Early uneven ear input induces long-lasting differences in left-right motor function.

How asymmetries in motor behavior become established normally or atypically in mammals remains unclear. An established model for motor asymmetry that is conserved across mammals can be obtained by experimentally inducing asymmetric striatal dopamine activity. However, the factors that can cause motor asymmetries in the absence of experimental manipulations to the brain remain unknown. Here, we show that mice with inner ear dysfunction display a robust left or right rotational preference, and this motor preference reflects an atypical asymmetry in cortico-striatal neurotransmission. By unilaterally targeting striatal activity with an antagonist of extracellular signal-regulated kinase (ERK), a downstream integrator of striatal neurotransmitter signaling, we can reverse or exaggerate rotational preference in these mice. By surgically biasing vestibular failure to one ear, we can dictate the direction of motor preference, illustrating the influence of uneven vestibular failure in establishing the outward asymmetries in motor preference. The inner ear-induced striatal asymmetries identified here intersect with non-ear-induced asymmetries previously linked to lateralized motor behavior across species and suggest that aspects of left-right brain function in mammals can be ontogenetically influenced by inner ear input. Consistent with inner ear input contributing to motor asymmetry, we also show that, in humans with normal ear function, the motor-dominant hemisphere, measured as handedness, is ipsilateral to the ear with weaker vestibular input.

Use of Nerve Conduction Assessments to Evaluate Drug-Induced Peripheral Neuropathy in Nonclinical Species-A Brief Review.

The peripheral nervous system (PNS) is subject to a wide range of structural and functional insults including direct damage to axons, loss of myelin, and progressive deficits in saltatory conduction. Drugs that damage the PNS often result in neuropathies that impact the structure and function of targeted nerves. In most cases, both sensory and motor neurons are affected with damage initially evident in the distal extremities. Drug-induced neuropathies are potentially reversible following cessation of treatment, but early stages of neuropathy can be subclinical and asymptomatic making diagnosis difficult. Nerve biopsy is highly validated and provides definitive evidence of nerve injury and corresponding severity; however, it is limited in some respects and electrophysiological measures can complement histopathological assessments and provide a functional measure of potential toxicity. In a drug development setting, nerve conduction assessments are valuable to monitor nerve function longitudinally if nerve damage is suspected or confirmed, and importantly, can be used to monitor progression and/or recovery of a drug-induced neuropathy. This review will summarize the methodology used in nerve conduction assessments as well as discuss data interpretation and considerations for use in nonclinical species. Finally, the use of nerve conduction assessments in nonclinical drug development is discussed.

Toxicologic Pathology of the Peripheral Nervous System (PNS): Overview, Challenges, and Current Practices.

Peripheral nervous system (PNS) toxicity is a frequent adverse effect encountered in patients treated with certain therapeutics (e.g., antiretroviral drugs, cancer chemotherapeutics), in occupational workers exposed to industrial chemicals (e.g., solvents), or during accidental exposures to household chemicals and/or environmental agents (e.g., pesticides). However, the literature and expertise needed for the effective design, conduct, analysis, and reporting of safety studies to identify and define PNS toxicity are hard to find. This half-day course familiarized participants with basic PNS biology; causes and mechanisms of PNS pathology; classic methods and current best practice recommendations for PNS sampling, preparation, and evaluation; and examples of commonly observed lesions and artifacts. Three concluding case presentations synthesized information from the prior technical lectures by presenting real-world examples of lesions caused by drugs and chemicals to demonstrate how PNS toxicity may be addressed in evaluating product safety during nonclinical studies. Topics emphasized comparative and correlative data among animal species used in toxicity studies and clinical evaluation in humans in order to facilitate the translation of animal data into human risk assessment with respect to PNS toxicologic pathology.

Safety and efficacy of ranirestat in patients with mild-to-moderate diabetic sensorimotor polyneuropathy.

We examined the efficacy and safety of ranirestat in patients with diabetic sensorimotor polyneuropathy (DSPN). Patients (18-75 years) with stable type 1/2 diabetes mellitus and DSPN were eligible for this global, double-blind, phase II/III study (ClinicalTrials.gov NCT00927914). Patients (n = 800) were randomized 1 : 1 : 1 to placebo, ranirestat 40 mg/day or 80 mg/day (265 : 264 : 271). Change in peroneal motor nerve conduction velocity (PMNCV) from baseline to 24 months was the primary endpoint with a goal improvement vs. placebo ≥1.2 m/s. Other endpoints included symptoms, quality-of-life, and safety. Six hundred thirty-three patients completed the study. The PMNCV difference from placebo was significant at 6, 12, and 18 months in both ranirestat groups, but <1.2 m/s. The mean improvement from baseline at 24 months was +0.49, +0.95, and +0.90 m/s for placebo, ranirestat 40 mg and 80 mg, respectively (NS). The treatment difference vs. placebo reached significance when ranirestat groups were combined in a post hoc analysis (+0.44 m/s; p = 0.0237). There was no effect of ranirestat on safety assessments, secondary or exploratory endpoints vs. placebo. Ranirestat was well tolerated and improved PMNCV, but did not achieve any efficacy endpoints. The absence of PMNCV worsening in the placebo group underscores the challenges of DSPN studies in patients with well-controlled diabetes.

Neurotoxicity of an Hepatitis B Virus (HBV) Transcript Inhibitor in 13-Week Rat and Monkey Studies.

The nonclinical safety profile of GS-8873, a hepatitis B virus RNA transcript inhibitor was evaluated in rat and monkey 13-week toxicity studies with 8-week recovery phases. Vehicle or GS-8873 was dosed orally for 13 weeks at 2, 6, 20, and 60 mg/kg/day to Wistar Han rats and at 0.5, 1.5, 3, and 6 mg/kg/day to cynomolgus monkeys. In vitro and in vivo screening results from an analog discovered prior to GS-8873 informed the 13-week toxicology study designs. Neuroelectrophysiology and neurobehavioral evaluations were included at weeks 4 and 13 of the dosing and recovery phases for GS-8873. No adverse neurobehavioral effects were observed. Significant nerve conduction velocity (NCV) decreases and latency increases occurred at the high doses after 4 weeks of dosing. By week 13, dose-responsive NCV reductions and latency increases worsened across all dose groups compared with controls. Some reversal occurred 8 weeks after the last dose administered, but not to vehicle control levels. A minimal, axonal degeneration was observed in rat spinal and peripheral nerves across dose groups compared with controls. No monkey nervous system microscopic findings were observed. No-observed-adverse-effect-levels could not be determined for either species due to the neuroelectrophysiology findings and development was halted in the interest of safety. A retrospective risk assessment approach utilizing benchmark dose (BMD) modeling contributed 13-week NCV BMDL estimates (lower limits of the 95% confidence interval) in lieu of no-observed-adverse-effect-levels. The best-fitted models extrapolated NCV BMDLs for the rat caudal and monkey sural nerve at 0.3 and 0.1 mg/kg/day, respectively.

Drug safety is a barrier to the discovery and development of new androgen receptor antagonists.

BACKGROUND: Androgen receptor (AR) antagonists are part of the standard of care for prostate cancer. Despite the almost inevitable development of resistance in prostate tumors to AR antagonists, no new AR antagonists have been approved for over a decade. Treatment failure is due in part to mutations that increase activity of AR in response to lower ligand concentrations as well as to mutations that result in AR response to a broader range of ligands. The failure to discover new AR antagonists has occurred in the face of continued research; to enable progress, a clear understanding of the reasons for failure is required. METHODS: Non-clinical drug safety studies and safety pharmacology assays were performed on previously approved AR antagonists (bicalutamide, flutamide, nilutamide), next generation antagonists in clinical testing (MDV3100, BMS-641988), and a pre-clinical drug candidate (BMS-501949). In addition, non-clinical studies with AR mutant mice, and EEG recordings in rats were performed. Non-clinical findings are compared to disclosures of clinical trial results. RESULTS: As a drug class, AR antagonists cause seizure in animals by an off-target mechanism and are found in vitro to inhibit GABA-A currents. Clinical trials of candidate next generation AR antagonists identify seizure as a clinical safety risk. CONCLUSIONS: Non-clinical drug safety profiles of the AR antagonist drug class create a significant barrier to the identification of next generation AR antagonists. GABA-A inhibition is a common off-target activity of approved and next generation AR antagonists potentially explaining some side effects and safety hazards of this class of drugs.

Diabetic polyneuropathies: update on research definition, diagnostic criteria and estimation of severity.

Prior to a joint meeting of the Neurodiab Association and International Symposium on Diabetic Neuropathy held in Toronto, Ontario, Canada, 13-18 October 2009, Solomon Tesfaye, Sheffield, UK, convened a panel of neuromuscular experts to provide an update on polyneuropathies associated with diabetes (Toronto Consensus Panels on DPNs, 2009). Herein, we provide definitions of typical and atypical diabetic polyneuropathies (DPNs), diagnostic criteria, and approaches to diagnose sensorimotor polyneuropathy as well as to estimate severity. Diabetic sensorimotor polyneuropathy (DSPN), or typical DPN, usually develops on long-standing hyperglycaemia, consequent metabolic derangements and microvessel alterations. It is frequently associated with microvessel retinal and kidney disease-but other causes must be excluded. By contrast, atypical DPNs are intercurrent painful and autonomic small-fibre polyneuropathies. Recognizing that there is a need to detect and estimate severity of DSPN validly and reproducibly, we define subclinical DSPN using nerve conduction criteria and define possible, probable, and confirmed clinical levels of DSPN. For conduct of epidemiologic surveys and randomized controlled trials, it is necessary to pre-specify which attributes of nerve conduction are to be used, the criterion for diagnosis, reference values, correction for applicable variables, and the specific criterion for DSPN. Herein, we provide the performance characteristics of several criteria for the diagnosis of sensorimotor polyneuropathy in healthy subject- and diabetic subject cohorts. Also outlined here are staged and continuous approaches to estimate severity of DSPN.

Correlation and dissociation of electrophysiology and histopathology in the assessment of toxic neuropathy.

The evaluation of neurotoxic damage involves a unique set of challenges. Vulnerable structures, such as neocortex, hippocampus, spinal cord, and peripheral nerve are complex and sharply differentiated; deficits can result from insults to one or more element(s) in the system (e.g., myelin, axon, soma, synapse, or glia). In-life assessment of neurotoxic damage is complicated by the relative inaccessibility of structures in the brain and spinal cord, and recovery is severely limited. Histopathology and electrophysiology represent two of the most commonly used and valuable techniques in this field. This review outlines the strengths and limitations of these procedures and focuses on circumstances in which findings from these measures are dissociated. Electrophysiology is noninvasive and affords a longitudinal view of onset and progression of deficits; however, measures are generally weighted to large-diameter myelinated axons and to regions of primary sensory and motor processing. Histology is a highly validated biomarker, but it is restricted by sampling issues and is insensitive to some elements of neurotoxicity (e.g., altered channel function) associated with profound functional consequences. The central tenet of the discussion is that histology and electrophysiology offer complementary views of neurotoxic damage and, whenever possible, they should be used in concert.

The rat caudal nerves: a model for experimental neuropathies.

This study provides a detailed investigation of the anatomy of the rat caudal nerve along its entire length, as well as correlated nerve conduction measures in both large and small diameter axons. It determines that rodent caudal nerves provide a simple, sensitive experimental model for evaluation of the pathophysiology of degeneration, recovery, and prevention of length-dependent distal axonopathy. After first defining the normal anatomy and electrophysiology of the rat caudal nerves, acrylamide monomer, a reliable axonal toxin, was administered at different doses for escalating time periods. Serial electrophysiological recordings were obtained, during intoxication, from multiple sites along caudal and distal sciatic nerves. Multiple sections of the caudal and sciatic nerves were examined with light and electron microscopy. The normal distribution of conduction velocities was determined and acrylamide-induced time- and dose-related slowing of velocities at the vulnerable ultraterminal region was documented. Degenerative morphological changes in the distal regions of the caudal nerves appeared well before changes in the distal sciatic nerves. Our study has shown that (1) rat caudal nerves have a complex neural structure that varies along a distal-to-proximal gradient and (2) correlative assessment of both morphology and electrophysiology of rat caudal nerves is easily achieved and provides a highly sensitive index of the onset and progression of the length-dependent distal axonopathy.

Longitudinal studies of time-dependent changes in both bladder and erectile function after streptozotocin-induced diabetes in Fischer 344 male rats.

OBJECTIVES: To provide sensitive physiological endpoints for the onset and long-term progression of deficits induced by diabetes mellitus (DM) in bladder and erectile function in male rats, and to evaluate parallel changes in urogenital and nerve function induced by hyperglycaemia over a protracted period as a model for chronic deficits in patients with diabetes. MATERIALS AND METHODS: The study comprised in 877 male, 3-month-old, Fischer 344 rats; 666 were injected intraperitoneally with 35 mg/kg streptozotocin (STZ) and divided into insulin-treated and untreated diabetic groups. The rats were studied over 8 months and measurements made of both erectile and bladder function, as well as nerve conduction studies over the duration of the study. RESULTS: There was an early (first month) abnormality of both erectile and bladder function that persisted through the 8 months of the study. The erectile dysfunction was manifest as reduced intracavernous pressure/blood pressure ratio, and the bladder dysfunction as a persistent increase in detrusor overactivity with no detrusor decompensation. Insulin treatment prevented or modified the abnormality in each organ. Hyperglycaemia caused a progressive decrease in caudal nerve conduction velocity. The mean digital sensory and tibial motor nerve conduction velocity did not deteriorate over time. Correlation measurements of nerve and organ function were not consistent. CONCLUSIONS: The results of this extensive long-term study show early and profound effects of hyperglycaemia on the smooth muscle of the penis and bladder, that were persistent and stable in surviving rats over the 8 months. The physiological changes did not correlate well with neurological measurements of those organs. Significantly, diverse smooth-muscle cellular and subcellular events antedated the measured neurological manifestations of the hyperglycaemia by several months. Although autonomic diabetic neuropathy is a primary life-threatening complication of long-term diabetes in humans, this rat model of STZ-induced diabetes showed that the rapid onset of physiological manifestations was based on many molecular changes in the smooth muscle cells in this model of type 1 DM.

Phospholipidosis in neurons caused by posaconazole, without evidence for functional neurologic effects.

The azole antifungal drug posaconazole caused phospholipidosis in neurons of the central nervous system, dorsal root ganglia of the spinal cord, and myenteric plexus in chronic toxicity studies in dogs. The time of onset, light and electron microscopic features, neurologic and electrophysiologic effects on the central and peripheral nervous systems, and potential for regression were investigated in a series of studies with a duration of up to one year. Nuclei of the medulla oblongata were the prominently affected areas of the brain. Neurons contained cytoplasmic vacuoles with concentrically whorled plasma membrane-like material (i.e., multilamellar bodies) morphologically identical to that commonly caused in other tissues by cationic amphiphilic drugs. Some axons in the brain and spinal cord were swollen and contained granular eosinophilic, electron-dense lysosomes. There were no features suggesting degeneration or necrosis of neurons or any associated elements of nervous tissue. The earliest and most consistent onset was in neurons of dorsal root ganglia. The observed neural phospholipidosis did not result in any alteration in the amplitude or latency of the auditory, visual, or somatosensory evoked potentials. The histopathologic changes did not progress or regress within the three-month postdose period. The results indicate that phospholipidosis can be induced in central and peripheral neurons of dogs by administration of posaconazole, but this change is not associated with functional effects in the systems evaluated.

Spectrotemporal analysis of evoked and induced electroencephalographic responses in primary auditory cortex (A1) of the awake monkey.

Electroencephalography is increasingly being used to probe the functional organization of auditory cortex. Modulation of the electroencephalographic (EEG) signal by tones was examined in primary auditory cortex (A1) of awake monkeys. EEG data were measured at 4 laminar depths defined by current source density profiles evoked by best frequency (BF) tones. Midlaminar multiunit activity was used to define the tuning characteristics of A1 sites. Presentation of BF tones increased EEG power across the range of frequencies examined (4-290 Hz), with maximal effects evident within the first 100 ms after stimulus onset. The largest relative increases in EEG power generally occurred at very high gamma frequency bands (130-210 Hz). Increases in EEG power for frequencies less than 70 Hz primarily represented changes in phase-locked activity, whereas increases at higher frequencies primarily represented changes in non-phase-locked activity. Power increases in higher gamma bands were better correlated with the A1 tonotopic organization than power increases in lower frequency bands. Results were similar across the 4 laminar depths examined. These findings highlight the value of examining high-frequency EEG components in exploring the functional organization of auditory cortex and may enhance interpretation of related studies in humans.

Reprint of "EEG: Characteristics of drug-induced seizures in rats, dogs and non-human primates".

Seizures are amongst the most frequent neurological issues encountered in pre-clinical safety testing. The objective was to characterize EEG morphologies and premonitory signs in drug-induced seizures in preclinical species. A comparative (inter-species) retrospective analysis for drug-induced seizures recorded by video-telemetry was conducted in rats (n = 53), dogs (n = 195), and non-human primates (n = 234). The most frequent premonitory signs were, in rats, myoclonus (100%), tremors (93%), salivation (75%), partial ptosis (58%) and chewing/bruxism (58%); in dogs, tremors (77%), ataxia/uncoordination (60%), myoclonus (45%), salivation (43%), excessive licking (38%), high vocalization (38%) and decreased activity (34%); in non-human primates, tremors (79%), decreased activity (70%), myoclonus (57%), retching/emesis (37%), hunched posture (30%) and ataxia/uncoordination (27%). Seizure duration ranged from 3 s to 14 min with an average of 46 ±â€¯21 s, comparable across species. At seizure onset, spike frequency averaged 9.4 Hz for the three species compared to 4.3 Hz at seizure end. Peak average amplitudes were attained at mid-seizure and amplitudes at seizure end decreased from peak but remained higher than onset amplitudes. Spike duration was inversely correlated with frequency and presented a crescendo pattern. Morphological characteristics can serve to refine automated EEG analysis. From a regulatory perspective, the most common paradigm is to use the most sensitive species in seizure liability studies but translational potential and clinical relevance may be under represented in the decision making process in some cases. EEG morphologies during drug-induced seizures presented remarkable similarities between species and tremors were identified as a predominant premonitory clinical sign in all species.

EEG: Characteristics of drug-induced seizures in rats, dogs and non-human primates.

Seizures are amongst the most frequent neurological issues encountered in pre-clinical safety testing. The objective was to characterize EEG morphologies and premonitory signs in drug-induced seizures in preclinical species. A comparative (inter-species) retrospective analysis for drug-induced seizures recorded by video-telemetry was conducted in rats (n = 53), dogs (n = 195), and non-human primates (n = 234). The most frequent premonitory signs were, in rats, myoclonus (100%), tremors (93%), salivation (75%), partial ptosis (58%) and chewing/bruxism (58%); in dogs, tremors (77%), ataxia/uncoordination (60%), myoclonus (45%), salivation (43%), excessive licking (38%), high vocalization (38%) and decreased activity (34%); in non-human primates, tremors (79%), decreased activity (70%), myoclonus (57%), retching/emesis (37%), hunched posture (30%) and ataxia/uncoordination (27%). Seizure duration ranged from 3 s to 14 min with an average of 46 ±â€¯21 s, comparable across species. At seizure onset, spike frequency averaged 9.4 Hz for the three species compared to 4.3 Hz at seizure end. Peak average amplitudes were attained at mid-seizure and amplitudes at seizure end decreased from peak but remained higher than onset amplitudes. Spike duration was inversely correlated with frequency and presented a crescendo pattern. Morphological characteristics can serve to refine automated EEG analysis. From a regulatory perspective, the most common paradigm is to use the most sensitive species in seizure liability studies but translational potential and clinical relevance may be under represented in the decision making process in some cases. EEG morphologies during drug-induced seizures presented remarkable similarities between species and tremors were identified as a predominant premonitory clinical sign in all species.

Efficacy and safety of pregabalin 600 mg/d for treating painful diabetic peripheral neuropathy: a double-blind placebo-controlled trial.

BACKGROUND: Recent consensus guidelines recommend pregabalin as a first-tier treatment for painful diabetic peripheral neuropathy (DPN). We evaluated the efficacy of pregabalin 600 mg/d (300 mg dosed BID) versus placebo for relieving DPN-associated neuropathic pain, and assessed its safety using objective measures of nerve conduction (NC). METHODS: In this randomized, double-blind, placebo-controlled trial, the primary efficacy measure was endpoint mean pain score (MPS) from daily pain diaries (11-point scale). NC velocity and sensory and motor amplitudes were assessed at baseline, endpoint, and end of follow-up (2 weeks post-treatment). At each timepoint, the median-motor, median-sensory, ulnar-sensory, and peroneal-motor nerves were evaluated. Secondary efficacy measures included weekly MPS and proportion of responders (patients achieving >or=50% reduction in MPS from baseline to endpoint). After 1-weeks' dosage escalation, pregabalin-treated patients received 300 mg BID for 12 weeks. RESULTS: Eighty-two patients received pregabalin and 85 placebo. Mean durations were 10 years for diabetes and approximately 5 years for painful DPN. Pregabalin-treated patients had lower MPS than controls (mean difference, -1.28; p <.001). For all four nerves, 95% CIs for median differences in amplitude and velocity from baseline to endpoint and baseline to follow-up included 0 (ie, no significant difference vs. placebo). Significant pain improvement among pregabalin-treated patients was evident at week 1 and sustained at every weekly timepoint. More pregabalin-treated patients (49%) than controls (23%) were responders (p <.001). CONCLUSION: Pregabalin 600 mg/d (300 mg BID) effectively reduced pain, was well tolerated, and had no statistically significant or clinically meaningful effect on NC in patients with painful DPN.

Neurotoxic effects of zoniporide: a selective inhibitor of the NA+/H+ exchanger isoform 1.

Zoniporide, an inhibitor of the Na+-H+ exchanger-1, was administered by continuous intravenous infusion to rats and dogs for up to 1 month. In 1-month studies, histological and functional changes were observed in select portions of the peripheral nervous system; however, these findings were not detected in 2-week studies at similar or higher doses. In the 1-month rat study, there was dose-dependent, minimal, focal, or multifocal nerve fiber (axonal) degeneration in the spinal cord and/or sciatic nerve. In a follow-up rat study, findings included slowing of caudal nerve conduction velocity and axonal degeneration in the spinal cord (dorsal funiculus), dorsal roots, dorsal root ganglia (DRG), radial, sciatic, and tibial nerves. In the 1-month dog study, there was impairment of the patellar reflex and associated postural reaction changes, minimal to marked proximal nerve fiber degeneration in the DRG, and minimal nerve fiber degeneration in the dorsal roots and funiculi of the spinal cord. Minimal nerve fiber degeneration of equivocal significance was noted in various peripheral nerves. Taken together, these findings were consistent with a specific effect on peripheral sensory nerve fibers. These studies demonstrated that zoniporide produces clinical, electrophysiologic, and microscopic evidence of peripheral sensory axonopathy and establishes the importance of careful preclinical evaluation of neurological function.

Neuropathy associated with microtubule inhibitors: diagnosis, incidence, and management.

Microtubule inhibitor (MTI)-based chemotherapies used in the treatment of breast cancer--including vinca alkaloids, taxanes, and epothilones--are known to be associated with peripheral neuropathy. The incidence and severity of neuropathy, most frequently sensory in nature, depend on the agent used, absolute and cumulative drug dose, administration schedule, and presence of comorbidities. Although some first-generation vinca alkaloids, such as vincristine, were associated with severe mixed sensory/motor neuropathy, the deficits associated with newer agents in this class (eg, vinflunine) are generally milder and limited to distal sensory signs and symptoms. Among the taxanes, sensory neuropathy is reported more often with administration of paclitaxel and albumin-bound paclitaxel and less frequently with docetaxel. Epothilones, a new class of MTI, may be associated with grade 3/4 peripheral neuropathy; however, the neuropathy associated with ixabepilone, a novel epothilone B analog, is generally mild to moderate and reversible to baseline or grade 1 levels. The neuropathy induced by MTI therapy is best managed with dose adjustments and/or treatment delay. This article provides an overview of the incidence, characteristics, and management of MTI-associated neurotoxicities for known vinca alkaloids and taxanes, as well as newer agents, such as vinflunine and ixabepilone.

Effects of fidarestat, an aldose reductase inhibitor, on nerve conduction velocity and bladder function in streptozotocin-treated female rats.

The effects of fidarestat, an aldose reductase inhibitor (ARI), were assessed on nerve conduction velocity (NCV) in somatic nerves and on multiple measures of bladder function in rats made hyperglycemic with streptozotocin (STZ) and in age-matched controls. Nerve conduction velocity was recorded at baseline and at 10, 20, 30, and 50 days after confirmation of the STZ-induced hyperglycemia in all rats (N=47); bladder function was assessed in a representative subset of rats (N=20) at Day 50. Caudal NCV was markedly slowed by STZ, and this effect was significantly reversed by fidarestat. The initial deficit and treatment-related improvement were especially evident for responses driven by high-frequency repetitive stimulation. Of the 11 parameters of bladder activity assessed, four measures-bladder capacity, micturition volume, micturition frequency, and bladder weight-were significantly different in the control and STZ-treated groups. These deficits were not affected by fidarestat. At Day 50, the induced deficits in bladder function were highly correlated with caudal NCV (r values ranging from 0.70 to 0.96; P values ranging from .02 to <.0001). These results suggested that fidarestat improved the slowing of somatic nerve NCV in hyperglycemic rats, but it was not effective in reversing associated bladder dysfunction, in spite of the highly significant correlation between these two diabetes-induced deficits. Possible explanations for this dissociation are discussed.

A randomized, double-blinded, placebo-controlled phase II trial of recombinant human leukemia inhibitory factor (rhuLIF, emfilermin, AM424) to prevent chemotherapy-induced peripheral neuropathy.

PURPOSE: To determine whether recombinant human leukemia inhibitory factor (rhuLIF, AM424, emfilermin) can prevent or ameliorate the development of chemotherapy-induced peripheral neuropathy (CIPN) after treatment with carboplatin (AUC 6) and paclitaxel (175 mg/m(2) over 3 hours). EXPERIMENTAL DESIGN: Randomized double-blind placebo-controlled phase II clinical trial. Eligible patients had solid tumors for which treatment with carboplatin/paclitaxel was appropriate. The primary end point was a standardized composite peripheral nerve electrophysiology (CPNE) score, based on nerve velocities and amplitudes, measured at baseline and after four cycles of chemotherapy. Secondary efficacy end points included CPNE score at last cycle and at exit evaluation, vibration perception threshold, H-reflex latency, symptom scores, and quantitative assessment of neurologic signs. Study drug was given s.c. daily for 7 days starting the day before chemotherapy. Patients were randomized to receive low-dose rhuLIF (2 microg/kg), high-dose rhuLIF (4 microg/kg), or placebo. RESULTS: Patients (n = 117) were randomized across seven neurology test centers. Thirty-six patients received low dose rhuLIF (2 microg/kg), 39 received high dose rhuLIF (4 microg/kg) and 42 received placebo. rhuLIF was well tolerated with 95% compliance and no adverse effects on quality of life. No differences between groups in CPNE or any of the individual neurologic testing variables were observed between baseline and cycle 4 or by the secondary efficacy variables. CONCLUSIONS: rhuLIF is not effective in preventing CIPN caused by carboplatin and paclitaxel. CPNE is a reliable and valid tool that was sensitive to the onset and progression of CIPN.

Long-Acting C-Peptide and Neuropathy in Type 1 Diabetes: A 12-Month Clinical Trial.

OBJECTIVE: Lack of C-peptide in type 1 diabetes may be an important contributing factor in the development of microvascular complications. Replacement of native C-peptide has been shown to exert a beneficial influence on peripheral nerve function in type 1 diabetes. The aim of this study was to evaluate the efficacy and safety of a long-acting C-peptide in subjects with type 1 diabetes and mild to moderate peripheral neuropathy. RESEARCH DESIGN AND METHODS: A total of 250 patients with type 1 diabetes and peripheral neuropathy received long-acting (pegylated) C-peptide in weekly dosages of 0.8 mg (n = 71) or 2.4 mg (n = 73) or placebo (n = 106) for 52 weeks. Bilateral sural nerve conduction velocity (SNCV) and vibration perception threshold (VPT) on the great toe were measured on two occasions at baseline, at 26 weeks, and at 52 weeks. The modified Toronto Clinical Neuropathy Score (mTCNS) was used to grade the peripheral neuropathy. RESULTS: Plasma C-peptide rose during the study to 1.8-2.2 nmol/L (low dose) and to 5.6-6.8 nmol/L (high dose). After 52 weeks, SNCV had increased by 1.0 ± 0.24 m/s (P < 0.001 within group) in patients receiving C-peptide (combined groups), but the corresponding value for the placebo group was 1.2 ± 0.29 m/s. Compared with basal, VPT had improved by 25% after 52 weeks of C-peptide therapy (Δ for combined C-peptide groups: -4.5 ± 1.0 µm, placebo group: -0.1 ± 0.9 µm; P < 0.001). mTCNS was unchanged during the study. CONCLUSIONS: Once-weekly subcutaneous administration of long-acting C-peptide for 52 weeks did not improve SNCV, other electrophysiological variables, or mTCNS but resulted in marked improvement of VPT compared with placebo.