Aldose reductase inhibition by AS-3201 in sural nerve from patients with diabetic sensorimotor polyneuropathy

OBJECTIVE: The primary purpose of this investigation was to determine whether AS-3201, a new aldose reductase inhibitor, penetrates the sural nerve and inhibits sorbitol and fructose accumulation in patients with diabetic sensorimotor polyneuropathy (DSP). An additional aim was to determine whether any changes in nerve function would manifest with AS-3201 therapy. RESEARCH DESIGN AND METHODS: Patients with mild to moderate DSP based on nerve conduction studies were randomized into one of three treatment groups in a double-blind fashion: placebo or AS-3201 at 5 or 20 mg/day. After 12 weeks of administration, the sural nerve was biopsied for measurement of sorbitol, fructose, and AS-3201. RESULTS: At baseline, no important clinical, electrophysiological, or laboratory differences were found between the three groups. The nerve sorbitol concentration of 3.14 x 10(-2) nmol/mg wet nerve in patients in the placebo group was inhibited by 65 and 84% in patients on AS-3201 at 5 and 20 mg/day, respectively (P < 0.001). Fructose levels were similarly inhibited. Sensory nerve conduction velocities improved by > or = 1 m/s (P < 0.05). CONCLUSIONS: AS-3201 penetrates the sural nerve and inhibits sorbitol accumulation in patients with DSP. Additional studies are needed to confirm the electrophysiological suggestion that AS-3201 delays progression or leads to regression of DSP.     

Morphine-induced mydriasis and inhibition of pupillary light reflex and fluctuations in the cat

Morphine has species-characteristic effects on pupillary size The effects of morphine on pupillary size, fluctuations and the light reflex were tested with an infrared video pupillometer in the gallamine-paralyzed cat. Compared with saline or base-line responses, i.v. morphine (0.06-1.5 mg/kg) caused a dose-related decrease in the light reflex and fluctuations but increased pupil size. Naloxone (1-100 micrograms/kg i.v.), injected 1 h after morphine, reversed all pupillary effects. Levorphanol (0.5 mg/kg i.v.) had pupillary actions like those of morphine, but dextrophan (0.5 mg/kg i.v.) was inactive. Sympathectomy did not alter the morphine response. It was concluded that morphine disrupts parasympathetic innervation of the iris through interactions with opiate receptors, some of which are in the brain. The morphine-induced changes on the light reflex and fluctuations in the cat are opposite those reported in the rat and rabbit. These results enlarge on the familiar species-dependent effects of opiates on pupillary size.     

Aldose reductase inhibitors and diabetic complications.

Aldose reductase inhibitors impede flux of glucose through the sorbitol pathway in diabetes mellitus. They therefore reduce the accumulation of the pathway metabolites, sorbitol and fructose, reduce the impact of the flux on the cofactors used by the pathway and reduce other derived phenomena, such as osmotic stress and myo-inositol depletion. As drugs, their targets are the chronic complications of diabetes--neuropathy, retinopathy, nephropathy and vasculopathy. In experimental models there is proof of activity against biochemical, functional and structural defects in all of the involved tissues, but we await full clinical verification of this potential.     

The pupillary light reflex in borderline diabetics

Computerized IR videopupilography, using an open-loop photic stimulator, was used to compare the reflexes of borderline diabetics with overt non-insulin-dependent diabetics and with age- and sex-matched non-diabetic healthy controls. The patients were all male, aged 41-59 years. Overt non-insulin-dependent diabetics in their 40s had a smaller pupillary area and pupillary diameter prior to photic stimulus compared with borderline diabetics and healthy controls. Overt non-insulin-dependent diabetics in their 50s had a lower pupillary area and pupillary diameter prior to photic stimulus, maximum velocity and acceleration of constriction and maximum velocity of dilation than did borderline diabetics or controls. The only abnormality observed among borderline diabetics compared to controls was a smaller amplitude of constriction in response to light in patients in their 50s. Amplitude of constriction in response to light and velocity of constriction measurements of borderline diabetics, however, were considerably more frequently abnormal than were those of controls. The frequency of abnormal pupillary diameter prior to photic stimulus, maximum velocity of dilation and acceleration of constriction was higher in overt non-insulin-dependent diabetics than in borderline diabetics. The results indicate that borderline diabetics have autonomic neuropathy before the disease becomes overt. The importance of the pupillary light reflex examination is discussed.     

Reproducibility of the pupillary light reflex over short intervals in psychiatric patients and community volunteers

The pupillary light reflex (PLR) is a method for measuring dynamic responses within the autonomic nervous system, and would have potential value as a point-of-care test in a psychiatry clinic if reproducible results could be obtained in a short period of time. We collected PLR from adult community volunteers and depressed outpatients with the purpose of demonstrating (1) that valid data could be obtained >90% of the time from both the community volunteers and the patients, and (2) that reproducible results could be obtained with repeated measurement over short periods of time. Valid data were captured for 90.3% of 76 participants, allowing for two attempts of the PLR per participant. Success rates were similar for depressed patients and community volunteers. Eighteen of these 76 participants provided repeated paired measurements after 5 and 10 min of dark adaptation, producing high correlations for maximum constriction velocity (MCV) between assay 1 and 2 (Pearson's r = 0.71, p < 0.001), but there was a significant 8% increase in velocity for MCV between assay 1 and 2 (∆ = 0.34 ± 0.59 mm/s, p < 0.05). In contrast, PLR measurements were stable when tested in a separate cohort of 21 additional participants at 10 and 15 min of dark adaptation with an MCV Pearson's correlation of r = 0.84, p < 0.001, with a nonsignificant 1% difference between the two time points. These findings indicate an acceptable rate of collecting valid and reproducible PLR data when contrasting two measurements of PLR after 10 or 15 min of dark adaptation in depressed and suicidal patients.     

Cardiac abnormalities in diabetic patients with neuropathy: effects of aldose reductase inhibitor administration

OBJECTIVE: The goal of this study was to determine whether treatment with an aldose reductase inhibitor (ARI) has beneficial effects on asymptomatic cardiac abnormalities in diabetic patients with neuropathy. RESEARCH DESIGN AND METHODS: Diabetic subjects with neuropathy (n = 81) with either a low diastolic peak filling rate or impaired augmentation of left ventricular (LV) ejection fraction (LVEF) during maximal bicycle exercise were identified by gated radionuclide ventriculography. Coronary artery disease, left ventricular hypertrophy, and valvular heart disease were excluded by clinical evaluation, myocardial perfusion imaging, and echocardiography. Subjects were randomized to receive blinded treatment with either the placebo or the ARI zopolrestat 500 or 1,000 mg daily for 1 year. RESULTS: After 1 year of ARI treatment, there were increases in resting LVEF (P < 0.02), cardiac output (P < 0.03), LV stroke volume (P < 0.004), and exercise LVEF (P < 0.001). In placebo-treated subjects, there were decreases in exercise cardiac output (P < 0.03), stroke volume (P < 0.02), and end diastolic volume (P < 0.04). Exercise LVEF increased with ARI treatment independent of blood pressure, insulin use, or the presence of baseline abnormal heart rate variability. There was no change in resting diastolic filling rates in either group. CONCLUSIONS: Diabetic patients with neuropathy have LV abnormalities that can be stabilized and partially reversed by ARI treatment.     

Simultaneously measured pupillary light reflex and heart rate variability in healthy children

We investigated the potential inter-relationship between two measures of autonomic nervous system: pupillary light reflex (PLR) and heart rate variability (HRV), in healthy children of 8-16 years old. PLR was measured at both dark- and light-adapted conditions with various stimulation intensities. Simultaneously measured HRV was obtained in five different PLR testing phases: before PLR test, light-adapted PLR test, dark adaptation, dark-adapted PLR test and after PLR test. The frequency domain HRV parameters measured during the PLR test were significantly different from those measured during rest. Both the regression analysis and factor analysis indicated that PLR and HRV parameters were not correlated, which suggests that they may provide complementary assessment of different aspects of the overall autonomic nervous system.     

Ultrasound assessment of extraocular movements and pupillary light reflex in ocular trauma

We present the case of a 26-year-old man with significant periorbital trauma after blunt head trauma. Ultrasound techniques for evaluation of extraocular movements and pupillary light reflex are described as a proposed adjunct to physical examination and manual retraction of the eyelids.     

Diabetes complications and their potential prevention: Aldose reductase inhibition and other approaches

Despite recent advances both in the chemistry and molecular pharmacology of antidiabetic drugs, diabetes still remains a life-threatening disease, which tends to spread all over the world. The clinical profile of diabetic subjects is often worsened by the presence of several long-term complications, namely neuropathy, nephropathy, retinopathy, and cataract. Several attempts have been made to prevent or at least to delay them. The most relevant are reported in this review, including the development of compounds acting as aldose reductase inhibitors, anti-advanced glycation end-product drugs, free radical scavengers, vasoactive agents, essential fatty acid supplementation, and neurotropic growth factors. © 1999 John Wiley & Sons, Inc. Med Res Rev, 19, No. 1, 3–23, 1999.     

Aldose reductase gene polymorphisms and peripheral nerve function in patients with type 2 diabetes

OBJECTIVE: We screened the human aldose reductase (ALR) gene for DNA sequence variants in type 2 diabetic and nondiabetic subjects and investigated whether the previously reported and novel polymorphisms were associated with neurophysiologic deterioration and clinical peripheral neuropathy. RESEARCH DESIGN AND METHODS: The study population included 85 Finnish type 2 diabetic and 126 nondiabetic subjects. The genetic analyses were performed using the PCR, single-strand conformation polymorphism, restriction fragment-length polymorphism, and automated laser fluorescence scanning analyses. A detailed neurologic examination and neurophysiologic analyses were performed at the time of diagnosis and at the 10-year examination. RESULTS: The genetic screening identified four polymorphisms: C-106T, C-11G, A11370G, and C19739A. The C and Z-2 alleles of the C-106T polymorphism and the previously reported (CA)(n) repeat marker were more frequent in type 2 diabetic subjects than in nondiabetic subjects. At baseline, the diabetic subjects with the T allele of the C-106T polymorphism had lower sensory response amplitude values in the peroneal (P = 0.025), sural (P = 0.007), and radial (P = 0.057) nerves and, during follow-up, a greater decrease in the conduction velocity of the motor peroneal nerve than those with the C-106C genotype. No associations were found between the polymorphisms examined and clinical polyneuropathy. CONCLUSIONS: The C-106T polymorphism of the ALR gene may contribute to an early development of neurophysiologic deterioration in type 2 diabetic patients.     

Aldose reductase genotypes and cardiorenal complications: an 8-year prospective analysis of 1,074 type 2 diabetic patients

OBJECTIVE—We report the independent risk association of type 2 diabetic nephropathy with the z−2 allele of the 5′-(CA)_n microsatellite and C-106T promoter polymorphisms of the aldose reductase gene (ALR2) using a case-control design. In this expanded cohort, we examined their predictive roles on new onset of cardiorenal complications using a prospective design.RESEARCH DESIGN AND METHODS—In this 8-year prospective cohort of 1,074 type 2 diabetic patients (59% male, median age 61 years; disease duration 7 years) with an observation period of 8,592 person-years, none had clinical evidence of coronary heart disease (CHD) or chronic kidney disease at recruitment. The renal end point was defined as new onset of estimated glomerular filtration rate <60 ml/min per 1.72 m² or hospitalizations with dialysis or death due to renal disease, and CHD was defined as hospitalizations with myocardial infarction, ischemic heart disease, or related deaths.RESULTS—After controlling for baseline risk factors and use of medications, we found that the ALR2 z−2 allele of (CA)_n microsatellite carriers had increased risk of renal (hazard ratio 1.53 [95% CI 1.14–2.05], P = 0.005) or combined cardiorenal (1.31 [1.01–1.72], P = 0.047) end points. Carriers of the ALR2 C-106T polymorphism also had increased risk of renal (1.54 [1.15–2.07], P = 0.004) and cardiorenal (1.49 [1.14–1.95], P = 0.004) end points. Compared with noncarriers, patients with two risk-conferring genotypes had a twofold increased risk of renal (2.41 [1.57–3.70], P < 0.001) and cardiorenal (1.94 [1.29–2.91], P = 0.002) end points.CONCLUSIONS—In Chinese type 2 diabetic patients, genetic polymorphisms of ALR2 independently predicted new onset of renal and cardiorenal end points, with the latter being largely mediated through renal disease.Cardiovascular diseases and end-stage renal disease (ESRD) are the main causes of mortality and morbidity in diabetic patients. The onset of chronic kidney disease (CKD) markedly increases the risk of cardiovascular disease as a result of further perturbation in the metabolic milieu and vascular homeostasis (1). In type 2 diabetes, control of hyperglycemia reduces proteinuria and the rate of decline in renal function (2). In type 1 diabetes, established renal lesions were reversed with restoration of normoglycemia after pancreatic transplantation (3). Aldose reductase (ALR2) converts glucose to sorbitol, especially under hyperglycemic condition. Accumulation of sorbitol can lead to increased oxidative and osmotic stresses, causing cataract, microvascular complications, and myocardial ischemic injury (4).In a case-control cohort consisting of 92 Chinese type 2 diabetic patients without nephropathy despite long disease duration and 121 patients with both retinopathy and nephropathy, the z−2 allele of 5′-(CA)_n microsatellite and promoter C-106T polymorphisms of the ALR2 gene independently conferred a risk of diabetic nephropathy (5). In this expanded consecutive cohort of 1,074 type 2 diabetic patients with documentation of risk factors, complications, and clinical outcomes, we examined the independent and additive effects of these two polymorphisms of the ALR2 gene on cardiorenal end points after an 8-year observational period.     

Walking strategy in diabetic patients with peripheral neuropathy

OBJECTIVE: Diabetic neuropathic patients show a peculiar loading pattern of the foot, which led us to hypothesize that a substantial modification exists in their deambulatory strategy. The aim of the present study was to support this hypothesis by quantifying the changes of the loading patterns and by monitoring the excursion of center of pressure (COP) during gait. RESEARCH DESIGN AND METHODS: -A total of 21 healthy volunteers (C) and 61 diabetic patients were evaluated: 27 diabetic subjects without neuropathy (D), 19 with neuropathy (DN), and 15 with previous neuropathic ulcer (DPU). A piezo-dynamometric platform was used to record the foot-to-floor interaction by measuring loading time and the instantaneous COP position during the stance phase of gait. RESULTS: Loading time was significantly longer in neuropathic patients than in control subjects (DPU: 816.8 +/- 150 ms; DN: 828.6 +/- 152 ms; D: 766.5 +/- 89.9 ms; C: 723.7 +/- 65.7 ms; P < 0.05). COP excursion along the medio-lateral axis of the foot clearly decreased from C to DPU groups (C: 6.41 +/- 0.1 cm; D: 4.88 +/- 0.2 cm; DN: 4.57 +/- 0.1 cm; DPU: 3.36 +/- 0.1 cm; P < 0.05) as well as COP excursion along the longitudinal axis for the DPU group only (C: 26.6 +/- 1 cm; D: 26.9 +/- 1 cm; DN: 27.2 +/- 1 cm; DPU: 24.2 +/- 1 cm; P < 0.05). COP integrals were significantly reduced for all pathological classes (DPU: 14.2 +/- 8 cm(2); DN: 25.8 +/- 6 cm(2); D: 27.7 +/- 3 cm(2); C: 38.6 +/- 6 cm(2); P < 0.05). CONCLUSIONS: The accurate quantification of loading patterns and of COP excursions and integrals highlights changes of foot-to-floor interaction in diabetic neuropathic patients. The decreased medio-lateral and longitudinal COP excursions and corresponding changes of loading times and patterns support our hypothesis that a change in the walking strategy of diabetic patients with peripheral neuropathy does occur.     

中潜伏期听觉电反应对糖尿病大鼠中枢神经病变的评估作用

背景糖尿病能引起中枢神经病变,中潜伏期听觉电反应(auditory middle latency response,MLR)在糖尿病时的动态变化研究至今尚不十分清楚.目的研究MLR在糖尿病中的变化,探讨MLR在早期诊断糖尿病中枢神经病变中的作用.设计用完全随机法,采用实验对照方式,进行纵向观察研究.地点和材料在暨南大学医学院生理研究室进行实验.用24只实验性糖尿病大鼠进行研究.方法应用链脲佐菌素腹腔注射法,建立实验性糖尿病动物模型.在成模前后按时间顺序动态观测血糖、MI R的变化.主要观察指标MLR的波峰潜伏期(peaklatency,PL)、波峰间潜伏期(interpeaklatency,IPL).结果建模后4周实验性糖尿病组MLR的PL(ms)各波延长[P0(7.19±0.97)、Na(11.90±1.53)、Pa(18.77±1.45)、Nb(32.86±3.12)、Pb(50.32±1.68)](P＜0.05).6周后出现MLR各波PL、Pa-Pb的IPL[(31.10±1.59)ms]延长(P＜0.01).8周后MLR各波PL、P0-Pn[(13.57±1.71)ms],Pa-Pb[(35.17±2.81)ms]IPL均延长(P＜0.05或P＜0.01).糖尿病组血糖与MLR的PL,IPL各波变化之间无相关,糖尿病组病程与MLR Na,Nb,Pb波PL变化呈正相关. 结论糖尿病早期MLR出现PL和IPL延长,该变化与病程进展有相关关系,MLR是早期诊断糖尿病中枢神经病变的客观灵敏指标.     

糖尿病性视神经病视觉诱发电位的实验研究

目的:动态观察糖尿病大鼠的视觉诱发电位(visualevokedpotential,VEP)变化,了解糖尿病与视神经病变的相关性。方法:制备糖尿病大鼠动物模型,将24只将造模成功大鼠按血糖值的高低,分为低血糖组和高血糖组,分别在第14,21,28天采用棋盘格模式翻转(patternreversal,PR)刺激,记录大鼠全野PRVEP。结果:大鼠正常PRVEP,其P波的潜伏期、幅值分别为(107.130±9.22)ms,(7.44±2.09)μV。糖尿病组大鼠,P波潜伏时随血糖的升高逐渐延长,幅值随血糖的升高逐渐降低,且随血糖值的升高、病程天数的增加差异逐渐增大(P<0.01)。低血糖组与高血糖组潜伏期、幅值比较亦差异具有显著性意义(P<0.01)。结论:PRVEP可检测糖尿病大鼠视觉传导路的异常,为临床糖尿病性神经病诊断及预后提供可靠的电生理指标。     

H反射在腰腿痛患者中的应用

目的：探讨H反射在腰腿痛患者中的应用价值。方法：对象为腰腿痛患者113例,女性38例,男性75例;年龄18－62岁;病程2周－20年。嘱患者安静放松。室温26－28℃。针电极记录。记录电极插入腓肠肌内侧头或外侧头肌腹,表面电极刺激Guo部胫神经,逐渐增加电流刺激强度,直至引出最大波幅H波至M波开始出现为止,并且进行双下肢自身对照。结果：健侧／患侧H反射潜伏期平均值分别为：腓肠肌内侧头28.75ms/30.41ms;外侧头28.65ms/30.09ms。两侧之间的差异有显著性,同侧之间均无差异。健肢H反射与年龄、身高、性别均呈正相关,同侧H反射潜伏期之间高度相关。回归方程分别为：H反射（内侧头）＝4.98 0.04年龄（岁） 0.13身高（cm);H反射（外侧头）=6.78 0.06年龄 0.11身高（cm)。H反射潜伏期的异常与下肢痛、直腿抬高、跟腱反射相关,与腰痛、椎旁压痛关系不大。结论：H反射潜伏期与年龄、身高和性别相关。运用所得方程,临床医生可通过患者的年龄和所测身高来预测H反射潜伏期正常值。H反射潜伏期可用于判断腰腿痛患者腰骶神经损害的部位及程度。     

1例糖尿病性颅神经病变患者的护理

糖尿病周围神经病变是糖尿病最常见的并发症之一,其中以远端对称性多发性神经病变最多,而颅神经病变最少。据报道,糖尿病患者中糖尿病性周围神经病变的发病率为21．8％～85％,其中糖尿病性颅神经病变占0．7％。1．0％。糖尿病性颅神经病变临床表现为复视、眼外肌麻痹,可伴有头痛、眼部胀痛。颅神经中以动眼神经、外展神经及面神经最易受累,单侧最常见,双侧少见。     

Evaluation and management of peripheral neuropathy in diabetic patients with cancer

Recently, chemotherapy-induced peripheral neuropathy has received a great deal of attention. However, the interaction of diabetic neuropathy with potentially neurotoxic chemotherapy is far less understood. The incidence of type II diabetes has risen exponentially in the past two decades. In concert with the rise in type II diabetes, the number of individuals with diabetes who need chemotherapy for cancer also is expected to increase. Diabetic neuropathy and the neurotoxic effects of chemotherapy have a significant potential to cause functional disability. Diabetics may be most at risk for the effects of neurotoxic agents on peripheral nerve functioning, in addition to the other effects induced by chemotherapeutic agents. The purpose of this article is to review the evaluation, management, and clinical implications of peripheral neuropathy in patients with cancer and diabetes.     

Duloxetine vs. placebo in patients with painful diabetic neuropathy

The aim of this study was to examine the efficacy and safety of duloxetine, a balanced and potent dual reuptake inhibitor of serotonin and norepinephrine, in the management of diabetic peripheral neuropathic pain. Serotonin and norepinephrine are thought to inhibit pain via descending pain pathways. In a 12-week, multicenter, double-blind study, 457 patients experiencing pain due to polyneuropathy caused by Type 1 or Type 2 diabetes mellitus were randomly assigned to treatment with duloxetine 20 mg/d (20 mg QD), 60 mg/d (60 mg QD), 120 mg/d (60 mg BID), or placebo. The diagnosis was confirmed by a score of at least 3 on the Michigan Neuropathy Screening Instrument. The primary efficacy measure was the weekly mean score of the 24-h Average Pain Score, which was rated on an 11-point (0-10) Likert scale (no pain to worst possible pain) and computed from diary scores between two site visits. Duloxetine 60 and 120 mg/d demonstrated statistically significant greater improvement compared with placebo on the 24-h Average Pain Score, beginning 1 week after randomization and continuing through the 12-week trial. Duloxetine also separated from placebo on nearly all the secondary measures including health-related outcome measures. Significantly more patients in all three active-treatment groups achieved a 50% reduction in the 24-h Average Pain Score compared with placebo. Duloxetine treatment was considered to be safe and well tolerated with less than 20 percent discontinuation due to adverse events. Duloxetine at 60 and 120 mg/d was safe and effective in the management of diabetic peripheral neuropathic pain.