1) had cervical magnetic resonance suggesting a nodular spinal cord vascular abnormality due to neck pain with limb weakness progressive increase for 3 months, and admission mALS scored 2 points. Because the lesion range of a patient is wide, the traditional treatment mode cannot effectively treat the lesion. According to the treatment scheme of the embodiment, the patient takes thalidomide (75mg-125mg) orally 1 month every 1 hour before sleeping at night, the symptoms are obviously relieved, spinal cord edema obviously subsides as seen by magnetic resonance (see figure 2), and physical examination shows that the color of the neck skin vascular malformation becomes lighter as compared with the former color as the mALS score is 1 point (see figure 3).

All publications and patent documents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference. Various changes may be made and equivalents may be substituted for elements thereof without departing from the true spirit and scope of the disclosure. Unless the context indicates otherwise, any feature, step, or embodiment of an embodiment of the present disclosure may be used in combination with any other feature, step, or embodiment.

Claims

1. Use of thalidomide or a thalidomide derivative for the manufacture of a medicament for the treatment of arteriovenous malformations.

2. The use of claim 1, wherein the thalidomide derivative is selected from the group consisting of lenalidomide, pomalidomide and apremilast.

3. Use according to claim 1 or 2, wherein the arteriovenous malformation is a central nervous system arteriovenous malformation, such as a cerebral arteriovenous malformation or a spinal arteriovenous malformation.

4. The use of claim 1 or 2, wherein the arteriovenous malformation is a non-central nervous system arteriovenous malformation.

5. The use of claim 1 or 2, wherein the arteriovenous malformation is a somite arteriovenous malformation.

6. The use of claim 4 or 5, wherein the arteriovenous malformation is a cutaneous arteriovenous malformation.

7. The use of any one of claims 1-6, wherein the arteriovenous malformation is a sporadic arteriovenous malformation.

8. A pharmaceutical composition comprising thalidomide or a thalidomide derivative for use in the treatment of arteriovenous malformations.

9. A method of treating arteriovenous malformations comprising administering to an individual in need thereof an effective amount of thalidomide or a thalidomide derivative.