DIABETIC NEUROPATHY: CLINICAL MANAGEMENT - PART 7 pdf

facilitate the recruitment of homogeneous study subject populations. Second, correction or partial correction of abnormalities in regeneration is a concrete target with a clear clinical interpretation. Furthermore, an improvement in the regeneration rate will pre- cede an improvement in nerve fiber density and is likely to be a more sensitive meas- ure. Finally, such a study designed to detect a 50% normalization of regeneration with 80% power in nonneuropathic subjects with diabetes would require about 65 subjects per treatment arm. A recent trial of Timcodar dimesylate in healthy control subjects used such measures of collateral and regenerative sprouting as outcome measures. Although the compound did not accelerate regeneration by either measure, the trial did demonstrate that such an approach was feasible and the measures were reproducible and robust (42). In conclusion, skin biopsy with determination of epidermal nerve fiber density is a powerful tool that provides investigators insight into a population of nerve fibers that is prominently affected in diabetes and yet has been relatively under investigated. The super- ficial nature of epidermal nerve fibers allows repeated sampling of these nerves in a 304 Polydefkis Fig. 7. For each subject, a regression line from postcapsaicin time-points is generated and the slope of this line is used as the rate of regeneration. The mean line for each group is shown as a thick solid line. The rate of regeneration following denervation is 0.177 ± 0.075 fibers per mm/day for control subjects (red), 0.10 ± 0.07 fibers per mm/day (p = 0.03) for subjects with diabetes but no neuropathy (green), and 0.04 ± 0.03 fibers per mm/day (p = 0.03) for subjects with diabetes and neuropathy (blue). relatively non invasive fashion, and in sites that cannot be assessed through conventional electrodiagnostical techniques. These features have allowed investigators to diagnose neuropathy earlier and to define an association between neuropathy and impaired glucose tolerance. Finally, the ability to injure these fibers in a standardized fashion has led to novel measures of human axonal regeneration that may provide a more sensitive scale by which to assess promising regenerative compounds. REFERENCES 1. Bolton CF, Winkelmann RK, Dyck PJ. A quantitative study of Meissner’s corpuscles in man. Neurology 1966;16(1):1–9. 2. Dyck PJ, Winkelmann RK, Bolton CF. 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Quantitation of epidermal nerves in diabetic neuropathy. Neurology 1996;47(4):1042–1048. 13. Silos-Santiago I, Molliver DC, Ozaki S, et al. Non-TrkA-expressing small DRG neurons are lost in TrkA deficient mice. J Neurosci 1995;15(9):5929–5942. 14. Kennedy WR, Nolano M, Wendelschafer-Crabb G, Johnson TL, Tamura E. A skin blister method to study epidermal nerves in peripheral nerve disease. Muscle Nerve 1999;22(3):360–371. 15. Kennedy WR, Wendelschafer-Crabb G. The innervation of human epidermis. J Neurol Sci 1993;115(2):184–190. 16. McCarthy BG, Hsieh ST, Stocks A, et al. Cutaneous innervation in sensory neuropathies: evaluation by skin biopsy. Neurology 1995;45(10):1848–1855. 17. Lauria G, Borgna M, Morbin M, et al. Tubule and neurofilament immunoreactivity in human hairy skin: markers for intraepidermal nerve fibers. Muscle Nerve 2004;30(3): 310–316. Punch Skin Biopsy in Diabetic Neuropathy 305 18. Polydefkis M, Hauer P, Sheth S, Sirdofsky M, Griffin JW, McArthur JC. 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Intradermal injection of capsaicin in humans produces degeneration and subsequent reinnervation of epidermal nerve fibers: correlation with sensory function. J Neurosci 1998;18(21): 8947–8959. 41. Nolano M, Simone DA, Wendelschafer-Crabb G, Johnson T, Hazen E, Kennedy WR. Topical capsaicin in humans: parallel loss of epidermal nerve fibers and pain sensation. Pain 1999;81(1–2):135–145. 42. Polydefkis M, Sirdofsky M, Hauer P, Petty BG, Murinson BB, McArthur JC. Factors influ- encing nerve regeneration in a trial of Timcodar dimesylate. Neurology 2006; 66(2):259–261. 43. Polydefkis M, Hauer P, Griffin JW, McArthur JC. Skin biopsy as a tool to assess distal small fiber innervation in diabetic neuropathy. Diabetes Technol Ther 2001;3:23–28. 44. Polydefkis M, Griffin JW, McArthur J. New insights into diabetic polyneuropathy. JAMA 2003;290:1371–1376. Punch Skin Biopsy in Diabetic Neuropathy 307 18 Aldose Reductase Inhibitors for the Treatment of Diabetic Neuropathy Aristidis Veves, MD, DSc SUMMARY It has been more than 30 years since the first aldose reductase inhibitor (ARI) was tested in diabetic and galactosemic rats and found to control the polyol accumulation. Since then, a considerable number of ARIs have been tested in experimental and human diabetes. Despite the initial encouraging results from tests that were conducted for the past 20 years, ARIs have not been established for the treatment of diabetic neuropathy yet. The main reasons for this are inconsistent results and the unacceptable high rate of side-effects associated with the initially tested compounds. The lack of well-defined end points and the inability to produce an inhibitor that achieves satisfactory tissue penetration and enzyme inhibition are other major contributing factors for this failure. This chapter focuses on the clinical trials that have examined the effect of all tested ARIs on human diabetic neuropathy. Key Words: Aldose reductase inhibitors; clinical trials; human diabetic neuropathy; efficacy; side effects; clinical use. INTRODUCTION It has been more than 30 years since the first aldose reductase inhibitor (ARI) was tested in diabetic and galactosemic rats and found to control the polyol accumulation (1). Since then, a considerable number of ARIs have been tested in experimental and human diabetes. However, very few new information have become available since the last edition of this book, probably an indication that either interest in these compounds is waning down in the scientific community or that despite all the intensive efforts, the ideal compound that will offer satisfactory enzyme inhibition with minimal side-effect has not been discovered as yet. A thorough review of work on experimental diabetes would be out of the spirit of this chapter; however, more information is provided in chapters of this edition. The following chapter will focus on the results from clinical trials in diabetic neuropathy (2). END POINTS FOR CLINICAL TRIALS IN DIABETIC NEUROPATHY Painful symptoms and foot ulceration are the two most important clinical problems related to peripheral somatic diabetic neuropathy. The conduction of clinical trials, which test the efficacy of new therapies for painful neuropathy is straight forward: From: Contemporary Diabetes: Diabetic Neuropathy: Clinical Management, Second Edition Edited by: A. Veves and R. Malik © Humana Press Inc., Totowa, NJ 309 patients with this condition are provided trial medication and the primary end point is the reduction of the symptoms, which is expected to occur during a reasonable period after the treatment has been initiated. In contrast, foot ulcers develop long after the initiation of events which lead to nerve damage and, by this time, the possibility of restoring the nerve lesions, or halting their progression, is close to nonexisting. Therefore, if a study was to be conducted having as primary end point the prevention of foot ulceration it should involve patients who have diabetic neuropathy in the early stages and follow them until they reach the very late stages of the disease. This would mean that a large number of patients should be followed for prolonged periods of time, even decades, before any conclusion would be reached. It is obvious from the aforementioned that more practical end points should be used in order to conduct clinical therapeutic trials, which will be financially supported by the pharmaceutical industry where efficient development of new medications are of para- mount importance. In addition, these end points should give an accurate and more detailed picture about the effects of the treatment on the progression of the disease, mainly to what extent it can restore the already established lesions. Sural nerve biopsies were initially considered to be the best method for evaluating new medications. However, the interpretation of the biopsy results was found to be more difficult than was originally believed and as a result, nerve biopsies fall out of favor. Most recent studies have used surrogate measurements, mainly nerve electrophysiolog- ical measurements and quantitative sensory testing. Regarding the electrophysiological measurements, Dyck and O’Brian, based on epidemiological data, initially suggested that a mean change of 2.9 m per second in the combined conduction velocities of the ulnar, median, and peroneal nerves, or a change of 2.2 m per second in the peroneal nerve alone should be achieved in order that the results can have a meaningful clinical significance (4). However, it should be emphasized that the selection of end points is not the only issue with the design of new clinical trials. Thus, the current prevailing opin- ion is that future studies will have to include large number of patients and be of long enough duration (probably around 18–24 months), pay particular attention to the vari- ability of the end point measurements, and have rigorous quality control in order to allow the drawing of definite conclusions regarding the efficacy of ARIs in treating diabetic neuropathy. CLINICAL TRIALS WITH ARIS Alrestatin Alrestatin was the first ARI to be tried in human diabetic neuropathy. In the first, uncontrolled study conducted in 1981, 10 patients with symptomatic neuropathy were treated with intravenous infusions of alrestatin for 5 days (5). Although, symptomatic improvement was noticed in seven patients, objective measurements failed to improve. Therefore, as the trial was not controlled, a placebo effect accounting for the sympto- matic improvement cannot be excluded. No adverse effects of alrestatin were noticed in this trial (Table 1). The next trial included nine patients with diabetes with severe symptomatic neuro- pathy, which had necessitated at least one hospital admission before the study (6). The trial was a single-blind, nonrandomized, placebo-crossover, which lasted for 4 months. Each patient received the maximum tolerated oral dose for 2 months and was on placebo for the other two. Subjective improvement was noted by most of the patients 310 Veves ARIs for the Treatment of Diabetic Neuropathy 311 Table 1 ARIs Trials in Human Neuropathy Duration of Authors Design active treatment Results Alrestatin Culebras (1981) Uncntr 5 days Symptomatic improvement Handelsman (1981) sb, nonrmd, co 4 months Symptomatic improvement Fagious (1981) db, rmd 12 weeks Improvement of symptoms, VPT and ulnar mcv Sorbinil Judzewitsch (1983) db, rmd 9 weeks Improvement of peroneal mcv and median mcv and scv Jaspan (1983) sb 3–5 weeks Symptomatic improvement Young (1983) db, rmd, co 4 weeks Improvement of symptoms and sural sap Lewin (1984) db, rmd, co 4 weeks No improvement Fagious (1985) db, rmd 6 months Improvement of posterior tibial mcv and ulnar nevre F wl and dsl O’Hare (1988) db, rmd 12 months No benefit Guy (1988) db, rmd 12 months No benefit Sima (1988) db, rmd 12 months Improvement of symptoms, sural sap and mfd Ponalrestat Ziegler (1991) db, rmd 12 months No benefit Krentz (1992) db, rmd 12 months No benefit Tolrestat Ryder (1986) db, rmd 8 weeks Improvement of median mcv Boulton (1990) db, rmd 12 months Improvement of paraesthetic symptoms and peroneal mcv Macleod (1992) db, rmd 6 months Improvement of VPT, median and ulnar mcv Boulton (1992) db, rmd, 12 months Improvement of symptoms, withdrawal median and peroneal mcv Giugliano (1993) db, rmd 12 months Improvement of autonomic measurements and VPT Giugliano (1995) db, rmd 12 months Improvement of autonomic measurements and VPT Didangelos (1999) db, rmd 24 months Improvement of autonomic measurements Greene (1999) db, rmd 12 months Increase in small diameter myelinated fibers Hotta (2001) db, rmd 12 months Improvement of symptoms, median fcv and median F-wave latency Johnson (2004) db, rmd 12 months Exercise LVEF and cardiac stroke volume sb, single blind; db, double-blind; Uncntr, uncontrolled; nonrmd, nonrandomized; rmd, randomized; co, crossover; mcv, motor nerve conduction velocity; scv, sensory nerve conduction velocity; sap, sensory action potential; wl, wave latency; dsl, distal sensory latency; VPT, vibration perception threshold; mfd, myelinated fibre density. (eight out of nine), but electrophysiological measurements remained virtually unchanged. The most notable side-effects were nausea, and photosensitivity, which was severe in two cases. Around the same time, the most comprehensive trial of alrestatin was conducted. Thirty patients with long-standing diabetes and mild to moderate neuropathy were stud- ied in a double-blind, randomized, placebo-controlled trial, which lasted 12 weeks (7). Symptomatic improvement, reduction of the sensory impairment score, and improve- ment of vibration perception threshold and ulnar nerve conduction velocity were noticed, but the rest of the electrophysiological measurements in the median, peroneal, and sural nerves did not show any significant difference. The earlier-mentioned studies indicated that treatment with ARIs might be helpful in treating diabetic neuropathy and also highlighted the need for well-conducted long-term trials in order to fully explore the potential of this new therapeutic approach. On the down side, the high incidence of side-effects of alrestatin prohibited its further devel- opment. This led the way for using some newly discovered compounds such as sorbinil and tolrestat. Sorbinil Sorbinil was the second ARI to be tested in human diabetic neuropathy and a con- siderable number of studies were conducted during the last decade using this drug. An early study using sorbinil for the treatment of neuropathy was published in 1983 and included 39 patients with stable diabetes and no clinical symptoms of neuropa- thy (8). The design of the study was randomized, double-blind, crossover and each patient received active treatment for 9 weeks. The results showed a small but statis- tically significant increase of the conduction velocity of the peroneal motor nerve (0.70 m per second), the median motor nerve (0.66 m per second), and the median sensory nerve (1.16 m per second) during the treatment with the active drug. Another important finding was that the increase declined rapidly after cessation of the treat- ment so that the nerve conduction velocity was similar to pretreatment levels 3 weeks later. Five patients were withdrawn from the study because of fever and rash, which were attributed to sorbinil. In contrast with the previous trial, the ones which followed included mainly patients with diabetes with symptomatic neuropathy. The first one studied 11 patients with severely painful neuropathy who failed to respond to conventional treatment with anal- gesics or tricyclic antidepressants (10). In a single blind design the patients were treated with sorbinil for 3–5 weeks and the pain relief was measured using a graphic scale. Marked to moderate pain relief was noted in eight patients usually 3–4 days after being on treatment, whereas the pain returned to pretreatment levels in seven of the respon- ders when they stopped taking the drug. The motor and sensory conduction velocities of the median nerve improved in four patients, whereas the peroneal motor conduction velocity improved in two patients. It is of interest however, that in four patients who responded to the treatment the pain was related to proximal motor neuropathy, a condi- tion, which is thought to be caused by mechanisms not related to polyol accumulation. No significant side-effects were noted in the 11 patients who finished the study whereas 12th patient who started the study was withdrawn because of rash. 312 Veves The next study had a double-blind, randomized, placebo-controlled crossover design, and included 15 patients with painful symptoms, which were present for more than 1 year (10). The patients were observed for 16 weeks but they were on active treatment for only 4 weeks, either from week 5 to 8 or from 9 to 12. Painful symptoms were assessed using a standardized symptom score, whereas other measurements included neurological findings on clinical examination, vibration perception threshold, motor and sensory nerve conduction velocities, and autonomic system function tests. A significant number of patients reported improvement of painful symptoms while on the active treat- ment, but when the pain score was calculated using their diaries no difference was found between sorbinil and placebo treatment. Significant improvement was also noticed in the sural sensory potential action, whereas the rest of the electrophysiological measure- ments remained unchanged. The number of patients who withdrew because of side- effects (mainly rash and fever) had increased in comparison with the previous study; four patients in total had an idiosyncratic reaction which resolved rapidly after the dis- continuation of the drug. The next trial used the same layout, i.e., double-blind, placebo-controlled crossover, and included 13 patients with diabetes with chronic symptomatic neuropathy (mean duration of symptoms 6 years) (11). The duration of treatment with sorbinil was the same as in the previous trial, 4 weeks out of a total study period of 16 weeks. The pain intensity was measured using a 100-mm visual analog scale whereas other measure- ments included vibration perception threshold, motor and sensory conduction veloci- ties, autonomic function tests, and duration of sleep. In contrast to the previous study, no difference was found in any parameter, including the severity of neuropathic symp- toms and the objective measurements of peripheral nerve function. Side-effects were present only in one patient who took sorbinil in the form of a febrile rash necessitating his withdrawal from the study. The aforementioned short-term trials were followed by long-term ones, which exam- ined the effects of aldose reductase inhibition for periods of 6–12 months. The first long-term study studied 55 male patients with diabetes with symptomatic neuropathy for 6 months in a double-blind placebo-controlled parallel group design (12). To avoid a possible long-term effect of the drug, the authors elected to randomize their patients to active- and placebo-treatment and to avoid the crossover design. Patients assessment included clinical examination, neurophysiological measurements, thermal and vibration perception thresholds, and autonomic system function tests. No significant improvement was found in the sorbinil-treated group when it was compared with the placebo group, although three sorbinil-treated patients reported a marked overall improvement compared with none from the placebo group. When these three patients were compared with the whole sorbinil-treated group their age was lower than the mean group age and the neuropathy assessed by electrophysiology was less severe. All three patients worsened to pretreatment levels when sorbinil was discontinued. No significant changes were found in the vibration and thermal discrimination thresh- old. From the electrophysiological measurements improvement was noticed in the motor posterior tibial nerve conduction velocity (approximately 1.5 m per second), F-wave latency of the ulnar nerve, and the distal sensory latency of the ulnar nerve. From the autonomic tests, a significant improvement in the R–R interval variation during deep ARIs for the Treatment of Diabetic Neuropathy 313 breathing was found in the sorbinil-treated group. The number of patients with serious side-effects was smaller in this study; only two patients had to be withdrawn from the study because of rash and lymphadenopathy. The next long-term study included 31 patients with mild to moderate neuropathy and lasted for 14 months (including a 2-month run-in period) (13). The study was designed as double-blind, randomized, placebo-controlled, and two-third of patients were treated with sorbinil whereas one-third received placebo. Assessments of the patients response were performed every 3 months and included the measurement of symptoms such as pain, tingling, and temperature insensitivity using a 100 mm visual analog scale, clin- ical examination, vibration perception thresholds, electrophysiology, and autonomic function tests. The results indicated no benefit for the sorbinil-treated patients in any of the measured parameters. In addition, as similar doses of the drug were used in this trial and the previous ones, and was accompanied by serum sorbinil levels measurements, inadequate drug dosage or poor patient compliance could not be held responsible for the observed discrepancies. Hypersensitivity reactions with fever, rash, and myalgia occurred in two patients who recovered completely after the drug was discontinued. No improvement was also found in another double-blind, randomized trial, which lasted for 12 months and included patients with severe neuropathy with or without symptoms (14). Thirty nine patients took part in this study and the severity of neuropa- thy is indicated by the fact that a history of foot ulceration was present in 21 patients. Efficacy assessments included clinical evaluation, vibration and thermal perception thresholds, nerve conduction velocities in 12 nerves, and somatosensory-evoked poten- tials. The results showed no difference in any of the above measurements between sorbinil and placebo-treated patients, both for the lower and upper extremities, despite the fact that the arms were less severely affected. As it can be seen from the aforementioned studies, the beneficial results, which were initially reported failed to be confirmed in subsequent, better designed, long-term trials. In an effort to clear the confusion, the next trial used sural nerve biopsies, which allow more precise evaluation of the therapeutic efficacy (15). This trial included 16 patients with established peripheral neuropathy and involved subjects undergoing fascicular sural nerve biopsies of the same limb at the beginning and the end of the study (16). The design of the trial was double-blind, randomized, placebo-controlled, and lasted 12 months. Additional investigations included clinical neurological assessments, ther- mal perception thresholds, and electrophysiological measurements. Although both actively- and placebo-treated groups showed some clinical improvement at the end of the study this was more pronounced in the sorbinil-treated group. The nonbiopsised sural nerve of the sorbinil group showed an improvement of 1 µV in the action-potential amplitude and of 2 m per second in the sensory conduction velocity (2 m per second), results that were not found in the placebo group. The analysis of the sural nerve biopsies showed that the sorbitol levels in the sorbinil group were reduced, indicating a successful aldose reductase inhibition in the nerve tissue. The myelinated fibers density, the best single histopathological criterion to quan- tify neuropathy, was similarly reduced at baseline by 50% in both the sorbinil and placebo groups when they were compared with age-matched nondiabetic subjects. 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