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.

The synthetic diazonamide DZ-2384 has distinct effects on microtubule curvature and dynamics without neurotoxicity.

Microtubule-targeting agents (MTAs) are widely used anticancer agents, but toxicities such as neuropathy limit their clinical use. MTAs bind to and alter the stability of microtubules, causing cell death in mitosis. We describe DZ-2384, a preclinical compound that exhibits potent antitumor activity in models of multiple cancer types. It has an unusually high safety margin and lacks neurotoxicity in rats at effective plasma concentrations. DZ-2384 binds the vinca domain of tubulin in a distinct way, imparting structurally and functionally different effects on microtubule dynamics compared to other vinca-binding compounds. X-ray crystallography and electron microscopy studies demonstrate that DZ-2384 causes straightening of curved protofilaments, an effect proposed to favor polymerization of tubulin. Both DZ-2384 and the vinca alkaloid vinorelbine inhibit microtubule growth rate; however, DZ-2384 increases the rescue frequency and preserves the microtubule network in nonmitotic cells and in primary neurons. This differential modulation of tubulin results in a potent MTA therapeutic with enhanced safety.

A causative link between inner ear defects and long-term striatal dysfunction.

There is a high prevalence of behavioral disorders that feature hyperactivity in individuals with severe inner ear dysfunction. What remains unknown is whether inner ear dysfunction can alter the brain to promote pathological behavior. Using molecular and behavioral assessments of mice that carry null or tissue-specific mutations of Slc12a2, we found that inner ear dysfunction causes motor hyperactivity by increasing in the nucleus accumbens the levels of phosphorylated adenosine 3',5'-monophosphate response element-binding protein (pCREB) and phosphorylated extracellular signal-regulated kinase (pERK), key mediators of neurotransmitter signaling and plasticity. Hyperactivity was remedied by local administration of the pERK inhibitor SL327. These findings reveal that a sensory impairment, such as inner ear dysfunction, can induce specific molecular changes in the brain that cause maladaptive behaviors, such as hyperactivity, that have been traditionally considered exclusively of cerebral origin.

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.

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.

SCH 412499: biodistribution and safety of an adenovirus containing P21(WAF-1/CIP-1) following subconjunctival injection in Cynomolgus monkeys.

Monkey studies were conducted for the preclinical safety assessment of SCH 412499, an adenovirus encoding p21, administered by subconjunctival injection prior to trabeculectomy for postoperative maintenance of the surgical opening. Biodistribution of SCH 412499 was minimal and there was no systemic toxicity. Findings included swollen, partially closed or shut eye(s) and transient congestion in the conjunctiva. A mononuclear cell infiltrate was present in the conjunctiva, choroid and other ocular tissues, but completely or partially resolved over time. Electroretinograms and visual evoked potentials revealed no adverse findings. Thus, the findings are not expected to preclude the clinical investigation of SCH 412499.

Intracortical responses in human and monkey primary auditory cortex support a temporal processing mechanism for encoding of the voice onset time phonetic parameter.

This study tests the hypothesis that temporal response patterns in primary auditory cortex are potentially relevant for voice onset time (VOT) encoding in two related experiments. The first experiment investigates whether temporal responses reflecting VOT are modulated in a way that can account for boundary shifts that occur with changes in first formant (F1) frequency, and by extension, consonant place of articulation. Evoked potentials recorded from Heschl's gyrus in a patient undergoing epilepsy surgery evaluation are examined. Representation of VOT varies in a manner that reflects the spectral composition of the syllables and the underlying tonotopic organization. Activity patterns averaged across extended regions of Heschl's gyrus parallel changes in the subject's perceptual boundaries. The second experiment investigates whether the physiological boundary for detecting the sequence of two acoustic elements parallels the psychoacoustic result of approximately 20 ms. Population responses evoked by two-tone complexes with variable tone onset times (TOTs) in primary auditory cortex of the monkey are examined. Onset responses evoked by both the first and second tones are detected at a TOT separation as short as 20 ms. Overall, parallels between perceptual and physiological results support the relevance of a population-based temporal processing mechanism for VOT encoding.

Lack of neurotoxicity of the vascular targeting agent ZD6126 following repeated i.v. dosing in the rat.

The vascular targeting agent ZD6126 is a water-soluble prodrug of N-acetylcolchinol that acts by disrupting the cytoskeleton of tumor endothelial cells. It is currently undergoing clinical evaluation in man. As peripheral neuropathy is a major dose-limiting toxicity associated with tubulin binding agents, the neurotoxic potential of ZD6126 was investigated in male and female Wistar rats. ZD6126 was administered i.v. at up to maximum tolerated doses using subacute (0 to 20 mg/kg/d for 5 days) and chronic (0 to 10 mg/kg/d for 5 days, repeated monthly for 6 months) dosing regimens. A separate study examined a combination of ZD6126 (three cycles of ZD6126 given as in the chronic dosing regimen) and paclitaxel (12 mg/kg/wk for 9 weeks) to assess whether coadministration of ZD6126 altered the time course or magnitude of a paclitaxel-induced neuropathy. Neurotoxic potential was examined using a comprehensive series of tests including a functional observation battery, measurements of muscle strength (forelimb and hind limb grip strength), nociception (tail flick test), locomotor activity, neuropathology, and whole nerve electrophysiology. There was no evidence that ZD6126 induced neurotoxicity in the rat following either subacute or chronic i.v. dosing. In a chronic electrophysiology study, ZD6126 produced a slight slowing of the maturational increase of caudal nerve amplitude, with some evidence of reversibility. However, this was not associated with any changes in caudal nerve conduction velocity, motor nerve conduction velocity or amplitude, functional observation battery behavioral and function parameters (including no effects on tail flick latency), and neuropathology. As expected, paclitaxel administration was associated with a significant decrease in caudal nerve conduction velocity (P = 0.0001). Coadministration of ZD6126 did not increase the neurotoxicity of paclitaxel. These studies suggest that ZD6126 should not induce the peripheral neuropathy associated with other antitubulin chemotherapeutic agents and that ZD6126 may not exacerbate the neurotoxicity of other agents with dose-limiting neuropathies.