MXPA97005920A - Treatment of neuropathy diabet - Google Patents

Abstract

Topical use of insulin in the treatment of diabetic neuropathy in a patient

Description

TREATMENT OF DIABETIC NEUROPATHY FIELD OF THE INVENTION This invention relates to the treatment of diabetic neuropathy, and in particular, it relates to a novel method and composition for the topical treatment of this condition.

BACKGROUND OF THE INVENTION Diabetic neuropathy (also known as diabetic neuritis) is a painful condition suffered by many diabetic patients, and arises from the malfunction of nerves, particularly in the extremities of the body, such as toes and feet. Table 1 presents the Classification and Stages of Diabetic Neuropathy, based on recommendations 1 of the American Diabetes Association, 1988 (American Diabetes Association). The first of the two major pathological disorders of normal nerve function in diabetes involves a postulated relationship between increased levels of glucose in the blood (hyperglycemia), the path of the polyol (the biochemical pathway that is targeted by glucose levels and which produces alcohol sugars called polyols as the final products), myo-inisitol (a substrate for energy storage in cells), Na + / K + activity ATPase (ion pump enzyme) and nerve conduction, ie the velocity of nervous impulse transmission (G reen and others2). The second post-physiological pathophysiologic mechanism of normal nerve function disorder in diabetes is related to the lack of oxygen within the nerve fibers, which is chemically induced by increased levels of blood sugar and activation of the path of the polyol, leading to changes in blood flow through the micro-vessels within the nerves (Williamson and others3).

TABLE 1 Classification and stages of diabetic neuropathy 1 (based on the recommendations of the American Diabetes Association, 1988) Class 1: Subclinical Neuropathy A. Abnormal electrodiagnostic tests: 1. Reduced nerve conduction velocity 2. Reduced amplitude of evoked potential of muscular or nervous action.

B. Abnormal quantitative sensory test: 1. Vibratory / tactile. 2. Thermal heating / cooling.

C. Abnormal automatic function tests: 1. Decreased sinus arrhythmia (change in heart rate, beat to beat). 2. Diminished function of the sudomotor.

Class 2: Clinical Neuropathy Diffuse neuropathy: 1. Distal symmetric sensorimotor polyneuropathy. 2. Autonomic neuropathy a. abnormal pupillary function, b. sudomotor dysfunction, c. genitourinary autonomic neuropathy, i. bladder dysfunction ii. sexual dysfunction d. autonomic gastrointestinal neuropathy i. gastric atony ii. atony of bladder bile iii. diabetic diarrhea e. cardiovascular autonomic neuropathy f. hyploglycemic unconsciousness.

B. Focal neuropathy: 1. Mononeuropathy / multiple mononeuropathy. 2. Plexopathy. 3. Radiculopathy. 4. Cranial neuropathy Methods to directly stimulate (via the blood vessel cover cells) and indirectly (via the sensory nerves of the thinnest skin) the response of skin redness using electric current (iontophoresis) and measure changes in blood flow of the skin (through laser Doppler velocimetry) are known and these techniques have been used by others4,5,6, and by the inventor and colleagues7,8. The treatments used in the prior art for the management of diabetic neuropathy have recently been reviewed by Pfeifer and others9,10 (1993), who describe three different clinical patterns and detailed algorithms for their diagnosis and management. The following are the types of treatments most commonly used in the management of painful diabetic neuritis or neuropathy (some of which are mentioned by Pfeifer9'10): (a) Physical therapies applied to the affected pain region can sometimes provide relief symptomatic, v. gr., i. electrical stimulation such as TENS, interferential, vibration, ultrasound ii. massage and rubbing iii. hydrotherapy iv. application of warm, hot or cold v. acupuncture or acupressure vi. application of Opsite bandage film11,12, (b) Drugs and medications taken by mouth to mitigate pain: i. non-spheroidal analgesics (eg, aspirin, paracetamol, ibuprofen, ketoprofen, etc.); ii. narcotics, for example codeine, morphine, pethidine, and sustained-release morphine preparations; iii. antidepressants including tricyclics such as amitriptyline, etc .; iv. anticonvulsants with inhibitory effects in the transmission of pain signals, such as carbamazepine, clonazepam; v. antiarrhythmic compounds, which reduce the electrical excitability of cells such as mexiliteno, lignocaine; saw. aldose reductase inhibitors, such as Sorbinil, ponalrestat (ICI), epalrestat (Ono), tolrestat (Wyeth-Ayerst), zoolrestat (Pfizer), which can improve the levels of the intraneural energy substrate (mi-inositol), reduce the accumulation of polyl-sugar (sorbitol), and improve the function of Na + / K + ATPase. vii. supplementary medication providing essential fatty acids (which are reduced in diabetes, for example gamma-linoleic acid (GLA) as Evening Primrose oil13,14. (c) Compounds (by injection) to promote neural regeneration (ie, repair, regrowth and reconnection); such as gangliosides (Cronassial), vitamin B12 (cyanocobalamin), and growth factors such as insulin. (d) Topical treatments for desensitizing superficial nerve fibers carrying pain signals, for example, cream or capsaicin ointment (usually as 0. 025% or 0.075%), which is a neurotixin and has been used for post-herpetic neuralgia .1"5,1160,1" 7, and for painful diabetic neuropathy18, ii aspirin in fading cream or sorbolene has been reported by Kassier19 that relieves post-herpetic neuralgia, and has been used by the inventors of the present (Westerman and Zimmet, unpublished) and was found to be sometimes effective in painful diabetic neuropathy of burn. It has been discovered that the topical application of insulin can be used as a specific treatment of painful neuropathy. Topical insulin therapy has not been previously reported, particularly in the treatment of diabetic neuropathy. In 1980, Synder & Kim20 made the first suggestion that insulin may be a factor of nervous survival. A little later, Low and others4 described the reduced responses to sudomotor axon reflex tests as a small fiber dysfunction in neuropathy, and it was found that electrically evoked axon reflex responses were reduced in diabetes mellitus7, and greatly restored. through an individual dose of insulin in experimental STZ-diabetes21 in rats. In the search for a possible modus operandi for insulin, Waldbilling and LeRoith's demonstration of insulin receptors in peripheral nerves, 22 and the location of these23 from Llewellyn, led the researchers of the present invention for an insulin role in function. Nervous sensory normal24. The technique of transdermal iontophoresis in dermatology25 has been shown to be effective in facilitating the transport of peptides, 26 including insulin27,28. The inventor of the present study has conducted studies of the short-term effects of insulin on the function of small nerves and axon reflexes both in animal studies in diabetic rats induced by streptozotocin and in diabetic patients dependent on insulin29. In both diabetic humans and rats, the size of the skin's redness response to noxious stimulation (so-called "axon reflex irritation") was significantly reduced, although the responses of small blood vessels were not reduced. This indicates that the reduced inflammation was due to sensory nerve dysfunction rather than microvascular damage. Topical application of insulin through six minutes of cathode electrical current, called inotophoresis, resulted in a highly significant restoration of axon reflex size, both in human IDDM axons and in rats made chemically diabetic with streptozotocin. The immediate restorative effect of inotophoresis by insulin indicates that the reduction in the axon reflex is reversible, and, therefore, due to functional changes in the nerves mediate the response, rather than any structural effect. The mechanisms by which insulin produces these acute effects are now known, but the rapid course of effect time (in minutes) suggests some ionic changes or excitability, such as calcium levels within the nerves based on other indirect evidence of such insulin actions30,31. It is generally accepted that there is currently no specific treatment for painful diabetic neuropathy. All treatments currently in use (discussed above) are intended to provide symptomatic relief. Some of these are also directed to identifiable physiological disorders, which occur in diabetes to a variable degree and for which there are no specific tests or evaluations.

COMPENDIUM OF THE INVENTION In its broadest aspect, the present invention provides topical use of insulin in the treatment of diabetic neuropathy in a patient. In one aspect, the present invention provides a method for the treatment of diabetic neuropathy in a patient, which comprises the topical administration of a therapeutically effective amount of insulin to the affected area of the patient's skin. In another aspect, the present invention provides a composition for the treatment of diabetic neuropathy in a patient, which comprises a therapeutically effective amount of insulin in a pharmaceutically acceptable diluent or carrier. In yet another aspect, the present invention provides the use of a therapeutically effective amount of insulin in the manufacture of a medicament for topical use in the treatment of diabetic neuropathy in a patient.

DETAILED DESCRIPTION OF THE INVENTION Preferably, the insulin used according to this invention is human insulin (available, for example, as Humulin R, Velosulin or Actrapid). It should be understood, however, that the present invention also extends to the use of porcine insulin, bovine insulin or insulin from another non-human animal species. The term "insulin", as used herein, is intended to encompass not only insulin per se, but also a- or β-sub-chains of insulin, separately or in combination. In accordance with this invention, insulin is administered in therapeutically effective amounts. A therapeutically effective amount means an amount necessary at least to partially obtain the desired effect, or delay the onset of, inhibit the progression of, or completely stop, the onset or progression of the diabetic neuropathy condition being treated. Said amounts will depend on, of course, the particular condition being treated, the severity of the condition and the patient's individual parameters including age, physical condition, size, weight and other current treatment. These factors are well known to those skilled in the art and can be addressed with no more than one experimentation routine. It is generally preferred that a minimum effective dose be used in accordance with medical judgment. It will be understood by those skilled in the art, however, that a higher dose may be administered for medical reasons, physiological reasons or virtually any other reason. The formulation of the preparations or compositions for topical administration is well known to those skilled in the art. The pharmaceutically acceptable carriers and / or diluents include any and all of the solvent, dispersion media, fillers, aqueous solutions, antibacterial and anti fungal agents, conventional absorption promoter agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art, and is described, by way of example, in Remington's Pharmaceutical Sciences, 18th. edition, Mack Publishing Company, Pennsylvania, USA. Except while some conventional media or agents are incompatible with the active ingredient, the use thereof in the pharmaceutical compositions of the present invention is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

Topical preparations contemplated by the present invention include aqueous cream, ointment, gel, movable ball fluid, spray, glass bead wound dressings, synthetic polymer dressings impregnated with insulin, or any other method of transdermal insulin application. The cream will include pH regulating agents and hydrophobic ingredients. These preparations may also include the use of compounds such as DMSO (dimethylsulfoxime), which facilitates the passage of insulin through the keratin barrier of the skin and into the epidermis. Since a cream is more likely to be more effective in promoting the transfer of the active ingredient of insulin through and into the affected skin, a detailed description of the method for preparing a cream is included herein by way of example. Topical Insulin Cream 70 g of fading cream base (such as Home Brand skin repair cream, Sorbolene cream or Cetomacrogol cream) containing purified water, steric acid, dimethicone, isopropyl myristate, cetyl alcohol, triethanolamine, polysorbate 80, aloe vera extract, methyl paraben, propil paraben, fragrance. Add 70 IU or 210 IU of Humulin R, Vesolusin or Actrapid - all these are neutral human monocomponent insulin, 100 IU per ml, in sodium phosphate pH regulator, conserved through meta-cresol at 0.3%. This gives a final concentration of 1 or 3 IU per gram of finished cream.

From preliminary tests, the final formula of the fade cream base seems relatively unimportant as the effectiveness of the cream. A different type of Sorbolene lotion was also used as the vehicle and is effective. It contains deionized water, glycerin, light mineral oil, cetyl alcohol, cetomacrogol 1000, stearic acid, triethanolamine, tocopheryl acetate, imidazolidinyl urea, methyl paraben, EDTA, para-cresol. Currently a similar cream is being developed but more hydrophobic and regulated in its pH. Suitably, the topical preparation of this invention is applied at least daily, or several times a day, to the affected area of the patient's skin. As an example, the application can be placed twice a day (morning and night), or even three times a day. Effective treatment begins with the careful selection of appropriate patients who have diabetic neuropathy and symptoms associated with a small fiber dysfunction. The clinical picture for which topical treatment with insulin is the most appropriate and most probably the most beneficial, is that complex of symptoms of particular neuropathy that involves the type of superficial burning of discomfort with diestesia or paraesthesia (Pfeifer9'10). Patients with diabetes not dependent on insulin or not previously treated with insulin are the most appropriate. The topical insulin cream is applied at a frequency of twice a day, restricted to areas of the skin with discomfort of superficial burn. This is very common in the toes, feet and lower parts of the legs. The re-measurement of thermal perception thresholds in the areas of the skin treated at monthly intervals is done according to 32,33,34 methods described by Jamal and others and Delane and others 6,24 using the Medelec TTT device. Perception thresholds were measured in both cold and heat. The clinically observable effect, in addition to pain relief (symptom classification), is a reduction in the thermal perception threshold, which can be interpreted as an improved thermal sensory acuity. This can be related to an improved sensory nervous function. The cold threshold improves faster than the threshold in heat, suggesting a greater benefit for the sensation of cold mediated by A-delta myelinated nerve fibers. Preferred aspects of topical use of insulin in the treatment of diabetic neuropathy include the following: i The concentration of insulin in a cream may vary from 0. 01-20 IU per gram, preferably 0.1-10 IU per gram, most preferably 1.3 IU per gram. ii The amount of cream applied is usually around 0. 5 g on each foot / leg. The consistency of the preferred cream tends to be a little wet, and, therefore, it spreads and rubs easily on the skin until it fades. iii. The recommended application frequency is two to three times a day, but after long-term analysis, a lower frequency, such as once a day, may be acceptable to maintain a skin ulcer therapy or prophylaxis, iv. Symptomatic patients, particularly those with diabetes mellitus type 2 (non-insulin dependent) very appropriately for treatment with topical insulin cream are identified after a careful history of symptoms (see Pfeifer algorithm9,10) and test for neuropathy with a research group. These include testing small sensory nerve function through a cotton-wood prick and sensitivity, and hot and cold perception thresholds on the wrist and back of the foot, and AC current perception thresholds (250 Hz or 5 Hz). Large nerve fibers were tested through sensory and motor nerve conduction / emg studies of the lower extremity (sural, peroneal TA, EDB), and by measuring vibration sensitivity with a biotensiometer, as well as AC current perception thresholds. Higher frequencies, such as 2000 Hz. v Body weight, height, body mass index (MBI), abdominal circumference, plasma glucose and insulin abstinence, and hemoglobin ATC were also measured to provide an indication of sensitivity of insulin in type 2 subjects and quality of glycemic control in subjects of type 1 and 2 No euglycemic fixation measurements were used in these studies for logistic reasons vi. The thresholds of heat and cold are usually high if a small fiber dysfunction is causing an uncomfortable burning of the affected skin. vii. The thresholds of current perception at a lower frequency stimulation (such as 250 Hz, 5 Hz) should provide another quantitative measurement of sensory nerve fiber function. Topical vehicles suitable for use in the administration of insulin according to this invention , and the methods to prepare them, include the following: 1. Fading creams: (i) Cream of cetomacrogol Peptide cs Emulsifying wax of cetomacrogol 15 Liquid paraffin (by weight) 1 0 Cholesterol 0. 1 Propylene glycol 5 Distilled water for 1 00 Melt the emulsifying wax of cetomacrogol with the paraffin at approximately 70 ° C. Dissolve cholesterol and propylene glycol in about 50 parts of the distilled water heated to approximately the same temperature. Mix, adjust to a weight and stir to cool. Then, add the peptide in an appropriate concentration, and mix thoroughly, (i i) APF of aqueous cream Peptide cs Ointment emulsifier 30 Glycerol 5 Phenoxyethanol 1 Distilled water for 100 Melt the emulsifying ointment at approximately 70 ° C. Dissolve phenoxyethanol in distilled water, heated to approximately the same temperature. Mix, adjust to a weight and stir until cooled. Add the peptide, mixing thoroughly. (iii) BPC 73 of cream regulated in its pH Peptide cs Citric acid 5 Sodium phosphate 25 Cholesterol 1 Emulsifying ointment 300 Distilled water 669 Melt the emulsifying ointment with the moderate heat aid, add the sodium phosphate, the citric acid and the cholesterol, previously dissolved in the distilled water at the same temperature, and shake moderately until it cools. Add the peptide and mix very well. 2. Ointments (i) Emulsifying ointment A PF Peptide cs Emulsifying wax 30 White soft paraffin 50 Liquid paraffin (by weight) 20 Melt together and shake until cool. Add the peptide in an appropriate concentration in a portion of the base and then gradually incorporate the rest, mixing thoroughly. (ii) Peptide Ointment - As Neomycin and Bacitracin Ointment BPC 73 Peptide cs Paraffin liquid 10 Paraffin soft white for 100 Melt the white soft paraffin, incorporating the liquid paraffin, and shake until cool. Titrate the drug with a portion of the base and gradually incorporate the rest of the base. 3. Gels (i) Peptide Gel - as used in Lignocaine Gel and Chlorhexidine APF Peptide cs Tragacanth 2.5 Glycerol 100 Distilled water for 100 Mix the tragacanth with the glycerol and add most of the distilled water. Heat to a boil, cool, adjust for a weight and mix well. Protect the finished product from light. 4. Sprays - as used in Adrenaline Spray and Atropine BPC 73 Peptide cs Sodium Metabisulfite 1 Chlorbutol 5 Propylene glycol 50 Distilled water for 1 000 (ii) - as used in Indosprav Peptide cs Alcohol 95%. Lotions (i) - as used in Aminobenzoic Acid Lotion BPC 73 Peptide cs Glycerol 20 Alcohol 95% 60 Distilled water for 100 (i i) - Cetomacrogol lotion APF Peptide cs Cetomacrogol emulsifying wax 3 Liquid paraffin 10 Glycerol 10 Chlorhexidine gluconate solution 0.1 Distilled water for 100 Melt the emulsifying wax of cetomacrogol with the liquid paraffin at approximately 60 ° C and add, with rapid stirring, to the chlorhexidine solution previously diluted to 50 parts with distilled water at the same temperature. Mix, adjust to a volume and shake until cool. Through this specification, unless the context requires otherwise, the word "comprises", or variations such as "comprises" or "comprising", shall be understood to imply the inclusion of an integer or set group of integers, but not the exclusion of any other integer or group and integers.

In the attached drawings, Figures 1 to 3 graphically show the results of a topical insulin treatment of feet burned with pain in cases of diabetic neuropathy, selected according to the previously described criteria (see page 10, par. Iv, v and Pfeifer9 , 10). Other aspects of the present invention are described more fully in the following Examples. However, it should be understood that this description is included only for purposes of illustrating the present invention, and should not be considered in any way as a restriction of the broad description of the invention as set forth above.

EXAMPLE A preliminary open analysis of topical insulin treatment for painful peripheral neuropathy was conducted. All the subjects were selected using the criteria of Pfeifer9'10, and had painful sensory polyneuropathy complicating their diabetes. This was confirmed by a battery of neurophysiological tests including sensory NCV and motor with latencies of potential action and amplitudes, threshold of vibration perception using a biotensiometer, thermal thresholds of heat and cold in the wrist and on the back of the foot using the Medelec device TTT, in many of the patients, current perception thresholds in the index finger and the big toe using the CPT Neurometer at 2000 Hz, 250 Hz, 5 Hz. Patients were given the topical insulin cream described above ( 1 IU insulin per gram of finished cream), with instructions to apply approximately 0.5 g on each foot / leg, two or three times a day. The results are shown in the Figures. Figures 1 and 2 refer to a maximum number of 10 Type 2 diabetic subjects, who had not been treated with systemic insulin. Figure 3 represents the results of a maximum of 16 subjects, who had received systemic insulin treatment. In all the graphs, the vertical axis represents the thermal threshold: the open rectangles being the threshold of perception of heat, the rectangles filled with black being the cold threshold. The severity of symptoms of painful burning on a 10-point visual analog scale is also shown on the vertical axis through the black-filled circles. The horizontal axis shows the duration of the treatment, to which the tests and additional tests were carried out. The horizontal dotted line shows the upper limit of the confidence interval of 95% normal (mean + 2.2 normal deviations). Figure 1 shows the results of a 12-week treatment, the number of subjects being 30 for weeks 0 and 4 and progressively reducing to 16 in week 12. It will be noted that with topical insulin treatment, the statistical significance for an improvement of symptoms scale as for an improved function in delta sensorial fibers has been achieved in 4 weeks and progressively improves beyond this. Figure 2 is a graph showing, on a time scale of months, the same trends, and it will be noted that the heat threshold has been significantly improved (i.e., reduced WPT) in 4 months of treatment. Thus, from the data of Figures 1 and 2, it is evident that in these diabetic patients not dependent on insulin with symptoms of painful burning neuropathy, there is a symptomatic relief and confirmation of thermal acuity of improved sensory nerve function in both kinds of small sensory nerve fibers. The most dramatic result is in the cold fibers and is obtained by almost all patients who report an awareness of general feeling of improvement in their feet, a deterioration of numbness and an improvement in the ability to feel socks, carpet and other surfaces about which they walk. This may imply some improvement in the great sensory fiber function, but it has not been measured. Figure 3 shows the treatment results of a smaller group of patients who have received systemic insulin treatment. These include some patients with Type 2 DM, whose deterioration eventually required the treatment of systemic insulin; the rest includes patients with Type 1 DM. The lack of improvement in the results of the thermal threshold for heat and cold in this group is in marked contrast with those of the previous group, but also surprising in the symptomatic improvement observed by these patients.

REFERENCES 1. American Diabetes Association / American Academy of Neurology Consensus statement: Report and Recommendations of the San Antonio Conference on Diabetic Neuropathy. Diabetes Care 11: 592-597, 1988. 2. Greene, D.A., Dima, A.A.F., Albers, J.W., Pfeifer, M.A. Diabetic neuropathy, In; Rifkin and Porto, D. Jnr. (Eds) Diabetes mellitus: Theory and practice. New York, Elsevier, pp710-755, 1990. 3. Wliliamson, J.R., Chang, K., Allison, W., Kilo, C. Endoneurial blood flow changes in diabetic rats. Diabetic Medicine, 10 (Suppl. 2): 49S-51S, 1993. 4. Low, P.A., Caskey, P.E., Tuck, R.R., Fealey, R.D., Dyck, P.J. Quantitative sudomotor axon reflex test in normal and neuropathic subjects. Ann. Neurol. 14: 573-580, 1983. 5. Parkhouse, N., LeQuesne, P.M. Quantitative objective assessment of nociceptive C-fiber function. J. Neurol. Neurosurg. Psychiatry, 51: 28-34, 1988. 6. Benarroch, E.E., Low, P.A. The acotylcholine-induced reliable response in evaluation of small fibre dysfunction. Annals of Neurology, 29: 590-595, 1990. 7. Westerman, R.A., Widdop, R.E., Hogan, C, Zimmet, P. Non-invasive tests of neurovascular function: reduced responses in diabetes mellitus. Neuroscl. Lett. 81: 177-192, 1987. 8. Delaney, C.A., Mouser, J.V., Westerman, R.A. Insulin sensitivity and sensory nerve function Clin. Expor. Neurol 31: In press, 1994. 9. Pfeifer, MA, Schumer, MP, Ross, DR, Crain, GM, Schrage, JP, Markwell, SJ, Gelber, DA, Jung, S. A highly successful and novel model for treatment of chronic painful diabetic neuropathy. Diabetes Care, 16 (8): 1103-1115, 1993. 10. Pfeifer, M.A. ' Beach, D.E., Schrage, J., Gelber, D., Miller-Crain, G., Chasen, J.K., Schumer, M.P. Treatment and practical management of diabetic somatic neuropathy: a working philosophy for the forgotten complication of diabetes. International Diabetes Monitor, 5 (1); 1-7, 1993. 11. Edmonds, M.E., Foster, A., McConville, D.O., O'Kane B.A., Eaton, C. Opsite dressings: a new effective treatment for dietary painful neuropathy (Abstract). Poster presented at the Symposium on Advanced Wound Care, San Francisco 7-9 April, 1991. 12. Foster, A.V.M., McConville, D.O., O'Kane, B.A., Eaton, C, Brown, A.S., Edmonds. ME. Appilcation of opsite film: a new and effective treatment for painful diabetic neuropathy (Abstract). Poster presented at the 1st European Tissue Repair Society Meeting, Oxford, August 27-29, 1991 13. Jamal, G.A., Carmichael, H.A., Weir, A. I. Gamma-linolenic acid in diebetic neuropathy. Lancet I, p.1098, 1986. 14. Hiorrobin, D.F Gamma linolenic acid an intermediate in essential fatty acid metabolism with potential as an ethical pharmaceutical and as a food. Rev. Contemp. Phannocother 1: 1-45, 1990. 15. Bernstein, J.E., Korman, J.J., Bickers, D.R. Topical capsaicin treatment of chronic postherpetic neuralgia. J. Am. Acad. Dermatol 21: 265-269, 1989. 16. Westerman, RA, Roberts, RGD, Kotzmann, RR, Westerman, DA, Delaney, CA., Widdop, RE, Carter, B. Effects of topical capsaicin on normal skin and affected dermatomes in herpes zoster Clin, Exper, Neurol.25: 71-84, 1989. 17. Roberts, RGD , Westerman, RA. Capsaicin: Hot stuff for pain relief. Current Therapeutics, 32: 43-49, 1991, 18. Scheoffler, N M, Sheitel, P L., Lipton, M.N. Treatment of painful diabetic neuropathy with capsaicin 0.075% J. Am. Podiat. Med Assoc. 81 (6): 288-293, 1991. 19. Kassirer, M. Transdermal aspirin in the treatment of postherpetic neuralgia. Geriatrics 45 (5): 16, 1990. 20. Snyder, E.Y, Kim, S.U. Insulin: is it a nerve survival factor? Brain Research, 196: 565-571, 1980. 21. Low, A., Westerman, R.A., Kozak, W.M., Zimmnet, P. Effect of insulin on reduced axon reflex vasodilation in streptozotocin diabetic rats. Proc. Aust. Physiol. Pharmacol. Soc. 18 (1); 97P, 1987. 22. Waldbillig, R.J., LeRoith, D. Insulin receptors In the nervous system: a structural and functional analysis. Brain Research, 409: 215-220, 1987. 23. Llewellyn, J.G., Patel, N.J., Thomas, P.K., Thompson, S.C., Workman, J.M. Autoradiographic localization of [125l] insulin binding in. In: Scarpini, E. ' Fiori, M.G., Pleasure, D., Scarlato., G. (eds.), Peripheral nerve development and regeneration.

Recent advances and clinical applications. Padova, Livinia Press, pp149-152, 1989. 24. Delaney, C.A., Mouser, J.V., Westerman, R.A. insulin sensitivity and sensory nerve function in non-diabetic human subjects. Nsurosci.

Lett. 180: 277-280, 1994. 25. Sloan, J B., Soitani, K. lontophoresis in dermatology. A review.

J. Am. Acad. Dermatol. 15: 671-634,1986. 26. Chien, Y.W., Siddiqui, O., Shi, W.M., Lelawongs, P., Liu, JC Direct current iontophoretic transdermal of peptide and protein drugs.

J. Pharm. Sci. 78 (5): 376-383, 1989. 27. Siddiqui, O., Sun, Y., Liu. J.C., Chien, Y.W. Facilitated transdermal transport of insulin. J. Pharm. Sci. 76 (4); 341-345, 1987. 28. Karl, B. Control of blood glucose levéis in alloxan-diabetic rabbits by iontophoresis of insulin Diabetes 35: 217-221, 1986. 29. Murchie, KJ Short term effects of insulin on sensory nerve function in insulin dependent diabetes mellitus. Unpubiished B.Sc. Hons. thesis, Department of Physiology, Monash University. 1994. (Supervised by R.A. Westerman). 30. Petersson, L., Frithz.G., Ronquist.G. Direct effect of insulin on 5calcium uptake in human erythrocytes. J. Int. Med. 236: 197-201 1994. 31. Levy, J., Gavin, J.R. Mellitus diabetes; a disease of calcium metabolism? Am. J. Med. 96 (3): 260-273, 1994. 32. Jamal, G.A., Hansen, S., Weir, A.I., Ballantyne, J.P. An improved automated method for measurement of thermal thresholds. 1. Normal subjects. J. Neurol. Neurosurg. Psychtat., 48: 354-360, 1985. 33. Jamal, G.A., Hansen, S., Weir, A.I., Ballantyne, J.P. An improved automated method for measurement of thermal thresholds. 2. Patients with neuropathy. J. Neurol. Neurosurg. Psychiat., 48: 361-366, 1985. 34. Jamal, G.A., Hansen, S., Weir, A.I., Ballantyne, J.P. The neurophysiological investigation of small fibre neuropathies. Muscle Nerve, 10: 537-545, 1987. 35. Rendell, M.S., Katims, J.J., Richter, R., Rowland, F. (1989). comparison of nerve conduction velocities and current perception thresholds as correlates of clinical severity of diabetic sensory neuropathy. J. Neurol., Neurosurg. Psychiat., 52; 502-511. 36. Rendell, M.S., Dovgan, D.J., Bergman, T.F., O'Donnell, G.P. Drobny, E.P., Katims, J.J., Diabetic sensory mapping and neuropathy by current perception threshold testing, Diabetes Care, 12; 638-640. 37. Masson, E.A. "Boulton, A.J. The neurometer, Validation and comparison with conventional tests for diabetic neuropathy.

Medicine 8 Symposium: S63-66, (1991). 38. Caputo, G.M., Cavanagh, P.R. Ulbrecht, J.S. Gibbons, G.W., Karchmer, A.W. Assessment and management of foot disease in patients with diabetes. N. Engl. J. Med. 331 (13): 854-860, 1994.

Claims (6)

1. A method for the treatment of diabetic neuropathy in a patient, which comprises the topical administration of a therapeutically effective amount of insulin to the affected area of the patient's skin. 2 - A method according to claim 1, wherein the insulin is human insulin. 3. A method according to claim 1, wherein the insulin is porcine insulin, bovine insulin or insulin from other species of animal that is not a human being. 4. A method according to any of claims 1 to 3, wherein the insulin comprises the a- and / or ß-substrings. 5. A method according to any of claims 1 to 4, wherein the insulin is topically applied as a cream, ointment, gel, spray or lotion. 6. A method according to claim 5, wherein the insulin is topically applied to a cream of fading cream. 7. A method according to any of claims 1 to 6, wherein the insulin is applied as a cream comprising 0.01-20 IU per gram, preferably 0.1-10 IU per gram, most preferably 1-3 IU per gram. 8 - A method according to claim 7, wherein the cream is applied in an amount of about 0.5 grams at a frequency of 2-3 times a day. 9. The use of a therapeutically effective amount of insulin in the manufacture of a medicament for topical use in the treatment of diabetic neuropathy in a patient. 10. A composition for the treatment of diabetic neuropathy in a patient, which comprises a therapeutically effective amount of insulin in a pharmaceutically acceptable topical diluent or vehicle. eleven . - A composition according to claim 10, wherein the insulin is human insulin. 1

2. A composition according to claim 10, wherein the insulin is porcine insulin, bovine insulin or insulin from another species of an animal that is not a human being. 1

3. A composition according to any of claims 10 to 12, wherein the insulin comprises the a- and / or β-sub-chains. 1

4. A composition according to any of claims 10 to 13, wherein the insulin is formulated as a cream, ointment, gel, spray or lotion. 1

5. A composition according to claim 14, wherein the insulin is formulated in a cream of fading cream. 1

6. A composition according to any of claims 10 to 15, wherein the insulin comprises 0.01 -20 IU per gram, preferably 0.1-10 lU per gram, most preferably 1-3 IU per gram.