Lack of peripheral neuropathy in Beagle dogs after 53 weeks oral administration of thalidomide capsules.

Thalidomide (Thalomid) is approved for use in the US to treat complications from leprosy. Peripheral neuropathy is a dose-limiting adverse event in humans. As part of a nonrodent regulatory toxicology study, Beagle dogs were fed orally via encapsulation for 53 weeks. A component of this study was to determine if the dogs developed peripheral neuropathy. Twenty-eight male and 28 female Beagle dogs approximately 8-10 months of age were used. They were dosed at 43, 200 or 1000 mg/kg for 53 weeks followed by a 4-week treatment-free recovery period. Nerve function was assessed by electrophysiological measurements of the tibial nerve prior to dosing and at weeks 13, 27, 38 and 51. Representative dogs from each group were sacrificed at 26, 53 and 58 weeks and histologic and ultrastructural evaluations were performed on the sural nerve. Thalidomide had no effect on sensory nerve conduction velocity, duration or amplitude of the action potential. At 27 weeks, mean sensory nerve action potential amplitude for females at 43 mg/kg was significantly greater than control but was not evident at 39 weeks. Mean duration of sensory nerve action potential seemed to increase with similar magnitude over time in all dose groups including controls. Histological and ultrastructural evaluation of sections of sural nerve did not identify treatment-induced differences between control and thalidomide-dosed animals after 26 and 53 weeks of treatment. Additionally, no differences were observed following a 5-week treatment-free period at week 58. In contrast to humans, Beagle dogs did not develop thalidomide-induced peripheral neuropathy under conditions of the study.

Effect of drug treatment on electroneurological measures of peripheral nerve function in leprosy patients.

OBJECTIVE: To investigate whether drug treatment improves the electroneurological measures of affected peripheral nerve function in leprosy patients. DESIGN: Clinical status of patients determined on the first visit by an investigator administered, pre-designed questionnaire, followed by measurement of motor conduction velocity (MCV) and distal latency (DL) of ulnar, median, common peroneal and posterior tibial nerves bilaterally in patients referred consecutively from the dermatology unit and leprosy clinic, Teaching Hospital, Galle. MCV and DL measurements were repeated after 6 to 12 months of treatment. SETTING: Department of Physiology, Faculty of Medicine, University of Ruhuna, Galle. SUBJECTS: 24 diagnosed leprosy patients; tuberculoid, lepromatous and borderline in clinical type. INTERVENTIONS: Based on clinical typing. Tuberculoid (paucibacillary) type rifampicin 600 mg monthly and dapsone 100 mg daily for six months. Lepromatous and borderline (multibacillary) type rifampicin 600 mg and clofazimine 300 mg monthly and dapsone 100 mg and clofazimine 50 mg daily for 24 months. RESULTS: DL in all 4 nerves and MCV in 3 nerves tested were significantly different (p > 0.001) to those for the normal population and remained so after 6 to 12 months of treatment. The DL in the ulnar nerve showed significant improvement (p < 0.05) after treatment. When analysed in each patient individually, before and after treatment, the MCV showed an improvement in 48 to 72% of patients and the DL in 41 to 59%, but differences were not significant. CONCLUSIONS: Electroneurological recovery (return to normal state) of the affected peripheral nerves of leprosy patients does not occur after 6 to 12 months of drug treatment. The significant (p < 0.05) improvement (becoming better) of ulnar nerve DL indicates that, if at all, electroneurologically detectable improvement of nerve function occurs in the early stages of nerve damage, and that it may take longer than one year after starting treatment.

Dapsone-induced neuropathy compounds Hansen's disease nerve damage: an electrophysiological study in tuberculoid patients.

In 17 previous cases of dermatological disorders, an axonal motor neuropathy was described as a dapsone (DDS) therapy side effect. In this study, we attempted to assess DDS-induced neuropathy in the ulnar and popliteal nerves of 39 tuberculoid Hansen's disease patients using electrophysiological recordings at the time of DDS withdrawal, owing to dermatological improvement, and 4 months after. Distal motor latencies, conduction velocities at forearm and leg and above the epicondyle and the neck of the fibula were improved at a highly significant level. Twenty-five percent of the patients presented abnormal values (outside of the 95% confidence interval) at the first recording session compared to those at the second session. By contrast, parameters exploring the degree of innervation of distal muscles showed a progressive denervation. These results lead to an impairment of Hansen's disease neuropathy during DDS therapy affecting the motor conduction velocities of one quarter of the patients, and are discussed in terms of physiopathological mechanisms.

Dapsone neuropathy--report of three cases and pathologic features of a motor nerve.

We report the clinical features, electrophysiologic findings, and dapsone and isoniazid excretion studies in three young people who ingested excessive amounts (2-4 times the prescribed dose) of dapsone for hypopigmented macules and who developed, subacutely, progressive motor neuropathy a few months later. Pathologic studies on a biopsied motor nerve confirmed the electrophysiologic conclusion of distal motor axonopathy. All made a rapid recovery in a few months after dapsone was stopped, although electrical abnormalities persisted. One patient was a rapid acetylator of isoniazid.

Electrophysiological evidence for motor unit impairment during the treatment of leprosy.

Although neuropathy is the most striking feature in leprosy, the effects of various drugs are usually assessed by dermatological and bacteriological improvement. This short term electrophysiological study shows that both antileprosy drugs, DDS and Sulforthomidine, do not affect the insidious deterioration of motor unit condition in lepromatous and borderline BT patients. Differences observed in the results of the two groups were discussed.

[Motor-conduction velocity of cubital nerves in patients with leprosy reactions. Summary of a 13-year observation series during thalidomide therapy]. / Motorische Leitungsgeschwindigkeit der Kubitalnerven bei Patienten mit Leprareaktion. Zusammenfassung einer dreizehnjährigen Beobachtungsreihe während der Thalidomidbehandlung.

The motor conduction velocity of the ulnar nerves was examined repeatedly in 34 patients with lepromatous leprosy. In patients with active lesions the reduction in velocity paralleled clinical deterioration. In "burned-out" control patients, who had never suffered from leprosy reaction, the conduction velocity remained slow and unchanged over many years. Twenty-six of 34 patients suffering from leprosy reaction received Thalidomide treatment over a period of 6-13 years in order to suppress the reaction, with good effect. In none of these 26 patients neurotoxic disturbances were found.