Diabetic neuropathy has been considered clinically as a heterogeneous disease state and its etiology may be multifactorial. Metabolic, vascular, rheological or aging factors are hypothesized to play important roles in the development of diabetic neuropathy. Consequently, diverse therapeutic means are applied to patients at present according to their physicians own concept about this disease state. Various vitamins such as B1, B6, B12 are widely prescribed without definite evaluation of their efficacy. Analgesics, anti-convulsants and anti-depressants may be effective on painful neuropathy though their use may not be tolerated for long term. Recent progress in understanding metabolic derangements of peripheral nerve in diabetes gives us valuable suggestion to modify the conventional way of the treatment of diabetic neuropathy. Aldose reductase inhibitors, myo-inositol, gangliosides, prostaglandin and others have been extensively studied as possible new therapeutic means. In this lecture some results of these new wave in the treatment of diabetic neuropathy, especially about methyl B12 and aldose reductase inhibitor, will be overviewed in search for effective and useful therapy
Morphometric evaluations of histopathological changes in postmortem materials from three patients with diabetes mellitus with neuropathy, nephropathy, and retinopathy were made on the sural nerve, lumbar spinal roots, lumbar dorsal root ganglion (two cases), and fasciculus gracilis. In all three patients, there was a marked decrease in the densities of both the large and the small myelinated fibers in the sural nerves. In the lumbar spinal roots, segmental demyelination and remyelination with or without decrease in the number of myelinated fibers per root was the main finding in both the dorsal and ventral roots, being more common in the dorsal roots. At the third cervical segment of the fasciculus gracilis, the myelinated fiber density was slightly decreased in one patient and moderately decreased in the other two. The number of cell bodies of the fifth dorsal root ganglion was within normal limits in the two patients in whom this was examined, although the median diameters approximated the lower limit found in controls. The potential presence of segmental demyelination and remyelination in the dorsal and ventral spinal roots should be considered, especially when assessing electromyographic changes and nerve conduction in diabetic patients.
The purpose of this study was to determine whether an aldose reductase inhibitor (ARI, ONO-2235) or prostaglandin E1 (PGE1) could prevent or improve the impairment of nerve conduction in diabetic patients. Two groups of patients with diabetic neuropathy were the subjects of the study. The first group was treated with ARI and the second group with PGE1. The treatment lasted for six weeks in both groups. Conduction velocities of the median, posterior tibial and/or ulnar nerve were measured before and after the treatment in each patient. Before ARI treatment, reduction of the motor nerve conduction velocity (MCV) of the median nerve was observed in one of three patents, and that of the sensory nerve conduction velocity (SCV) of the median nerve in all three. Four out of six patients had reduction of the MCV in the ulnar nerve and four out of seven in the posterior tibial nerve. After the treatment, slight improvements of the conduction velocities were observed in six of 12 (50%) measurements in the above nerves with decreased conduction velocities. But no significant alteration in the mean values of nerve conduction velocities between before and after the treatment was observed. Before the PGE 1 treatment, impairment of the MCV of the median nerve was observed in four of five patients, reduction of the mixed nerve conduction velocity (MNCV) of the median nerve in all five and reduction of the SCV of the median nerve in three of five. Two out of six patients showed reduction of the MCV in the postrior tibial nerve. After the PGE1 treatment, a slight improvement was observed in five of 14 (36%) measurements in the peripheral nerves with impaired conduction velocities. But there were no significant changes in the mean values of the nerve conduction velocities before and after PGE1 treatment. It is concluded that ARI or PGE1 treatment results in some improvement the peripheral nerve function in diabetic neuropathy and that there is a limitation on the efficacy of these treatments in advanced neuropathic states.
Streptozotocin-diabetic rats were maintained on a 72% fructose diet for 4 weeks or 6-8 mos and some were treated with an aldose reductase inhibitor (ONO-2235: 50 mg·kg-1·day-1). Fructose feeding significantly influenced the development of impaired motor nerve conduction velocity in the diabetic rats and this effect was positively correlated with sorbitol accumulation and myo-inositol decrease in the sciatic nerve of diabetic rats maintained on fructose-rich diet. Treatment with ONO-2235 prevented both slowing of the motor nerve conduction velocity and elevation of sorbitol and decrease in myo-inositol in the sciatic nerve. A morphometric study of the treatment with aldose reductase inhibitor for 8 months was performed in the sural nerve of diabetic rats maintained on a fructose-rich diet, and these microscopic observations were confirmed by morphometric analysis of the myelinated fibers by using a computer. The axonal area of fructose-fed diabetic rats (21.6±4.1μm2) was significantly less than that of normal fructose-fed rats (27.8±3.6μm2, p<0.05), and this reduction of the axonal area was reversed by treatment with the aldose reductase inhibitor (26.5±2.4μm2, p<0.05 versus fructose-fed diabetic rats). In the linear regression of myelin thikness on fiber diameter, the myelin thickness of aldose reductase inhibitor treated rats was larger in both small (x=4) and large (x=8) myelinated fibers than that of fructose-fed diabetic rats not treated with ONO-2235. These changes in myelinated fibers were also confirmed by determination of the index of circularity (IC). The mean IC of fructosefed diabetic rats (72.9±6.0%) was significantly less than that of fructose-fed normal rats (86.5±2.0%, p<0.001). However, this reduction in IC in fructose-fed diabetic rats was completely reversed by the treatment with the aldose reductase inhibitor (86.8±3.6%, p<0.001 versus fructose-fed diabetic rats). Thus, our findings suggest that increased polyol pathway activity and decreased myo-inositol levels in the nerves may be related to the pathogenesis of diabetic neuropathy and the aldose reductase inhibitor may be a useful treatment for it.
Bladder dysfunction is known to be a frequent manifestation of autonomic neuropathy in diabetic patients. In this study we developed a new system of cystometric analysis to evaluate bladder function in diabetic rats, which could be used for animal experiment on diabetic cystopathy. Diabetic rats were produced by intravenous injection of streptozotocin 60mg per kg body weight. Some of the diabetic rats were treated with subcutaneous insulin injection between 8th and 12th week after the induction of diabetes. The system of cystometric analysis was composed of a 26 G needle connected with plastic tubes, injector, transducer, polygraph and recorder. On the 4th and 12th week after the induction of diabetes, midline laparotomy was performed and the bladder was exposed under anesthesia with intraperitoneal pentobarbital injection. After the 26 G needle connected with the injector containing saline was inserted into the bladder, saline was infused stepwesly through one plastic tube, and the intravesical pressure was measured through another plastic tube connected to a transducer. This procedure was repeated until the beginning of urine voiding from the urethra. The volume at voiding was 0.7ml±0, 4ml in normal rats and 4.5ml±1.7ml in diabetic rats in the 4th week (Normal vs DM, p<0.05), while the pressure at voiding was not significantly different between the two groups. Similar results were obtained on 12 th-week experimental rats. Insulin treatment improved the cystometric abnormality. However, there was a remarkable increment of urine volume in diabetic rats, which might physically modify the results. Therefore we produced nondiabetic polyuric rats by giving 5% glucose solution freely and performed the same examination in order to evaluate the effect of polyuria on the cystometric results. No cystometric abnormality was detected in non-diabetic polyuric rats by our system. These results suggest that this system for cystometric analysis may be a useful means of investigating bladder dysfunction in diabetic rats.
Male wistar rats were made diabetic at 7 weeks of age by the injection of streptozotocin, 80mg/kg body weight. R-R interval variations (CV value) were recorded by electro-sphygmomanometer PE 300 with a recording speed of 1cm/second and measured light microscopically using a Nikon micrometer. CV values were 3.12±0.20% in diabetic rats at 6 weeks' duration of diabetes, which was significantly decreased compared with 4.12±0.34% in control rats (p<0.05), similar to autonomic neuropathy in human diabetics. Atrial ganglion cells were studied pathologically with Kliiger-Barrela staining.: Ganglion cells of control rats showed clear nucleic membranes and nucleic bodies, and diffusely and finely disseminated Nissl bodies in cytoplasma, while diabetic rats showed lysis or picnosis of nuclei with peripherally located aggregated and in creared Nissl bodies. These findings were similar to those in celiac ganglion cells in human diabetics. These data suggest diabetic autonomic neuropathy (parasympathetic) might take place in diabetic rats. Plasma catecholamine levels, determined by high-performance liquid chromatography, were elevated in response to blood withdrawal in normal rats. Such a response was also observed in streptozotocin diabetic rats 2 and 6 weeks after the onset of disease but was no longer seen at 13 weeks. Tissue (adrenal, heart, skin, kidney) catecholamine levels in diabetic rats were increased at 6 weeks as well as at 13 weeks. These abnormalities were corrected by insulin treatment in at least some of the diabetic rats. The present data suggest that there might be a catecholamine accumulation, which is later accompanied by impaired catecholamine secretion in diabetic rats, and they provide a basis for the inference that similar changes might play some role in the pathogenesis of diabetic autonomic neuropathy in humans.
The present studies tested the hypothesis that the aldose reductase inhibitor (ARI) ONO-2235 prevents the decrease of sympathetic nervous system (SNS) activity and motor nerve conduction velocity (MNCV) through reduction of the increased sorbitol accumulation in streptozotocin (STZ) diabetic rats. One week after the injection of STZ (65mg/kg) or saline, STZ rats were divided into the following groups: 1) untreated STZ, 2) ONO-2235 treatment (50mg/kg/day, p.o.); STZ (ARI) and 3) NPH insulin treated (at doses varying between 4-8 U according to plasma glucose level); STZ (INS). After 3 weeks, studies of NE turnover began utilizing the NE synthesis inhibition technique with a-methyl-p-tyrosine as the index of SNS function. As we expected, the untreated STZ group had a marked reduction of fractional NE turnover (k), and total NE turnover rate in intercapsular brown adipose tissue (IBAT), heart and pancreas, and reduced MNCV in tail nerve. They showed an increase of sorbitol content in both red blood cells and sciatic nerve when compared with contro rats (p<0.01). Daily ARI treatment to STZ diabetic rats significantly prevented the decrease of NE turnover in IBAT, heart and pancreas and the reduction of MNCV, and also, the increase of sorbitol content in both red cells and sciatic nerve compared with untreated STZ rats (p<0.01). Insulin treatment also had a preventive effect (p<0.01). These findings showed that STZ diabetic rats had not only motor neuropathy but also sympathetic nervous dysfunction, and that ARI treatment might prevent these through the reduction of sorbitol accumulation. Insulin therapy was also proved to be effective.
Recently, various reports have suggested that aldose reductase inhibitor (ARI) provides the possibility of preventing diabetic neuropathy. In this study, we observed the effectiveness of ARI (ONO-2235) on diabetic neuropathy in the studies of experimental diabetic rats and investigated the clinical effects of ONO-2235 on diabetic patients with neuropathy. (I) In the animal research, streptozotocin-induced diabetic male Wistar rats were treated with ONO-2235 50mg/kg/day for two weeks, and the results of examinations were compared with those of normal and diabetic controls. 1) Parasympathetic nerve function was assessed by analysis of the variation in R-R intervals on ECG, and the coefficient of variation (CV R-R) was calculated. 2) Somatic nerve function was assessed by measuring motor nerve conduction velocity (MNCV) of the tail, density of myelinated fibers and sorbitol content of the sciatic nerve. As a result of treatment with ONO, 1) CV R-R was greater than that of the diabetic control group (p<0.05) consequently parasympathetic function was improved. 2) MNCV was significantly (p<0.005) recovered in the treatment group. The density of myelinated fibers in the treatment group was not significantly decreased compared with that of the normal control group, and the sorbitol content of the treatment group was significantly (p<0.001) lower than that of the diabetic control group. (II) In the clinical trials, 300mg or 600mg of ONO-2235 was administered daily to 22 cases for four weeks and the effects were estimated subjectively and objectively. The global subjective improvement rating (including slight improvement) was as high as 81.8% but objectively there was no significant difference in MNCV and CV R-R. In conclusion, it is considered that aldose reductase inhibitor therapy could be effective.
Motor and sensory nerve coduction studies were performed on 56 consecutive diabetic patients (NIDDM). Maximum conduction velocities of the motor and sensory nerves and action potential amplitudes of the sensory nerves were measured in the limbs. Twentyeight nerve measurements were obtained for each patient. In order to exclude the effects of age and to evaluate the nerve impairments quantitatively under standard conditions, the values measured in patients were represented as the percent of the the mean value in age-matched controls (‘percent’ representaion method). Based on the ‘percent’; representation method, the incidence of polyneuropathy in the diabetic patients and the nature of the degeneration of the peripheral nerves were clarified. Out of 56 patients 27 (48.2%) had abnormal measurements in more than half of the 28 nerve measurements and were considered to have polyneuropathy. Fifteen patients (26.8%) were abnormal in less than half and the other 14 (25.0%) were normal in almost all the nerves tested. A highly significant correlation was observed between motor and sensory conduction velocities and also between the conduction velocities of the forearms and legs. However, in the action potential amplitude and the conduction velocity of the sural nerve, the amplitude was more severely decreased than the conduction velocity. Such a decrease of amplitude is considered to reflect axonal loss, which is the main histopathological finding in diabetic polyneuropathy. Consequently, changes of amplitude in sensory nerve action potential are more important than those of conduction velocity in observing peripheral nerve impairments in diabetic patients.
In order to elucidate whether sorbitol accumulation in cells including Schwann's cells as well as erythrocytes (RBC), might be responsible for diabetic neuropathy, the sorbitol content (SOR-RBC, nmole/gHb), glyceraldehyde reductase activity (GAR-RBC, mU/ml) and sorbitol dehydrogenase activity (SDH-RBC, mU/ml) in RBC were determined concomitant with the motor nerve conduction velocity (MCV) in 98 diabetic patients (46men and 52 women, mean age 51.4 years old, mean duration 7.5 years). SOR-RBC levels (38.0±1.9 (SD) nmole/gHb) in diabetics were significantly higher than in normal controls (22.2±4.2). Diabetics with clinical neuropathy showed higher, but not significantly, higher, levels of SOR-RBC (47.2±5.7) as compared to those in diabetics without neuropathy (37.8±4.0). The duration of diabetes did not show any correlation with any of these three parameters, SOR-RBC, GAR-RBC or SDH-RBC. However SOR-RBC was positively correlated with fasting plasma glucose (r=0.628, n=91, p<0.01), as well as HbAi (r=0.335, n=98, p<0.05), suggesting its relatively rapid fluctuation possibly depending on plasma glucose levels. In addition, the MCV in the median and ulnar nerve was negatively correlated with SOR-RBC (p<0.05 to 0.01). The results suggest that SOR-RBC, which fluctuates depending on plasma glucose levels during a relatiely short period, might be responsible for diabetic neuropathy.
Heart rate (HR) variation tests are all considered to be mainly affected by parasympathicus. However, diabetic patients sometimes show normal HR variation on standing, although respiratory HR variations are remarkably decreased. This study was aimed at clarifying the reason for this discrepancy. Eight healthy subjects and six diabetic patients with autonomic neuropathy were used for the HR variation tests, which were performed in the supine resting position and during deep breathing (respiratory HR variations) and on standing (orthostatic tachycardia: JHR) by using atropine and propranolol. The results in both healthy subjects and diabetic patients showed that: 1) After the administration of atropine (40μg/kg, IV), the respiratory HR variations were almost completely abolished, whereas the decrease in ΔHR was insignificant. With additional propranolol (10mg, IV), ΔHR was significantly reduced as compared with that subsequent to atropine 2) Propranolol alone did not affect the respiratory HR variations, whereas JHR was significantly reduced. We conclude that the respiratory HR variations are prediominantly affected by the parasympathetic nervous system and the orthostatic tachycardia is influenced by both the parasympathetic and sympathetic nervous systems, particularly by the latter. These HR variation tests are valuable for the early detection of the cardiac parasympathetic or sympathetic damage in diabetic patients.
In patients with diabetes mellitus, the coefficient of variation (CV) of the R-R interval on electrocardiography and the threshold of taste were determined in a study that related these parameters to diabetic status and complications. In 160 normal subjects and 112 diabetics, after 15 minutes rest in the supine position, the CV was measured by Autonomic R-100 (MEC, Tokyo, Japan). In 109 normal subjects and 112 diabetics, the threshold of taste in the chorda tympani nerve area was measured by an electrogustometer (MEC, Tokyo, Japan). In both groups, the CV decreased and the taste threshold increased with aging. However, the CV in diabetics older than 30 showed a statistically significant decrease as compared with that in normal subjects of the same age. The taste threshold in diabetics of 30 to 60 years of age, showed a statistically significant increase as compared with that in normal subjects of the same age. In diabetics, the longer the duration of diabetes mellitus, the more the CV decreased and the taste threshold increased. Further, in diabetics with poorer metabolic control, CV showed a lower level and the threshold of taste a higher level. Patients with symptomatic neuropathy had a statistically significant decrease of CV and an increase of the taste threshold as compared with patients without such clinical symptoms. The taste threshold was found to increase with progression of diabetic retinopathy. CV in diabetics with proteinuria showed a significant decrease as compared with that in those without proteinuria. Furthermore, even in the patients without retinopathy, proteinuria or clinical symptoms of neuropathy, CV showed a significant decrease and the taste threshold a significant increase as compared with those of age-matched normal subjects, and the CV and taste threshold showed a significant negative correlation. These findings indicate that autonomic nerve dysfunction as well as gustatory disorder as dicated in by an electrogustometer precede other diabetic complications, and suggest that these examinations in diabetics may be useful as predictors of the complications in diabetic patients.
1. Quantitation of autonomic neuropathies. Autonomic neuropathies are diagnosed clinically by the following function tests in our department. 1) heart rate variation test (deep breathing test, orthostatic test by Autocorder, Nihon Medix Co.) 2) esophageal motility test 3) gastric emptying time (isotope method and ultrasonographic “US” method) 4) small bowel transit time 5) gallbladder contractability (US method) 6) residual urine volume (US method) 7) vasomotor nerve function (ice-water immersion test using thermography) 8) nicotine elicited axon reflex sweating 2. Autonomic neuropathy and hypoglycemia-induced endocrine response. Plasma glucagon, growth hormone, cortisol, pancreatic polypeptide, epinephrine and norepinephrine were measured during insulininduced hypoglycemia in diabetic patients with and without autonomic neuropathy. A differnce in endocrine response was seen in epinephrine and norepinephrine only between cases with positive deep breathing test and negative orthostatic test (vagal neuropathy) and cases with postive deep breathing and orthostatic test (sympathetic neuropathy). A phenomenon of unawareness of hypoglycemia may occurr in cases with sympathetic neuropathy. 3. Autonomic neuropathy and diabetic retinopathy. Aggravation of diabetic retinopathy is more frequently observed in cases with autonomic neuropathy, especially with orthostatic hypotension. The possible mechanism is discussed. 4. Difficulty of blood glucose control in cases with impaired GI tract motility. Abnormal GI tract motility is one factor making blood glucose control difficult in conventional insulin-therapy cases.
Various methods for evaluating diabtic autonomic neuropathy have been reported. Using thermography, we tried to examine the vasodilating activity of the autonomic nerves of one leg of diabetic patients while the other leg was immersed in a warm bath. This study attempted to determine the significance of thermography with a warm water stimulus in diabetic sympathetic neuropathy. Sixty-two patients with well palpable dorsal pedal arterial pulse, whose ages ranged from 50 to 69 years, received warm water-stimulated thermography at least twice during the observation period of 3 years. Thermography was carried out by a modification of Gibbon's method, using Thermoviewer MPJTGMD in an air-conditioned room with a temperature of 24.5 to 25.5°C. Right leg thermography was recorded every 30 seconds for 20 minutes, while the lower two-thirds of the left leg was immersed in a 45°C warm water bath for 10 minutes. These patterns are extremely reproducible. No increase in the temperature of one leg, or rather paradoxical vasoconstriction following immersion of the other leg, that is to say, the so-called flat pattern, is thought to be due to sympathetic disorder, and this pattern is developed slowly, requiring at least several years' of poor blood sugar control. The flat pattern is seen more frequently in diabetics with a long history. Though these patterns did not change easily, we observed transition of the thermographic pattern during the three years. In a few cases, thermograhic patterns improved, and in all of these blood sugar control had remained fairly good. The flat pattern was related to microangiopathy, R-R intrval variation and motor nerve conduction velocity. R-R interval variation was often abnormal in patients with normal thermograhic patterns, showing sympathetic nerve dysfunction appearing later in the development of diabetic neuropathy. In conclusion, this type of thermography is a reliable, reproducible, non-invasive index for determining and following diabetic sympathetic disorders.
Real time ultrasonograhy was used to assess bladder volumes in subjects with residual urine (RU). Postvoiding urinary bladder was scanned in both longitudinal and transverse planes at the largest diameter with the subject in the supine position, and each bladder area from these pictures was measured using a calculator. A significant correlation (r=0.917, p<0.001) was found between the bladder area from the ultrasound picture on the midline longitudinal plane and the actual volume of RU obtained by catheterization. As compared with healthy controls (N=56), some imaging of RU was more frequently found in diabetics with no evidence of organic urological disease (N=116), regardless of age, and 20 (17.2%) showed abnormal RU with a bladder area of over 10cm2. Most of the cases were poorlycontrclled, had a long duration of diabetes and revealed some neurolongical abnormalities including autonomic neuropathy, as judged from the coefficient of variation of the R-R interval in resting ECGs. These results confirm that ultrasonography represents a reliable technique for detecting RU and suggest that RU in diabetics may have some relationship with neurological abnormalties.
This randomized prospective study was undertaken to determine whether strict glycemic regulation could have beneficial effects on the course of diabetic microangiopathies in 43 insulin-treated diabetic patients. In the conventional treatment group, in which patients continued intermediateacting insulin injections once a day, glycemic regulation did not show any significant changes. As far as the neuropathy was concerned, motor nerve conduction velocity of the median nerve (MCV) and the coefficient of variation of 100 R-R intervals on ECG (CV) were not altered at all for 24 months. In the experimental group, consisting of 22 patients whose insulin regimes were switched to multiple insulin injections, a significant amelioration of glycemic regulation was achieved within 3 months and was maintained for 24 months. A remarkable improvement in MCV was observed, but CV was not altered. To assess the contribution of metabolic improvement and autonomic nervous system activity to hypoglycemia-induced glucagon secretion, insulin tolerance tests were performed in these patients. The presence of autonomic neuropathy was evaluated when CV was less than 2.5% In 11 IDDM without autonomic neuropathy, glucagon response to hypoglycemia was improved remarkably after 1-3 months of strict glycemic control, whereas in the patients with autonomic neuropathy, the severely dimished glucagon response existed even after strict long-term glycemic control. Thus, it was concluded firstly that improvement in autonomic neuropathy may require more strict and longer glycemic normalization in diabetics, and secondly that diminished hypoglycemiainduced glucagon secretion in diabetes is secondary to metabolic derangement associated with insulin deficiency and intact autonomic nerve function is necessary to raise glucagon secretion during hypoglycemia.
Coefficient of variation of R-R intervals in ECG were used as an indicator of parasympathetic nerve function in diabetic patients with neuropathy. Coefficient of variation (CV) calculation was carried out with computerized “Autonomic R-100” after 5 minutes rest in the recumbent position in diabetic patients whose ages range from 50 to 69. For the evaluation of methyncobalamin administration, patients with a CV value of less than 2 were selected. Twenty-seven patients (14 male, and 13 female) were placed on methycobalamin, 1500-3000μg a day, and 24 patients (12 male, and 12 female) were used as controls. CV values were divided into 3 degrees. (1) less than 1, (2) more than 1 and less than 2, and (3) more than 2. The change in CV value was judged as follows; improvement, ameliorated more than 1 degree; no change, stayed within original degree; and deterioration, got worse by more than 1 degree. The overall effect of methylcobalamin was not significantly different between the treated and control group as far as percentages were concerned. Improved cases accounted for 30%(8/27) in the treated group and 33%(8/24) in the control group. No-change cases were 56%(15/27) in the treated group and 54%(13/24) in the control croup. Deteriorated cases accounted for 14.8%(4/27) in the treated group and 12.5%(3/24) in the control group. However change of HbA1 was taken into account in these results: 11.25%(3/27) improved under the deterioration of HbA1 in the treated group (3/8), and no cases were improved in this condition in the control group (0/8). Other background conditions such as duration of diabetes and neurologic disorders (numbness, orthostatic hypotension, vibratory perception disturbances and inpaired tendon reflexes) were all more severe in treated group than control group. These data sugest favorable effects of methylcobalamin can be expected in some cases of diabetic neuropathy, but further elucidation is needed.
Fifty-three diabetie patients with diabetie neuropatlry, 30 males and 23 females, aged 41-76 years, with a mean duration of diadetes mellitus of 13.6 years, were given 300mg of trapidil/day orally for 3 months. Subjective symptoms such as spontaneous pain, paresthesia and dizziness on standing up were followed in all patients. Thirty-three were further examined for changes in the motor nerve conduction velocity (MCV) of the median nerve and the sensory nerve conduction velocity (SCV), and coefficient of variation in the R-R interval on ECG (CVR-R), before and after the treatment. After treatment with trapidil, subjective symptoms were improved remarkedly in 3.8%, improved slightly in 52.8%, and unchanged in 43.4% of 53 patients. MCV was improved markedly in 17.9%, improved slightly in 10.7%, unchanged in 55%, and aggravated in 6% of 33 patients. Improvement of more than 15% in CVR-R was noted in 35.7%, but remained practically unchanged, varying only within±15%, in the other 33 patients. These results suggest that trapidil is a useful drug for the treatment of diabetic neuropathy and that angiopatlry may at least in part contribute to the pathogenesis of diabetic neuropathy.
L-threo-3, 4-dihydroxyphenylserine (L-DOPS) is an immediate precursor of noradrenaline which is converted to noradrenaline by L-aromatic amino acid decarboxylase. Thus, this drug is useful in diseases associated with noradrenaline deficiency. Its effect has been confirmed in patients with orthostatic hypotension secondary to familial amyloid polyncuropathy and those with freezing phenomena secondary to Parkinson disease. We tried to confirm that this drug has a similar effect on diabetic autonomic dysfunction. Our subjects were three patients (one man and two women) aged 42 to 66 years who had severe orthostatic hypotension and syncope attack, and had very low basal plasma noradrenaline levels which did not increase after postural change. Oral administration of DOPS (400mg of DL-stereoisomer in case 1, 200mg of L-stereoisomer in case 2 and 400mg in case 3) induced substantial and sustained elevation of blood pressure and removed patients syncope attacks. Further, this drug improved other autonomic dysfunctions, e. g., bladder dysfunction in cases 1 and 2, diarrhea in ease 2, and severe radiculopathy in case 3.
The etiology of diabetic neuropathy has not yet been established, however, abnormal carbohydrate methabolism seems to be an important precipitating factor in the pathogenesis of diabetic neuropathy. Recently, there have been reports that prostaglandin E1 (PGE1) administration improves or alleviates the severity of diabetic peripheral neuropathic symptoms such as numbness, dull pain and hypesthesia. It is known that marked reduction or absence of beat-to-beat variations in ECGs is recognised as diabetic autonomic neuropathy. The aim of the present trial was to estimate the effect of PGE1 on diabetic autonomic neuropathy, using the coefficient of variation (CV) of R-R intervals in ECGs as the activity index of the parasympathetic nervous system. Thirteen NIDDM patients were studied. Ages ranged from 40 to 69 years (mean 57.5) and duration of diabetes ranged from 1 to 20 years (mean 10.5 years). Their baseline CV was less than 2.5 and all had normal ECGs. Their average HbA1 was 9.2%, ranging from 7.4% to 10.9% Each patient was kept in a supine position with quiet breathing for more than 5 min before the measurement of baseline CV, which was calculated by the Autonomic R-100. CV measurement was repeated directly after PGE1 administration and once again 20 min. after the infusion. Thirteen patents were divided into two groups according to CV ratio (CV after/CV baseline). Group I consisted of 5 patients whose CV ratio was less than 1.2. Mean age was 52.4±9.8 y. o., mean duration was 10.2±6.3 years, and average HbA1 was 9.9±0.8%. Sixty percent of cases suffered from peripheral neuropathy. Group II consisted of 8 patients whose CV ratio was more than 1.2. Mean age was 60.8±5.2 y. o, mean duration was 10.6±6.9 years, and average HbA1 was 8.8±1.3%. Seventy-five percent of cases suffered from peripheral neuropathy. Although the level of HbA1 in group II was lower than that in group I, there were no statistically significant differences between the two groups in age, duration of diabetes, controlled state of carbohydrate metabolism or other complications. The results suggest that PGE1 may contribute to the improvement of diabetic autonomic neuropathy as well as peripheral neuropathy through the dilatation of small vessels, increase of blood flow, and reduced platelet aggregation.
Prostaglandin E1 (PGE1) is a potent vasodilator and au efficient iiihibitor of platelet aggregation. The clinical use of PGE1 Ibr peripheral artery disease has become established, especially for severe resting pain. It is said that peripheral vascular complications and/or metabolic disarrangement clue to hyperglycemia may play an important role in the pathogmesis of diabetic neuropathy, and there is no standardized treatment for symptoms of this disorder. We observed a striking effect of PGE1 on diabetic neuropathy with pain and dysesthesia of distal extremities. Two types of PGE1 were used; one was stabilized with cyclodextrin (PGE1-CD) and the other was dissolved in a lipid emulsion (Lipo-PGE1). PGE1-CD (20-80μg/day) was administered intravenously for 14 days in three patients, and improvements in subjective symptoms and vibration senses were observed. However, there were no significant changes in tendon reflexes, R-R intervals, or nerve conduction velocities. Lipo-PGE1 (5μg/day) was used for 14 days in four patients, and a remarkable improvement in subjective symptoms and vibration senses was observed in all four cases. In two of the four cases, motor nerve conduction velocities and/or R-R intervals were also restored toward normal. There were no significant changes in blood glucose levels or retinal findings before and after the treatment. PGE1 therapy is effective for diabetic neuropathy; Lipo-PGE1 especially seems to be useful, even in a small dose.
It is thought that the pathogenesis of diabetic peripheral neuropathy consists of various factors including vascular and metabolic disorders. Therefore, prostaglandin E1 (PGE1) has been used clinically both for patients with peripheral vasculr disease and those with diabetic peripheral neuropathy due to the vasodilative and anti-platelet effects of PGE1. Recently, a novel prostaglandin E1 infusion therapy using a lipid microsphere was developed in order to increase some of the advantages of PGE1 therapy. In this study, we investigated the clinical effects of lipo-prostaglandin E1 (Lipo-PGE1) on diabetic peripheral neuropathy. Fifty-two diabetics with neuropathy were given Lipo-PGE1 once daily by intravenous drip infusion at a dosage of 5μg of PGE1. Thc treatment lasted for a period of at least 2 weeks as a rule. An improvement rating of 70% in the subjective symptoms was obtained in diabetic peripheral neuropathy including spontaneous pain (81.3%), hypesthesia and numbness (72.0%). Though there was a significant improvement (p<0.05) in motor nerve conduction velocity of the ulnar nerve, no appreciable effect on other nerve function tests (the Achilles tendon reflex, vibratory sense, motorsensory nerve conduction velocity, etc.) was observed. The global improvement rating, which was assessed on the basis of improvement in subjective symptoms and nerve function tests, was 82.7%, or 43 out of 52 cases. Side efThets were seen in 4 patients: these included slight phlebitis, dizziness, faintness and diarrhea in one patient each. An assessment of usefulness demonstrated that Lipo-PGE1 was useful in 13 eases or 82.7%. The above results suggest that Lipo-PGE1 is a useful drug for the improvement of subjective symptoms and nerve function tests in diabetic neuropathy.
This work started in May 1982. By investigation on the clinical stages and acupuncture treatment for Diabetic cystopathy of urinary bladder in 42 cases and under the condition of basically-unchanged blood sugar control, 5 examinations of urine dynamics (measurement of residual urine, measurement of intravcsical pressure, examination of musculi detrusor urine and sphincter, measurement of urine flow rate and ice water test) were used as objective indices of the theraputic effects the results of this investigation are seen as follows: There were 32 cases in acupuncture group. Points were selected in line with the differentiation of symptoms and signs, and acupuncture treatment was given every other day, with 10 sessions being 1 course. The total effective rates 90.6% after 1-3 courses (out of 32 cases, 21 were in the intial stage with 100% effective rates obtained, 11 were in the advanced stages with 72.7% effective rates obtained). 10 cases were in the control group. No marked results have been seen for them, which shows that acupuncture treatment does obtain remarkable results for this problem, especially for the cases in the initial stage, excellent results are available. Furthermore, acupuncture treatment does not have any side-effects, but has the value to the clinical applyment. This paper has also made a preliminary exploration on the action of mechanism of acupuncture treatment for this problem.
The hypothesis that the metabolic effects of hyperglycemia on nerve function are mediated by the potential role of polyol pathway activity was assessed using an aldose reductase (AR) inhibitor in diabetic patients. We studied the effects of ONO-2235-a new AR inhibitor-on diabetic neuropathy in 21 patients (12 men and 9 women). During 12 weeks of treatment with AR inhibitor (300mg/day or 600mg/day), significant improvement in ulnar MNCV and SNCV was observed and this was in good correlation with the sorbitol content in red cells. Improvement in subjective signs such as pain and numbness was also found within 2 weeks of treatment. Either objective or subjective symptoms were improved in 76% of our cases. There was no significant difference between the two groups treated with ONO-2235. However, on discontinuation of the medication, both nerve conduction velocity and subjective signs were again impaired more significantly in the group given 300mg/day. At a dose of 600mg/day, the continuation of the effects was observed for longer period compared with the lesser dose. None of these effects of the AR inhibitor were related glycemic control. Our findings suggest that the possible role of the polyol pathway in the pathogenesis of diabetic neuropathy was clarified and that AR inhibitors may become an important tool in the treatment of diabetic neuropathy.
The effects of aldose reductase inhibitor (ARI) and prostaglandine E1 (PGE1) on diabetic neuropathy were preliminarily investigated by our clinic* in 1984. This report deals with the detailed effects both drugs on diabetic neuropathy with special reference to the function of the autonomic nervous system. 17 patiens were given ONO-2235 orally at a daily dose of 600 mg for 8 weeks. PGE1 was administered intravenousyl to 16 patients at a daily dose of 40 μg for 2 weeks. The subjective symptoms were relieved in approximately 80% of patients studied. Lowered coefficient variation of beat-to-beat interval during rest, CV, was observed in 5 out of 7 patients in ARI group and in 4 out of 9 in the PGE1 group at the start of medication, and the CV values increased by 20% in 86% of ARI-treated and in 56% of PGE1 treated subjects, respectively. Resting temperature showed no significant change. However, abnormal elongation of recovery time of skintemperature after cold water exposure noted in all 9 patients in the PGE1 group shortened in 7 patients, suggesting a functional ameriolation in autonomic nerve function. These effects paralleled improvement in subjective symptoms. Nerve conduction velocity was not significantly changed.
One of the troublesome complication in diabetic patients is peripheral neuropathy, particularly numbness and tingling. We have assessed the effects of new drugs for the treatment of peripheral neuropathy. The patients with peripheral neuropathy had subjective symptoms, such as numbness, tingling, severe pain and a sensation of tightness. Twenty-three patients with diabetic neuropathy were given trimetazidine which has vasodilator and vasomotion. An action aldose-reductase inhibitor (ONO-2235) was given to another 19 patients with neuropathy. Sixteen individuals with diabetic neuropathy were treated with prostaglandin E1 by the drip infusion method, and lipoprostaglandin E1 which is a lipid emulsion of prostaglandin E1 particles was administrated to 10 diabetic patients with neuropathy. For evaluating the clinical effects of these agents, sbjective symptoms, vibration sensation, peripheral nerve conduction velocity and R-R interval on the electrocardiogrm were observed before and after administration. For each agent there was a tendency foward improvement of was and significant improvement in vibration sensation subjective symptoms observed.
Diabetic neuropathy is a common complication of diabetes mellitus for which there is no definite treatment. To investigate their therapeutic effiect in diabetic neuropathy, we administered trimetazidine hydrochloric (VF group: VF 45 mg/day to 78 patients for over 3 months), prostaglandin E1 (PGE1 group: drip infused PGE1 60 μg/day to 10 patients for 4 weeks), and aldose reductase inhibitor (ONO 2235 group: ONO-2235 450 mg/day to 13 patients for 4 weeks). Subjective symptoms were monitored, motor and sensory nerve conduction velocities (MCV, SCV) were measured at, before and after treatment. Aldose reductase inhibitor (ONO-2235) seemed ineffective for diabetic patients with neuropathy of a long duration. We suspect that it could be a preventive agent in the treatment of diabetic neuropathy. Vasodilators VF and PGE1 were more effective in improving subjective symptoms and objective neurological findings than ONO-2235. Recently, the Schwann cell hypothesis has been supported by numerous investigators, however, we could not invalidate the vascular hypothesis.