KR20030047907A - Method of Treating Peripheral Vascular Diseases, Peripheral Neuropathies, and Autonomic Neuropathies - Google Patents

Abstract

The present invention relates to a method of treating a patient with peripheral vascular disease, peripheral neuropathy or autonomic neuropathy by administering a cGMP PDE5 inhibitor such as sildenafil. This method is particularly applicable to diabetic foot ulcers, Raynaud's phenomenon, CREST syndrome, Lupus, rheumatic diseases, diabetic retinopathy and angina. In accordance with the present invention the cGMP PDE5 inhibitor may be administered as a prophylactic to patients who are likely to cause peripheral vascular disease, peripheral neuropathy or autonomic neuropathy.

Description

Method of Treating Peripheral Vascular Diseases, Peripheral Neuropathies, and Autonomic Neuropathies

The present invention relates to the use of cyclic guanosine 3 ', 5'-monophosphate type 5 (cGMP PDE5) inhibitors, including the compound sildenafil, in the treatment of peripheral vascular diseases, peripheral neuropathy, autonomic neuropathy, especially diseases associated with diabetes. It is about.

Peripheral vascular disease and diseases associated with autonomic neuropathy vary widely, consistent in terms of chronic pathological symptoms and difficulty in treatment. Many of these diseases are associated with diabetes mellitus. Although other diseases are not known to be associated with diabetes, the pathology of the peripheral vascular system is similar. Such diseases include Raynaud's phenomenon, including CREST syndrome, autoimmune diseases such as lupus, rheumatic diseases and diabetic retinopathy.

Diabetes mellitus is a serious and widespread chronic disease. Studies have predicted that the prevalence of diabetes in 1996, which is 120 million, will more than 250 million by 2025, mainly due to aging, obesity, sedentary lifestyles, and changes in dietary patterns. Patients with diabetes mellitus suffer from many serious and expensive complications, including heart disease, kidney failure and blindness. Nevertheless, foot complications are the biggest victims to date. It is believed that between 40 and 70% of all lower limb cutting patients are involved in diabetes mellitus. In addition, foot ulcers appear first in about 85% of all diabetic-related lower extremity cuts.

Patients with diabetes mellitus are at higher risk of developing one or more foot ulcers as a result of long-term complications of this disease, including impaired nerve function (neuropathy) and / or ischemia.

Local tissue ischemia is a major cause of diabetic foot ulcers. In addition to macrovascular disease, diabetics are at greater risk for skin perfusion in at least two additional ways. The first is due to the involvement of non-vascular arteries that are fatally affected by the progression of atherosclerosis. Secondly, perhaps more importantly is the impairment of uncirculating control mechanisms (small vessel disease). Normally, if a body part is injured in some form, that part of the body increases blood flow as part of the body's recovery mechanism. As with many diabetics, this natural blood flow response is significantly reduced in the presence of small vessel disease and ischemia. This fact is believed to be a pivotal factor in ulcerosis, coupled with diabetes's tendency to form blood clots (thrombosis) in the circulatory system during low blood flow.

Neuropathy is another major complication of diabetes mellitus. There is no symptomatic remedy or established treatment to prevent gradual degeneration of nerve function. The incidence of neurological disorders in diabetes varies from as low as 5% to as high as 80%, largely due to myriad definitions and clinical explanations for neurological disorders. Nevertheless, the additional effects of neuropathy in diabetics are well known and proven.

The action of neuropathy is complex. Loss of sensory information from the foot is associated with abnormal and long-term pressure on the surface of the foot (sensory neuropathy). Motor neuropathy causes deformation and also increases pressure on the foot. In autonomic neuropathy, nerve loss of the glands causes the skin to dry, creating cracks that are susceptible to infection. Autonomic neuropathy is also affected by changing the distribution of the circulating blood flow that causes blood flow through the shunt and away from the nutrient skin capillaries. These factors generally cause skin destruction and ulcers along with foot trauma.

Scientists still have not identified the mechanism by which nerve damage occurs in diabetes and believe it is due to several factors. Such factors include genetic predisposition, subject abnormalities, vascular abnormalities, and lack of variation in growth factors. The response of the peripheral nervous system to the metabolic action of diabetes suggests that type 1 diabetes and type 2 diabetes do not seem to be different, ie that these two major forms of the disease will similarly respond clinically to treatment. There will be many unknown susceptibility factors for the development of neurological disorders that operate in the presence of hyperglycemia.

Scientists have found that nerve ischemia is involved in the pathogenesis of nerve conduction. In diabetic neuropathy experiments, researchers in the field have theorized that a decrease in nitric oxide (NO) levels contributes to a decrease in neuronal blood flow. NO is a short-lived radical with a broad spectrum of metabolic functions, including the mediation of vascular tension. The action of NO is mediated by cyclic guanosine monophosphate (cGMP). Various therapies, all of which increase levels of NO, have been demonstrated to increase neuronal blood flow and neurotransduction in diabetic neuropathy experiments in which NO levels are reduced.

Known cGMP PDE5 inhibitors are known, for example, sildenafil citrate, a potent and selective competitive inhibitor of cGMP-specific phosphodiesterase (PDE5), a compound known to cause degradation of cGMP. Thus, such inhibitor compounds will increase the intracellular concentration of cGMP derived from nitric oxide, thus enhancing the action of NO which is the cause of sildenafil efficacy in the treatment of male sexual dysfunction.

In recent years, the beneficial effects of sildenafil in the treatment of erectile dysfunction have been widely demonstrated and published, but the effect of this compound on diabetic foot ulcers was not expected at all. Presented by Reuters (Reuters Health Information, June 18, 2000) in a controlled study of Viagra (registered trademark, Sildenafil, Pfizer), a commercial product for diabetics by Dr. Stanley Korrenman, University of California, Los Angeles Has shown interest in the use of sildenafil for the treatment of erectile dysfunction in diabetics. However, no interest or interest has been reported on the effects of cGMP PDE5 inhibitors in the treatment of diabetic foot ulcers.

<Cross Reference to Related Application>

This application claims the benefit of U.S. Provisional Application No. 60 / 215,065, filed Jun. 30, 2000, and U.S. Provisional Application No. 60 / 219,029, filed July 18, 2000, both applications entitled "Diabetic Ulcers". Therapeutic methods "are incorporated herein in their entirety.

Surprisingly, the inventors have found that during treatment of erectile dysfunction in male diabetic patients chronically incurable foot ulcer patients unexpectedly and quickly achieved complete healing of foot ulcers. The same surprising results were achieved by repeatedly administering the inhibitory compound to additional diabetic patients (some of whom were patients with foot ulcers that had not healed for over a year). Similar surprising results have been observed in the treatment of other disease symptoms associated with peripheral vascular disease.

Clearly, the use of such inhibitor compounds represents a dramatically effective treatment for diabetic foot ulcer patients. It is known that NO is secreted from vascular endothelial cells and regulates local blood flow by relaxing vascular smooth muscle. This system is destroyed in diabetes, and therefore, increased intracellular concentrations of nitric oxide-derived cGMP, for example sildenafil, is believed to reverse the microangiopathy of diabetic foot ulcer patients and improve the rate of healing. Although the present invention is not limited to this theory of the pathological mechanism of the present invention, the present inventors believe that the administration of sildenafil may increase the blood supply to the ulcered limbs and increase the rate of treatment of diabetic foot ulcers. I think.

It is therefore an object of the present invention to provide a method of treating a diabetic ulcer patient comprising treating the diabetic ulcer patient with an effective amount of a cGMP PDE5 inhibitor or a pharmaceutical composition thereof.

It is yet another object of the present invention to provide such patients with a risky outcome of limb amputation, which is susceptible to diabetic ulcers, and which usually leads to diabetic foot ulcers, and a number of diabetic patients who are likely to have it.

In addition, cGMP PDE5 inhibitors or pharmaceutical compositions thereof may be used in combination with other therapeutic agents and therapies that may be useful in the treatment of the above-mentioned disease symptoms now or later.

The invention also provides the use of a cGMP PDE5 inhibitor in the preparation of a composition for treating diabetic ulcers.

It is also included in the concept of the present invention to treat peripheral vascular diseases such as Raynaud's phenomenon, including CREST syndrome, autoimmune diseases such as systemic lupus, rheumatic diseases and diabetic retinopathy.

The present invention will also be effective in peripheral and autonomic neuropathy or any other disease due to small vessel disease and direct macrovascular disease.

Another object of the present invention is the treatment of ringworm (fungal infection of the nail).

Many potent and selective cGMP PDE5 inhibitors are currently known and their activity can be readily determined by in vivo screening for cGMP PDE enzymes from many sources according to published procedures. That is, for example, many pyrazolopyrimidinone compounds are described as cGMP PDE5 inhibitors in EPO 0463756, EPO 0526004, WO 93/12095, WO 94/05661, WO 94/00453, WO 95/19978 and WO 98/49166. The entire disclosure of the documents is hereby incorporated by reference in its entirety.

Some cGMP PDE5 inhibitors that may be used in the present invention include, for example, 5- (2-ethoxy-5-morpholinoacetylphenyl) -1-methyl-3-n-propyl-1,6-dihydro-7H -20 pyrazolo [4,3-d] pyrimidin-7-one; 5- (5-morpholinoacetyl-2-n-propoxyphenyl) -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidine- 7-one; 5- [2-ethoxy-5- (4-methyl-1-piperazin-1-yl-sulfonyl) -phenyl] -1,6-dihydro-1-methyl-3-propylpyrazolo [4, 3-d] pyrimidin-7-one; 5- [2-allyloxy-5- (4-methyl-1-piperazinylsulfonyl) -phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4 , 3-d] pyrimidin-7-one; 5- (2-ethoxy-5- [4- (2-propyl) -1-piperazinyl-sulfonyl] phenyl} -1-methyl-3-n-propyl-1,6-dihydro-7H- Pyrazolo [4,3-d] pyrimidin-7-one; 5- (2-ethoxy-5 [4- (2-hydroxyethyl) -1-piperazinyl-sulfonyl] phenyl) -1- Methyl-3-n-propyl-1,6-dihydro 7H-pyrazolo [4,3-d] pyrimidin-7-one; 5- (5- [4- (2-hydroxyethyl) -1- Piperazinylsulfonyl] -2-n-propoxyphenyl) -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one 5- [2-ethoxy-5- (4-methyl-1-piperazinylcarbonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro 7H-pyrazolo [4, 3-d] pyrimidin-7-one; 5- [2-ethoxy-5- (1-methyl-2-imidazolyl) phenyl] -1-methyl-3-n-propyl-1,6-di Hydro-7H pyrazolo [4,3-d] pyrimidin-7-one; 3-ethyl-5- [5- [4-ethylpiperazin-1-yl) sulfonyl] -2- (2-methoxy Ethoxypyridin-3-yl] -2- (2-pyridylmethyl) -6,7-dihydro-2H-pyrazolo- [4,3-d-pyrimidin-7-one; and 3-ethyl- 5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2-n-pro Oxyphenyl] -2- (pyridin-2-yl) methyl-2,6-dihydro-7H pyrimidin-7-one.

The present inventors have preferred compound 5- [2-ethoxy-5- (4-methylpiperazin 1-ylsulfonyl) -phenyl] -1,6-dihydro-1-methyl-3-propylpyrazolo [4, 3-d] It has been determined that pharmaceutically acceptable salts thereof, including pyrimidin-7-one (sildenafil) and citrate salts, are very effective in the treatment of foot ulcers associated with diabetes.

Other peripheral vascular diseases, such as CREST syndrome, have been associated with other uses of cyclic guanosine 3 ', 5'-monophosphate type 5 (cGMP PDE5), including the compound sildenafil, which has been shown to be effective in treating diabetic foot ulcers. It is also within the concept of the present invention to treat Raynaud's phenomenon, autoimmune diseases such as systemic lupus, rheumatic diseases and diabetic retinopathy. The treatments of the present invention also benefit from peripheral and autonomic neurological disorders or other diseases caused by small vessel disease or diseases caused by direct macrovascular disease. The inventors have also found that angiosis (fungal infection of nails), especially infections of the lower extremities, is completely cured without antifungal treatment when treated with sildenafil alone. The patient in this case was under treatment for erectile dysfunction, and we found this unexpected beneficial result. The present inventors have observed the above results in several diseases having a common component of peripheral vascular disease and peripheral neuropathy. The beneficial effect of the method is believed to be due to increased blood flow in small blood vessels that help the body repair itself.

Patient 1 is an erectile dysfunction patient with an insulin-independent diabetic who later has foot ulcers. Foot ulcers were observed to heal during the treatment of erectile dysfunction. The foot ulcer started about two years ago, the patient underwent an angiogram, an outpatient oncologist and a wound care clinic with minimal results. She was also admitted to the hospital for about one month with IV antibiotics, and the threat that the patient would have to cut her knee was very urgent. Sometimes foot ulcers seemed to heal, but returned to their size and depth before treatment. After starting sildenafil treatment because of erectile dysfunction, the size of the ulcer was observed to be instructed to instruct the patient to take 50 mg of sildenafil per day. As a result, diabetic foot ulcers were completely resolved in a month, and the patient continued to receive this treatment without recurrence for the past two years.

Patient 2 was suffering from chronic deformity in both lower extremities concomitant with peripheral vascular disease and diabetes mellitus. He subsequently stated that she had diabetes mellitus and had a problem with erectile dysfunction, and after initiating sildenafil treatment, not only did the erectile dysfunction significantly improve, but also the chronic deformation of both lower limbs accompanying peripheral vascular disease was significantly improved or completely resolved.

Patient 3 was suffering from a severe peripheral vascular disease that was associated with atherosclerosis. Conventional treatments such as femoral knee and vascular bypass surgery, (greenfield filter) thrombus prevention surgical insertion of Umbrella, heparin administration and coumadine administration did not cure this condition. Due to erectile dysfunction, sildenafil was prescribed, and the patient immediately observed the improvement of arteriosclerosis symptoms.

Patient 4 was suffering from erectile dysfunction. He was also suffering from ringworm, a fungal infection of the nail. Sildenafil treatment was given to take one 50mg pill as needed. Erectile dysfunction was improved during the treatment, and surprisingly, fungal infections also healed.

The cGMP PDE5 inhibitor is preferably administered in a pharmaceutical composition. Thus, the compound may be administered in any conventional oral, parenteral, rectal, or transdermal dosage form, usually with a pharmaceutically acceptable carrier or diluent. Methods of administration are known in the prior art and are described in US Pat. Nos. 5,520,534, 5,346,901, 5,719,283, 5,272,147, 5,426,107, 5,482,941, 5,591,742, 5,734,053, 6,025,494 and 5,859,006, the entire disclosure of which is incorporated herein by reference in its entirety.

Oral administration of the pharmaceutical composition may be in the form of solutions, suspensions, tablets, pills, capsules, powders, and the like. Tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate can be used for various disintegrants, for example potato or tapioca starch and certain composite silicas (with binders such as polyvinylpyrrolidone), sucrose, gelatin And acacia gum. Lubricants such as magnesium stearate, sodium lauryl sulfate, and talc are also commonly used in the manufacture of tablets. Solid compositions of a similar type can be used as fillers in soft and hard filled gelatin capsules. Preferred materials for this include lactose or lactose, and high molecular weight polyethylene glycols. Where aqueous suspensions and / or elixirs are desired for oral administration, the compounds may be used as various sweetening, flavoring, coloring, emulsifying and / or suspending agents, and water, ethanol, propylene glycol, glycerin and various similar combinations thereof. It can be mixed with a diluent. Administration of the active compounds as additives in foodstuffs or beverages is also within the concept of the present invention.

For parenteral administration, oil solutions or aqueous propylene glycol solutions can be used, as well as sterile aqueous solutions of the corresponding water-soluble salts. The aqueous solution can be suitably buffered as necessary and the liquid diluent is first isotonic with sufficient saline or glucose. The aqueous solution is particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal injection purposes. In this regard, the sterile aqueous media used can all be readily obtained according to standard techniques well known to those skilled in the art.

For transdermal (eg topical) administration, dilute sterile aqueous solutions or partial aqueous solutions (usually at a concentration of about 0.1% to 5%), or other solutions similar to the parenteral solutions, are prepared. Treatment of transdermal compounds for therapeutic purposes has gradually increased to become common practice, such as with nicotine patches and motion sickness preventives. More recently, transdermal application of relatively large molecules, such as those contained in compositions of antigens and adjuvants, is described in US Pat. No. 5,910,306 and US Pat. No. 5,980,898, the entire disclosures of which are fully incorporated herein by reference. It proved effective. Transdermal application can be carried out by applying directly to the skin in admixture with a carrier such as an ointment or cream, or by covering or applying with a patch placed on the skin of the patient.

Methods of preparing various pharmaceutical compositions containing specific amounts of active ingredients can be determined by reference to prior art documents that are well known to those skilled in the art or known to those skilled in the art.

The exact dosage of the cGMP PDE5 inhibitor will depend on the specific compound prescribed, the subject of treatment, the severity of the condition, the mode of administration, and the judgment of the prescribing physician. Therefore, because of the variation between patients, the dosage is only a guideline and one may be able to adjust the dosage of the compound to achieve an effective level of treatment that the physician considers appropriate for the patient. In consideration of the desired degree of treatment, the attending physician should consider a balance of various factors such as the age of the patient and the presence or absence of other diseases or symptoms (eg cardiovascular disease). Generally, cGMP PDE5 inhibitors are described in U.S. Pat. And 5,859,006, the entire disclosure of which is incorporated herein by reference in its entirety. More particularly, the preferred therapeutic dose is 25 to 100 mg per day as disclosed in WO 98/49166, the entire disclosure of which is incorporated herein by reference. Safe and effective dosages prescribed for an individual will be well understood by the attending physician based on the disclosure of the patent and the personal knowledge of the attending physician on the health status of the particular patient.

In the case of sildenafil, the preferred compound, the effective amount is 5 to 125 mg per day, more preferably 10 to 110 mg per day, most preferably 25 to 100 mg, and can be administered as a tablet or capsule up to three times a day. However, the exact dosage will be determined by the prescriber and will depend on the age and weight of the patient and the severity of the symptoms as described above.

Administration of an effective dose of a compound of the invention may also provide prophylaxis to help prevent foot ulcers in diabetic patients. One skilled in the art can prescribe an effective amount of a compound using dosages described above and tailored to the specific needs of the treated patient.

Claims (7)

A method of treating a type of disease selected from peripheral vascular diseases, peripheral neuropathy, and autonomic neuropathy, comprising administering an effective amount of a pharmaceutical composition comprising a cGMP PDE5 inhibitor or a derivative or salt thereof. The method of claim 1, wherein the disease is selected from the group consisting of Raynaud's phenomenon, CREST syndrome, Lupus, rheumatic disease and diabetic retinopathy. A method of treating tinea erythematosus comprising administering an effective amount of a pharmaceutical composition comprising a cGMP PDE5 inhibitor or a derivative or salt thereof. A method of treating a diabetic foot ulcer patient comprising treating a diabetic foot ulcer patient with an effective amount of a pharmaceutical composition comprising a cGMP PDE5 inhibitor or a derivative or salt thereof. A method for preventing the development of foot ulcers in a diabetic, comprising administering to a diabetic an effective amount of a pharmaceutical composition comprising a cGMP PDE5 inhibitor or a derivative or salt thereof. A method of producing a therapeutic agent for diabetic foot ulcers comprising providing an active ingredient selected from the group consisting of a cGMP PDE5 inhibitor, a derivative thereof and a salt thereof, and combining the active ingredient with a carrier suitable for administration to a patient. The method of claim 4 or 5, wherein the cGMP PDE5 inhibitor is sildenafil.