USOO5981594A United States Patent (19) 11 Patent Number: 5,981,594 Okamoto et al. (45) Date of Patent: Nov. 9, 1999

54 METHOD OF TREATMENT FOR DIABETIC 4,062,950 12/1977 Frommer et al...... 514/35 NEUROPATHY FOREIGN PATENT DOCUMENTS 75 Inventors: Tasuku Okamoto, Tokyo; Masaharu Shiga, Kanagawa; Koji Miyata, Kanagawa; Yuji Kuwabara, Saitama; 0248999 12/1987 European Pat. Off.. Shigeru Aoki, Tokyo; Hajimu. Kurumatani, Kanagawa, all of Japan OTHER PUBLICATIONS 73 Assignee: Toray Industries, Inc., Japan Windholz et al., The Merck Index, 10th Ed. (1983) p. 723-724 ab.No. 4866 21 Appl. No.: 09/037,400 22 Filed: Mar 10, 1998 Primary Examiner Kevin E. Weddington 30 Foreign Application Priority Data Attorney, Agent, or Firm Austin R. Miller Mar. 11, 1997 JP Japan ...... 9-0S6019 57 ABSTRACT 51) Int. Cl...... A61K 31/557; A61K 38/28; A61K 31/70; A61K 31/135 A method of treatment for diabetic neuropathy using com 52 U.S. Cl...... 514/573; 514/3; 514/35; bined administration of a formulation including as an active 514/654, 514/866 ingredient a prostaglandin I derivative, especially a proStag 58 Field of Search ...... 514/573, 35, 654, landin I derivative with an anti-diabetic agent is applied to 514/866, 3 hypofunction of motor nerve and Sensory nerve to which conventional anti-diabetic agents do not provide Sufficient 56) References Cited treatments, with nerve conduction Velocities improved. U.S. PATENT DOCUMENTS 2.961,377 11/1960 Shapiro et al...... 514/654 10 Claims, 1 Drawing Sheet U.S. Patent Nov. 9, 1999 5,981,594 Fig. 1 Changes in Nerve Conduction Velocity (median nerve) S.on 1 O9 Sodium peraprost N1 hypoglycemic agent 8 g 7 9 6 S 5 4 Sodium beraprost 5 O C 2 OD 1 2 O Odministrationbefore Odministrationofter . . . Fig. 2 Changes in Nerve Conduction Velocity (tibial nerve) 4 Sodium peraprost hypoglycemic agent 3

2

Sodium 1 beraprost

O before ofter Odministration administration 5,981594 1 2 METHOD OF TREATMENT FOR DIABETIC of objectively evaluating Severity of diabetic neuropathy. NEUROPATHY For motor nerves, two different locations at a nerve are Selected to be Stimulated with intensities Selected to induce BACKGROUND OF THE INVENTION the largest peak for each of the corresponding controlling muscles in electromyograms. Then the distance between the 1. Field of the Invention two locations is divided by the balance between the obtained The present invention relates to a method of treatment of latencies in the two electromyograms. The Sensory nerve is diabetic neuropathy, which is a complication of diabetes. electrically Stimulated in the orthodromic direction at an 2. Description of the Related Art intensity Selected to obtain the largest action potential, and Diabetic neuropathy occupies an important place as one then the distance between the Stimulated location and the of three major complications of diabetes, along with retin induced location is divided by the latency. opathy and nephropathy, because it develops at relatively AS methods of treatment of diabetic neuropathy, it has earlier Stages of diabetes among various other complications been reported that Some trial treatments have been con of diabetes. It occurs very frequently, ruins patients’ quality ducted during the 1970s and 1980s based upon the hypoth of life, and leads to distinctively poor prognosis in cases 15 esis that abnormality of metabolic factors is viewed as a where an autonomic disorder develops as a complication. cause, Greene DA, DeJesus PVJr., et al. (Effects of insulin Diabetic neuropathy is currently categorized into three and dietary myoinositol on impaired peripheral motor nerve groups comprising mononeuropathy, Symmetrical peripheral conduction Velocity in acute StreptoZatocin diabetes, J. Clin. polyneuropathy and autonomic neuropathy (Williams Text Invest., 1975, 55, 6, 1326-36.) and Yagihashi S., Nishihira Book of Endocrinology, 8th Edition, p. 1301, Harrison's M., et al. (Morphometrical analysis of the peripheral nerve Principles of Internal Medicine, 12th Edition, p. 1754). lesions in experimental diabetes rats, Tohoku J. Exp. Med., Mononeuropathy is a focal or multifocal mononeural 129, 2, 139-49, 1979). These confirmed that peripheral disorder which appears as lesions of the cerebral nerve or nerve fibers of model rats for diabetic neuropathy were affects Soma and/or extremities. Its major Symptom emerges morphologically impaired and NCV was reduced. In addi 25 tion to that, they reported that when insulin was adminis as dyskinesia in many cases. It is known to develop more tered to the rats, improvements in NCV could been often in elder patients. observed, thus finding that control over blood glucose level Symmetrical peripheral polyneuropathy is the most fre led to improvements in NCV. quent form of diabetic neuropathy. It generally makes slow Since then, tests measuring NCV have been always con progreSS, So that patients tend to become aware of the ducted to evaluate the therapeutic efficacy of diabetic neu Symptoms only after it has reached an advanced Stage. The ropathy. Afterward, no adequate results, however, have been initial Symptoms are often a reduced Achilles refleX and a practically provided by the treatments for diabetic neuropa decline or absence of vibratory sensibility. Urtication rep thy targeting improvements of NCV. In detail, Pietri A, et al. resented as a Smarting feeling and then numbness on both feet follow. (Changes in nerve conduction velocity after six weeks of 35 glucoregulation with portable insulin infusion pumps. With autonomic neuropathy, patients show representative Diabetes, 29, 8, 668, 1980) and Graf RJ, et al. (Glycemic Symptoms for autonomic disorder, Such as orthoStatic control and nerve conduction abnormalities in non-insulin hypotension, cardiac rate alteration, dyshidrosis, atony of dependent diabetic subjects: Ann. Intern. Med., 94, 3, 307, esophagus or gastric atony, diabetic diarrhea, impotence and 1981) separately gave drug therapies using insulin to others. 40 patients with insulin-dependent diabetes and patients with AS mechanisms for development of these Symptoms, non-insulin-dependent diabetes in 1980 and 1981, metabolic hypothesis and vascular/ischemic hypothesis have respectively, in order to treat diabetic neuropathy. It was been implied. For the former hypothesis, hyperegasia of consequently reported that motor nerve conduction Velocity polyol metabolic pathway, a pathway where Sorbitol and (MCV) was improved by controlling blood glucose level. It fructose are produced from glucose provided due to hyper 45 was also reported, however, that only by controlling blood glycemia is considered to be the major contributing factor. glucose level, improvements in Sensory nerve conduction Another theory involving a reduced content of myoinositol velocity (SCV) could not be observed, and that treatments is related to peripheral nerve disorder. In the latter mainly proposing to control blood glucose level, hypothesis, neuro-microvascular occlusion and/or destruc accordingly, only provided very limited improvements of tion of blood-nerve barrier are thought to be related to the 50 functions Such as thermal Sensitivity and Vibratory Sensibil nerve disorders. ity. For diagnosis and follow-up of diabetic neuropathy a Although Pfeifer M A (Effects of glycemic control and variety of neurologic tests are required. In the first place, aldose reductase inhibition on nerve conduction Velocity: Achilles refleX, knee refleX, biceps refleX and triceps refleX Am. J. Med., 79, 5A, 18–23, 1985) and Yoshio Goto, et al. are usually examined as deep reflexes. Other than that, tests 55 (Clinical research for diabetic neuropathy using epalrestat are performed wherein thermal Sensitivity is examined (ONO-2235)-Inter-group double-blind placebo (including through unmyelinated fibers (C-fibers), cold Sensation a trace amount of a curative medicine)-controlled trial: through small (thinly) myelinated fibers (Aö-fibers), heat Igaku-no-Ayumi, 152, 6, 405, 1990) tested treatments using pain through Aö-fibers and C-fibers, and cold pain through aldose reductase inhibitors (ARIs) based upon a hypothesis C-fibers. Accordingly, for testing Sensory nerve functions, 60 of abnormality in polyol metabolic pathway as one of the Vibratory Sensibility, pain Sensation and thermal Sensation candidates of the cause of the disease in 1985 and 1990, (using both warm tests and cold tests) are examined respectively, the effects of aldose reductase inhibitors (Clinical Medicine for Diabetic Neuropathy, edited by (ARIs) on improving motor nerve conduction Velocity Masatada Hirata and Norihei Matsuoka, 1992, Gendai (MCV) and sensory nerve conduction velocity (SCV) Iryou-sha, p. 95). 65 remained low. Among various neurologic tests, nerve conduction Veloc Accordingly, current methods of treatment for diabetic ity (NCV) examination is the most widely used as a method neuropathy, dietary therapy and administration of insulin, 5,981594 3 4 both mainly proposing to control blood glucose level, FIG. 2 represents therapeutic efficacy of combined use of administration of aldose reductase inhibitors and Sodium beraprost with an oral hypoglycemic agent on tibial aminoguanidine, both mainly proposing to improve abnor nerve conduction Velocity. mal glucose metabolism, administration of troglitaZone, and administration of agents for limb ischemia mainly proposing DESCRIPTION OF THE PREFERRED to improve blood flow, have been conducted. EMBODIMENT In any treatments, improvement of nerve conduction In accordance with this invention, the following may be Velocity was not always Sufficient when a single drug was employed: prostaglandin I, derivatives, proStaglandin I used, and methods of treatment by combined use of different derivatives, prostaglandin I, derivatives or salts thereof, and therapeutic agents which have different functions have yet to preferably prostaglandin I2 derivatives or Salts thereof are be established. Accordingly, combined drug therapies for used. More preferably, derivatives of 4, 8-inter-m-phenylene diabetic neuropathy, aiming at recovering once reduced prostaglandin I2 are used. They are represented by the nerve conduction Velocity, have not yet been confirmed. following general formula (I) It has been reported that therapeutic efficacy obtained by Single use of an anti-diabetic agent has achieved only limited improvements, i.e., applying 12-week treatment using an 15 (I) aldose reductase inhibitor alone (for 86 subjects), MCV (median motor nerve conduction velocity) and SCV (median Sensory nerve conduction Velocity) achieved improvement by only 2 m/sec and 3.2 m/sec, respectively. (Clinical research on diabetic neuropathy using epalrestat (ONO 2235)-Double-blind placebo (including a trace amount of a curative medicine)-controlled trial): Igaku-no-Ayumi, 152, 6, 405, 1990). In addition, when treatments with single use of an oral hypoglycemic agent (for 51 Subjects) or an insulin (for 10 subjects) had been continued separately for 5 through 25 10 years, both nerve conduction velocities were rather reduced, i.e. MCV (median motor nerve conduction wherein R represents velocity) and SCV (median sensory nerve conduction (A) COOR wherein R represents Velocity) were reduced by 2.9 m/sec and 0.6 m/sec, respec 1) hydrogen or pharmacologically acceptable positive tively (Juhani Partanen et al., Natural history of peripheral neuropathy in patients with non-insulin-dependent diabetes ion, or mellitus: N. Eng. J. Med., 333, 2, 89–94, 1995). 2) Straight alkyl containing 1-12 carbons or branched Accordingly, it has been found that using methods of treat alkyl containing 3-14 carbons, or ment with an anti-diabetic agent alone, nerve conduction 3) -Z-R velocities were only improved 3.2 m/sec at the best. Even in wherein Z represents a Valence bond, or a straight or Some cases these velocities rather were reduced as the illness 35 branched alkylene group represented by CH2, proceeded. wherein t represents an integer from 1-6, and It has been Verified through animal experiments using wherein R represents cycloalkyl containing 3–12 beraprost, a prostaglandin-12 derivative, that beraprost has carbons or Substituted cycloalkyl containing 3-12 therapeutic efficacy on diabetic neuropathy. (Publication of carbons substituted with 1-3 groups of R", unexamined application for Japanese Patent: Serial Number 40 wherein R" represents hydrogen or alkyl contain 1990-262519). No reports, however, have been published on ing 1-5 carbons, combined effects of beraprost with an anti-diabetic agent on 4) -(CH2CH2O), CH diabetic neuropathy aiming at functional improvements of wherein in represents an integer of 1-5, Sensory nerve and motor nerve. 5) -Z-Ar" AS described hereinbefore, in the treatments of diabetic 45 wherein Z has the Same meaning as defined above, neuropathy aiming at recovering once-reduced nerve con and Ar' is selected from the group consisting of duction Velocity, any of the conventional anti-diabetic phenyl, C.-naphthyl, B-naphthyl, 2-pyridyl, agents with its single use even shows Some effects, but the 3-pyridyl, 4-pyridyl, C.-furyl, B-furyl, C-thienyl, degrees of which are not evaluated as clinical Satisfaction. f3-thienyl, or substituted phenyl (wherein the Sub Moreover, no combined therapies using two curative agents 50 stituted phenyl is substituted by at least one sub with different functions have yet been achieved. Stitute of chlorine, bromine, fluorine, iodine, SUMMARY OF THE INVENTION trifluoromethyl, alkyl containing 1-4 carbons, The present invention relates to a method of treatment of nitro, cyano, methoxy, phenyl, phenoxy, diabetic neuropathy characterized by combined administra p-acetamidobenzamide, -CH=N-NH-C tion of a prostaglandin-I derivative, especially a formula 55 (=O)-NH, -NH-C(=O)-Ph, -NH-C tion whose active ingredient is a prostaglandin-I derivative (=O)-CH or -NH-C(=O)-NH). with an anti-diabetic agent. The present invention Specifi 6) -CHCOOR" cally provides a method of treatment to deliver functional wherein CH, and R' have the same meanings as recoveries by targeting improvements in motor and Sensory defined above, nerve conduction Velocities for hypofunction of a motor 60 7) -CHN(R"). nerve and Sensory nerve to which conventional anti-diabetic wherein CH2, and R' have the same meanings as drugs could not provide adequate treatment. defined above, 8)-CH(R)-C(=O)-R BRIEF DESCRIPTION OF THE DRAWINGS wherein R represents hydrogen or benzoyl, and R' FIG. 1 represents therapeutic efficacy of combined use of 65 represent S phenyl, p - bro mop he nyl, Sodium beraprost with an oral hypoglycemic agent on p-chlorophenyl, p-biphenyl, p-nitrophenyl, median nerve conduction Velocity. p-benzamidophenyl or 2-naphthyl, 5,981594 S 6 9) -CH2-W-R7 cyclopenthyl or cyclohexyl with 1-4 Straight alkyls where in W represents -CH=CH-, containing 1-4 carbons, or -CH=CR'- or -C=C-, and wherein R' 4) -Z-R represents hydrogen or Straight or branched alkyl wherein Z and R have the same meanings as defined or aralkyl groups containing 1-30 carbons, and p above, or represents an integer of 1-5, or 5) –CH-CH=C(R)R’ 10)-CH(CHOR), wherein CH has the same meaning as defined above, wherein R represents alkyl or acyl containing 1-30 R" and R' independently represent hydrogen, or carbons, methyl, ethyl, propyl or butyl, or (B) —CH-OH 6) -CH2-C=C-R'" (C) –C(=O)N(R), wherein u represents an integer of 1-7, -CH2 rep wherein R represents hydrogen or straight alkyl con resents straight or branched alkylene, and R7 rep taining 1-12 carbons, branched alkyl containing resents Straight alkyl containing 1-6 carbons, and E 3-12 carbons, cycloalkyl containing 3-12 carbons, represents hydrogen or -OR cycloalkylalkylene containing 4-13 carbons, phenyl, 15 wherein R represents acyl containing 1-12 carbons, substituted phenyl (wherein the substitutes are the aroyl consisting of 7-15 carbons, or R (wherein R has same as defined for (A)5 described above), aralkyl the same meaning as defined above), and the general containing 7-12 carbons, or -SOR', where R' formula can be in the isomeric d-form, 1-form or represents alkyl containing 1-10 carbons, cycloalkyl dl-form, or pharmacologically acceptable Salts thereof. containing 3-12 carbons, phenyl, Substituted phenyl, Specific examples of preferred prostaglandin I derivatives wherein the Substitutes are the same radical as of the present invention, but not limited thereto, include defined for (A)5 described above), aralkyl contain beraprost identified as (II) below: ing 7-12 carbons, provided that the two R's are the (II) Same or different, but when one represents -SOR'', the other does not represent -SOR', 25 O (D) -CHOTHP (THP represents tetrahydropyranyl), where A represents 1) -(CH2)- 2) -CH=CH-CH 3) -CH-CH=CH 4) -CH-O-CH 5) -CH=CH 6) -O-CH- or 7) -C=C-, 35 wherein m represents an integer of 1-3, Y represents hydrogen, alkyl containing 1-4 carbons, chlorine, or Salts thereof, ataprost, iloprost, climprost, ciprostene, bromine, fluorine, formyl, methoxy or nitro, and naxaprostene, taprostene, cicaprost, pimilprost, CH-169 and where B represents 40 CS570. - X-C(R)(R')OR Although the prostaglandin I derivatives of the present wherein R' represents hydrogen or alkyl containing invention can be produced by well-known methods, the 1–4 carbons, R' represents hydrogen or acyl compounds shown in the general formula (I) or salts thereof, containing 1-14 carbons, aroyl containing 6-15 for example, can be produced in accordance with the method carbons, tetrahydropyranyl, tetrahydrofuranyl, 45 described in Publication of examined application for Japa 1-ethoxyethyl or t-butyl, X represents nese Patent, Serial Number 1989-53672. 1) -CH-CH The prostaglandin I derivatives of the present invention 2) -CH=CH- or are generally used as, but not limited to, general formula 3) -C=C-, and tions for oral administration use, Such as tablets, capsules, R' represents 50 powders, granules, or liquids combined with medically 1) Straight alkyl containing 1-12 carbons, branched alkyl acceptable carriers or vehicles. containing 3-14 carbons, or AS anti-diabetic agents used in the present invention, but 2) -Z-Art not limited thereto as long as they serve as medicines for wherein Z has the same meaning as defined above, Arf diabetes, insulin and oral anti-diabetic agents, for example, represents phenyl, C.-naphthyl, B-naphthyl, or at least 55 can be used. Oral hypoglycemic agents, which are oral one chlorine, bromine, fluorine, iodine, anti-diabetic agents, can be categorized into the following trifluoromethyl, alkyl containing 1-4 carbons, nitro, four groups, those embraced in any of which can be utilized cyano, methoxy, phenyl or phenoxy-Substituted in the present invention. The representative formulations in phenyl, or each group are follows. 3) -CHOR'' 60 (1) Sulfonylureas: wherein CH has the same meaning as defined above, tolbutamide formulations, chlorpramide formulation, R" represents straight alkyl containing 1–6 carbons, tola Zamide formulations, ace to he X amide branched alkyl containing 3–6 carbons, phenyl, or at formulations, glibenclamide formulations and gli least one chlorine, bromine, fluorine, iodine, clazide formulations, trifluoromethyl, alkyl containing 1-4 carbons, nitro, 65 (2) bigdanides: cyano, methoxy, phenyl or phenoxy-Substituted buformin hydrochloride formulations, metformin phenyl, cyclopenthyl, cyclohexyl, or Substituted formulations, 5,981594 7 8 (3) C-glycosidase inhibitors: To patients with diabetic neuropathy, Sodium beraprost acarbose formulations, Voglibose formulations, was administered alone for Single use or with a gliclazide as (4) agents for insulin-resistance: an oral hypoglycemic agent for combined use, and then the noScal. degrees of improvement in medial nerve conduction Velocity One or more of the above-mentioned anti-diabetic agents were compared. Specifically, one patient with diabetic neu can be administered in combined therapy. ropathy was allocated to each administration Schedule for 24 Use and dose of the proStaglandin I derivatives and weeks, i.e. a Sodium beraprost administration Schedule (40 anti-diabetic agents are, but not limited to, those for Single pigt.i.d., the total dose of 120 ug per day) or a combined use of each medicine, in principle. A medicine which administration Schedule of Sodium beraprost (40 ugt.i.d., the includes a prostaglandin I derivative as an active ingredient total dose of 120 ug per day) with a gliclazide as an oral is administered in a daily dose of 0.01-100 mg per patient hypoglycemic agent (a single daily dose of 20 mg), and then in 1-3 portions. median nerve conduction Velocities before and after the Although one or more of the prostaglandin I derivatives administration were compared for each patient. Nerve con may be used as it is or as they are, it/they can be orally duction Velocities were measured using electromyograph administered in the form of a Solid including additive agents 15 and then chances in observed Velocities and rates of change as shown hereinafter. over the velocities before the administration were used to AS the additive agents, vehicles Such as Starches, lactose, evaluate the degrees of improvement of nerve functions. In Sucrose, glucose, mannitol, calcium carbonate, calcium Sul the case of motor nerve conduction Velocity, if ten percent fate and others: binderS Such as Starches, dextrin, gum of the initial measured value is recovered, it is generally Arabic, gum tragacanth, methylcellulose, gelatin, considered that useful therapeutic efficacy is provided. AS polyvinylpyrrolidone, polyvinylalcohol, and others, disinte the result, the median nerve conduction Velocities of the gratorS Such as Starches, polyvinylpyrrollidone, crystalline patient given sodium beraprost alone were 50.6 and 53.5 cellulose and the others, lubricants Such as magnesium mi?sec, respectively, before and after the administration, Stearate, talc and the others, and coloring agents and flavors indicating that a slight improvement of 2.9 m/sec was are useful. 25 brought about by the sodium beraprost administration. The The prostaglandin I derivatives of the present invention rate of change over the value prior to administration was 5.7 can be used in various dosage forms, but Specifically the percent of improvement. While the median nerve conduc conventional dosage forms Such as tablets, Sugar-coated tion Velocities of the patients given the combined adminis tablets, powders, troches, capsules, balls, Syrups and the tration of sodium beraprost with the gliclazide were 42.6 and others can be mentioned. 50.6 m/sec, respectively, before and after administration, The prostaglandin I derivatives of the present invention indicating that a 8.0 m/sec of improvement was brought can also be parenterally administered in the form of Sterile about. The rate of change over the value before the admin liquid. Sodium chloride, glucose or the others can be added istration was 18.8 percent, indicating that a significantly to the liquid in adequate amounts to make the Sterile liquid larger improving effect was obtained compared with that for isotonic. 35 the treatment with the Single administration of Sodium In addition to the above-mentioned oral formulations, beraprost (FIG. 1). Accordingly, this result shows that the because a wide range of parenteral administration routes can large therapeutic efficacy on median nerve conduction be applied to the prostaglandin I derivatives of the present Velocity was only achieved when the combined administra invention, the derivatives may be formulated into dosage tion of Sodium beraprost with the anti-diabetic agent was forms for parenteral use Such as various injections, Supposi 40 employed. tories and the like. Example 2 For combined administration of the prostaglandin I derivatives of the present invention with anti-diabetic Therapeutic efficacy of combined use of Sodium beraprost agents, these two types of medicines do not always need to and an oral hypoglycemic agent on tibial nerve conduction be simultaneously administered. Even time intervals within 45 Velocity. the degree, where the combined effects cannot be lost, may In accordance with a Similar method to that of Example 1, be placed between the times of administration of the two one patient with diabetic neuropathy was allocated to each types of medicines. administration Schedule for 24 weeks, i.e. a Sodium bera The method of treatment for diabetic neuropathy of the prost administration Schedule or a combined administration present invention affords recoveries of once reduced nerve 50 Schedule of Sodium beraprost with a gliclazide as an oral conduction velocities for unmyelinated fibers (C-fibers), hypoglycemic agent, and then tibial nerve conduction Small (thinly) myelinated fibers (AY-fibers, Aö-fibers and Velocities before and after administration were compared for B-fibers), large (thickly) myelinated fibers (AC-fibers and each patient. Nerve conduction Velocities were measured A?-fibers), as well as reduced motor nerve functions and using an electromyograph and then changes, of observed Sensory nerve functions including cold, warm and vibratory 55 Velocities and rates of change over the Velocities before sensibilities by improving blood flow of peripheral nerve administration, were used to evaluate the degrees of fascicle. improvement on nerve functions. AS a result, the tibial nerve conduction Velocities of the EXAMPLES patient given sodium beraprost alone were 38.5 and 39.3 60 mi?sec, respectively, before and after the administration, The examples described hereinafter are to illustrate the indicating that a slight improvement of 0.8 m/sec by the present invention. Sodium beraprost administration was brought about. The rate of change over the value before administration was 2.1 Example 1 percent of improvement. The median nerve conduction Therapeutic efficacy of combined use of Sodium beraprost 65 Velocities measured for the patients given the treatment of with an oral hypoglycemic agent on median nerve conduc combined administration of Sodium beraprost with gli tion Velocity. clazide were 38.3 and 41.3 m/sec, respectively, before and 5,981594 9 10 after administration, indicating that a 3.0 m/sec of improve p-acetamidobenzamide, -CH=N-NH-C ment was brought about. The rate of change over the value (=O)-NH, -NH-C(=O)-Ph, -NH before administration was 7.8 percent, indicating that a C(=O)-CH or -NH-C(=O)-NH) remarkably larger improvement was obtained compared 6) -CHCOOR' with that for treatment with administration of Sodium bera wherein C.H., and R' have the same meanings as prost alone (FIG. 2). Accordingly this result shows that a defined above, large therapeutic efficacy on tibial nerve conduction Velocity 7) -CHN(R"). was only achieved when the combined administration of wherein C.H., and R' have the same meanings as Sodium beraprost with the anti-diabetic agent was employed. defined above, What is claimed is: 8)-CH(R)-C(=O)-R 1. A method of treatment of diabetic neuropathy charac wherein R represents hydrogen or benzoyl, and terized by combined administration of a prostaglandin I R represents phenyl, p-bromophenyl, derivative, as an active ingredient, with an anti-diabetic p-chlorophenyl, p-biphenyl, p-nitrophenyl, agent. p-benzamidophenyl or 2-naphthyl, 2. A method of improvement of Sensory and/or motor 15 9) -CH2-W-R7 nerve functions of a patient having diabetic neuropathy, where in W represents -CH=CH-, comprising the combined administration to Said patient of a -CH=CR'- or -C=C-, and wherein R' prostaglandin I derivative, as an active ingredient, with an represents hydrogen or Straight or branched anti-diabetic agent. alkyl or aralkyl groups containing 1-30 3. The method according to claim 1 or 2, wherein said carbons, and p represents an integer of 1-5, or prostaglandin I derivative is a prostaglandin I2 derivative or 10) -CH(CHOR), a pharmacologically acceptable Salt thereof. wherein R represents alkyl or acyl containing 4. The method according to claim 1 or 2, wherein Said 1-30 carbons, prostaglandin I derivative is 4, 8-inter-m-phenylene proS (B) —CH-OH taglandin I represented by the following general formula 25 (C) –C(=O)N(R), (I): wherein R represents hydrogen or straight alkyl containing 1-12 carbons, branched alkyl contain (I) ing 3-12 carbons, cycloalkyl containing 3-12 carbons, cycloalkylalkylene containing 4-13 carbons, phenyl, Substituted phenyl (wherein the Substitutes are the same as defined for (A) 5 described above), aralkyl containing 7-12 carbons, or -SOR", where R' represents alkyl containing 1-10 carbons, cycloalkyl containing 35 3-12 carbons, phenyl, Substituted phenyl, wherein the Substitutes are the same radical as defined for (A) 5 described above), aralkyl containing 7-12 carbons, provided that the two R's are the same or different, but when one represents -SOR', the wherein R represents 40 other does not represent -SOR", or (A) COOR wherein R represents (D) -CHOTHP (THP represents tetrahydropyranyl), 1) hydrogen or pharmacologically acceptable posi where A represents tive ion, or 1) -(CH-)- 2) Straight alkyl containing 1-12 carbons or 2) -CH=CH-CH branched alkyl containing 3-14 carbons, or 45 3) -CH-CH=CH 3) -Z-R 4) -CH-O-CH wherein Z represents a Valence bond, or a Straight 5) -CH=CH or branched alkylene group represented by 6) -O-CH- or CH2, whereint represents an integer from 1-6, 7) -C=C-, and wherein R represents cycloalkyl contain 50 wherein m represents an integer of 1-3, Y rep ing 3-12 carbons or Substituted cycloalkyl resents hydrogen, alkyl containing 1-4 containing 3-12 carbons substituted with 1-3 carbons, chlorine, bromine, fluorine, formyl, groups of R", wherein R" represents hydrogen methoxy or nitro, and where B represents or alkyl containing 1-5 carbons, -X-C(R)(R')OR' 4) -(CH2CH2O), CH 55 wherein R' represents hydrogen or alkyl con wherein in represents an integer of 1-5, taining 1–4 carbons, R' represents hydrogen 5) -Z-Ar" or acyl containing 1-14 carbons, aroyl con wherein Z has the same meaning as defined taining 6-15 carbons, tetrahydropyranyl, above, and Ar' is selected from the group tetrahydrofuranyl, 1-ethoxyethyl or t-butyl, X consisting of phenyl, C.-naphthyl, B-naphthyl, 60 represents 2-pyridyl, 3-pyridyl, 4-pyridyl, C.-furyl, 1) -CH-CH B-furyl, C.-thienyl, B-thienyl, or substituted 2) -CH=CH- or phenyl (wherein the substituted phenyl is sub 3) -C=C-, and Stituted by at least one Substitute of chlorine, R' represents bromine, fluorine, iodine, trifluoromethyl, 65 1) Straight alkyl containing 1-12 carbons, branched alkyl alkyl containing 1-4 carbons, nitro, cyano, containing 3-14 carbons, or methoxy, phenyl, phe no Xy, 2) -Z-Ar 5,981594 11 12 wherein Z has the same meaning as defined above, Arf resents Straight alkyl containing 1-6 carbons, and E represents phenyl, C.-naphthyl, B-naphthyl, or at least represents hydrogen or -OR one chlorine, bromine, fluorine, iodine, wherein R' represents acyl containing 1-12 carbons, trifluoromethyl, alkyl containing 1-4 carbons, nitro, aroyl consisting of 7-15 carbons, or R (wherein R has cyano, methoxy, phenyl or phenoxy-Substituted the same meaning as defined above), and the general phenyl, or formula can be in the isomeric d-form, 1-form or 3) -CHOR'' dl-form, or pharmacologically acceptable Salts thereof. wherein CH has the same meaning as defined above, R" represents straight alkyl containing 1–6 carbons, 5. The method according to claim 1 or 2, wherein said branched alkyl containing 3–6 carbons, phenyl, or at prostaglandin I derivative is beraprost or a Salt thereof. least one chlorine, bromine, fluorine, iodine, 6. The method according to claim 1 or 2, wherein Said trifluoromethyl, alkyl containing 1-4 carbons, nitro, prostaglandin I derivative is Selected from the group con cyano, methoxy, phenyl or phenoxy-Substituted Sisting of ataprost, iloprost, clin prost, ciprostene, phenyl, cyclopenthyl, cyclohexyl, or Substituted naxaprostene, taprostene, cicaprost, pimilprost, CH-169 and cyclopenthyl or cyclohexyl with 1-4 Straight alkyls 15 CS570. containing 1-4 carbons, or 7. The method according to claim 1 or 2, wherein said anti-diabetic drug is an insulin formulation. 4) -Z-R 8. A method as defined in claim 1 or 2, wherein said wherein Z and R have the same meanings as defined prostaglandin I derivative is beraprost or a Salt thereof and above, or Said anti-diabetic agent is an insulin formulation. 5) –CH-CH=C(R')R’ 9. The method according to claim 1 or 2, wherein said wherein CH has the same meaning as defined above, anti-diabetic drug is an oral anti-diabetic agent. R" and R' independently represent hydrogen, or 10. The method according to claim 1 or 2, wherein said methyl, ethyl, propyl or butyl, or prostaglandin I derivative in beraprost or a Salt thereof and 6) -CH -C=C-R'7 25 Said anti-diabetic agent is an oral anti-diabetic agent. wherein u represents an integer of 1-7, -CH2 rep resents straight or branched alkylene, and R7 rep k k k k k