The neurotoxicity of radiosensitizing drugs: a biochemical assessment of desmethylmisonidazole (DMM) in the rat.

This study evaluates a major metabolite of misonidazole, desmethylmisonidazole, for its potential to induce peripheral nerve damage using the lysosomal enzyme correlates of neuropathological change, namely beta-glucuronidase and beta-galactosidase. The results showed that desmethylmisonidazole like misonidazole had a similar potential for inducing peripheral nerve damage as measured biochemically, but the dosing regimen had to be maintained for 10 consecutive days as opposed to the 7 days required for misonidazole.

The use of the trimethyltin model of CNS neurotoxicity to study biochemical indices of neuropathological change in the rat.

Trimethyltin (TMT)-induced CNS neurotoxicity in the rat was used to study biochemical indices of neuropathological change. The parameters measured were DNA and the lysosomal enzymes beta-glucuronidase and beta-galactosidase. Three brain regions were investigated, hippocampus, medulla and cerebellum. Rats received 4 mg/kg TMT weekly for a maximum of 5 weeks. The largest changes were found in the hippocampus, with smaller changes in medulla and no changes in the cerebellum. In the hippocampus the beta-glucuronidase activity was increased after three weeks to a maximum of 264% of the mean control value, while the beta-galactosidase activity was reduced to 87% of the control value. The lysosomal enzyme changes were attributed to processes of astrocytic and microglial hypertrophy and neuronal cell loss. The neuronal cell loss was further substantiated by the gradual reduction in the level of DNA in the hippocampus. It was concluded that the TMT model of CNS neurotoxicity in the rat hippocampus was a useful tool for studying biochemical indices of neuropathological change.

Protection against misonidazole-induced neuropathy in rats: a biochemical assessment.

A biochemical method for assessing the chemically induced neurotoxicity of misonidazole (MISO) in the rat has been used to assess whether the concurrent administration of thiamine, thiamine pyrophosphate (TPP) or vitamin E (Vit.E) could afford protection against the neurotoxic side effects of the drug. The tissues analysed were distal sections of the sciatic/posterior tibial nerve (SPTN), trigeminal ganglia and cerebellum. MISO was administered i.p. to Wistar rats at a dose of 400 mg/kg per day for 7 consecutive days to produce the maximal measurable enzyme changes after 4 weeks. The concurrent i.p. and i.m. dosing of thiamine (0.1-100 mg/kg) for 15 consecutive days did not abate the subsequent PNS and CNS enzyme changes. However, with concurrent i.m. dosing of 1.0 mg/kg TPP or p.o. dosing of vitamin E (30 mg/kg) afforded some protection against both the PNS and CNS MISO-induced neurotoxic side effects as measured biochemically.

Lack of behavioural teratogenic effect of phenytoin in rats.

A small battery of tests (static and air-righting reflexes, eye opening and a narrowing bridge test) was used to investigate the behavioural teratogenic potential of prenatal oral exposure (day 7-19 of gestation) of up to 100 mg phenytoin/kg/day to female rats. No treatment-related effects upon mother or offspring were detected. In order to validate our narrowing bridge test, neonatal old rats were tested over 4 weeks following early postnatal exposure to acrylamide (5 X 50 mg/kg/day i.p.). These animals showed a severe transient deficit compared with saline-treated controls. Despite the absence of an effect using phenytoin, the narrowing bridge test is considered worthy of further validation.

Effect of vitamin E and other amelioratory agents on the fenvalerate-mediated skin sensation.

Previous investigations have demonstrated that dermal exposure to fenvalerate or other synthetic pyrethroid insecticides can produce a skin sensory response characterized by an itching/tingling sensation in humans and animals. The objective of this investigation performed in guinea pigs was to establish treatments which would be effective against pyrethroid-mediated skin sensation. Two classes of agents were tested. Barrier agents, which block penetration of substances through the skin, did not significantly reduce the fenvalerate-mediated skin sensations. Post-treatments with steroidal Dermolate, antihistamine Delamine or anti-inflammatory aspirin did not significantly reduce the pyrethroid-mediated skin sensation. However, Bicozene (a local anesthetic cream) and Tashan (a vitamin A, D, and E-containing cream) were effective in reducing the pyrethroid-mediated skin sensations. Prior (30 min and 5h) dermal application of vitamin E was found to be effective in significantly reducing the fenvalerate-mediated skin sensation; even when applied 29 h prior to fenvalerate exposure, there appeared to be a reduced skin response. Piperonyl butoxide (PBO), a pesticide synergist, reduced the fenvalerate skin sensations when applied either directly to the skin or in conjunction with the pyrethroid.

Intoxication with four synthetic pyrethroids fails to show any correlation between neuromuscular dysfunction and neurobiochemical abnormalities in rats.

The neurological effects of four synthetic pyrethroids resmethrin, permethrin, cypermethrin, and deltamethrin have been investigated in the rat to establish whether there is a correlation between the clinical-functional status of the animal and peripheral nerve damage as measured biochemically. Neuromuscular dysfunction was assessed by means of the inclined plane test and peripheral nerve damage by reference to beta-glucuronidase and beta-galactosidase activity increases in nerve tissue homogenates from treated and control animals. A transient functional impairment was found in animals treated with any one of the four pyrethroids tested and in all cases this was maximal at the end of the 7 day subacute dosing regimen. Significant increases in beta-glucuronidase and beta-galactosidase were found 3-4 weeks after the start of dosing in the distal portion of the sciatic/posterior tibial nerves from permethrin, cypermethrin, and deltamethrin treated animal; but no changes were found in remesthrin-dosed animals. It is concluded therefore, that there is no direct correlation between the time-course of the neuromuscular dysfunction and the neurobiochemical changes. This suggests that these pyrethroids have at least two distinct actions--a short-term pharmacological effect and at near-lethal dose levels a more chronic neurotoxic effect that results in sparse axonal nerve damage.

A biochemical method for assessing the neurotoxic effects of misonidazole in the rat.

A proven biochemical method for assessing chemically induced neurotoxicity has been applied to the study of the toxic effects of misonidazole (MISO) in the rat. This involves the fluorimetric measurement of beta-glucuronidase and beta-galactosidase activities in homogenates of rat nervous tissue. The tissues analysed were sciatic/posterior tibial nerve (SPTN) cut into 4 sections, trigeminal ganglia and cerebellum. MISO administered i.p. to Wistar rats in doses greater than 300 mg/kg/day for 7 consecutive days produced maximal increases in both beta-glucuronidase and beta-galactosidase activities in th SPTN at 4 weeks (140-180% of control values). The highest increases were associated with the most distal secretion of the nerve. Significant enzyme-activity changes were also found in the trigeminal ganglia and cerebellum of MISO-dosed rats. The greatest activity occurred 4-5 weeks after dosing, and was dose-related. It is concluded that, in the rat, MISO can produce biochemical changes consistent with a dying-back peripheral neuropathy, and biochemical changes suggestive of cerebellar damage. This biochemical approach would appear to offer a convenient quantitative method for the detection of neurotoxic effects of other potential radio-sensitizing drugs.

A biochemical assessment of the neurotoxicity of the radiosensitizing drug misonidazole in the rat.

We have obtained biochemical evidence that misonidazole when administered in large doses to rats produces a sparse dying-back peripheral neuropathy and degenerative changes in the trigeminal ganglia and cerebellum. In our experience these neurotoxic effects of misonidazole cannot be detected reliably by the use of simple behavioural and functional tests, e.g., inclined plane and narrowing bridge tests (Rose and Dewar, unpublished results). Therefore, these methods would be of limited use in the neurotoxicity screening of misonidazole analogues. On the other hand, the biochemical approach provides a convenient quantitative method which could be used as the basis for comparing the neurotoxicity of other candidate radiosensitizing drugs.