Effect on the peripheral nervous system of the short-term intravenous administration of paclitaxel in the rat.

The effectiveness of paclitaxel (Taxol) in the treatment of different tumors is well-known but, on the other hand, there is little information regarding its neurotoxicity and the mechanism(s) underlying this potentially severe side effect. In this study, using behavioral, neurophysiological, morphological and morphometric methods, we evaluated the effect of intravenous administration of paclitaxel on the rat nervous system. After 2 pilot studies, 40 female Wistar rats were treated with intravenous paclitaxel via a catheter placed in the jugular vein, while 20 animals were used as controls. Paclitaxel dissolved in ethanol/Tween 80/saline (5/5/90%) was administered 5 times over a period of 10 days. At the end of the experiment half the surviving animals in each group were evaluated and sacrificed (day 11), while the rest of the rats were evaluated and sacrificed on day 25. On day 11 the treated animals had significant impairment in pain perception (tail-flick test), coordination (rota-rod test) and nerve conduction velocity in the tail nerve. At the light microscope minimal axonal damage and Schwann cell activation were observed in the sciatic nerve. At the electron microscope microtubular accumulation was present within the axon in dorsal and ventral spinal roots and in the sciatic nerve. On day 25 the behavioral tests were normal in treated rats, while the nerve conduction velocity was still moderately reduced in comparison with the controls. At the electron microscope a morphological examination evidenced that microtubular accumulation was less severe, but still evident, especially in the sciatic nerve. Morphometric determinations performed on days 11 and 25 did not evidence differences between paclitaxel-treated rats and controls. The results of this study, the first in which an extended examination of the nervous system of animals treated intravenously with paclitaxel has been carried out, suggest that short-term administration of the drug induces mainly reversible changes in the peripheral nerves and spinal roots. Microtubules seem to be the main target of paclitaxel neurotoxicity, in much the same way as has been described for its antineoplastic activity. Finally, no pathological changes were seen in the neuronal bodies of the spinal cord and dorsal root ganglia. This model may be used for further studies with combination treatments with other antineoplastic or neuroprotective agents.

Comparative toxicology of two enantiomers of the peripherally acting non-narcotic antitussive drug moguisteine.

Moguisteine (R,S(+/-)-2-(2-methoxyphenoxy)-methyl-3-ethoxycarbonylacetyl-1,3-t hiazolidine, CAS 119637-67-1), a new peripheral non-narcotic antitussive drug, is a racemate composed of an equimolar mixture of R(+) and S(-) enantiomers (BBR 2221 and BBR 2222, respectively). Since in some cases the use of only one enantiomer instead of a racemate may increase the efficacy and/or the tolerability of a compound, moguisteine enantiomers were submitted to toxicological evaluation. Given in a single oral (gavage) or intraperitoneal administration to mice and rats, both moguisteine enantiomers show very low general toxicity. Administered by gavage to rats and dogs for four consecutive weeks, BBR 221 and BBR 2222 are tolerated at up to the dose of 240 mg/kg/day in both sexes with no appreciable toxic changes. Finally, the mutagenicity tests show that both enantiomers are devoid of any mutagenic potential both in vitro and in vivo. Considering the overall results of the toxicological studies and comparing them with the data obtained from the previously performed studies with the racemate moguisteine, it can be affirmed that no differences can be identified between the two enantiomers and the racemate moguisteine. These findings justify the development of moguisteine as a racemate since neither enantiomer should offer any advantage over the racemate.

Reproductive toxicology of the new antitussive moguisteine.

Moguisteine (R,S(+/-)-2-(2-methoxyphenoxy)-methyl-3-ethoxycarbonylacetyl- 1,3-thiazolidine, CAS 119637-67-1), a new oral non narcotic peripherally acting antitussive drug, was examined for effects in the rat on general reproductive performance (at 0, 50, 212, 900 mg/kg/d,) for embryotoxicity (at 0, 25, 75, 225, 900 mg/kg/d) and for peri-postnatal toxicity (at 0, 62.5, 250, 1000 mg/kg/d). Embryotoxicity (at 0, 75, 225, 900 mg/kg/d) was also examined in the New Zealand White rabbit. In all the studies, moguisteine was administered orally as a suspension by gavage. At the tested doses, moguisteine did not interfere with general reproductive performance, either in the F0 or in the F1 generation. The drug did not show any toxic effect on the dams and their fetuses, nor did it have any teratogenic effect in either of the tested species. Finally, moguisteine had no adverse effects, either on parturition or on peri-and postnatal survival and/or development of the offspring.

General toxicology of the new antitussive moguisteine.

Moguisteine (R,S(+/-)-2-(2-methoxyphenoxy)-methyl-3-ethoxycarbonylacetyl- 1,3-thiazolidine, CAS 119637-67-1), a new oral non-narcotic peripherally acting antitussive drug, was submitted to toxicological evaluation. The oral (gavage) and intraperitoneal routes in mice and rats and the oral route in rabbits produce very low acute toxicity. Administered by oral route, moguisteine proved to be well tolerated for 26 consecutive weeks and did not induce any general or local effect at up to the respective doses of 240 and 60 mg/kg/day for rats and dogs. In oral (dietary) carcinogenicity studies, moguisteine did not exhibit any carcinogenic effect in mice and rats treated for 87 and 104 weeks, respectively, at up to the dose of 600 mg/kg/day. These results are supported by the absence, both in vitro and in vivo, of mutagenic potential. Considering the overall results of the toxicological studies, it can be affirmed that moguisteine enjoys reliable tolerability, as also shown by a wide safety margin calculated on the basis of the animal and human exposures.

Acute intravenous toxicity of dimethyl sulfoxide, polyethylene glycol 400, dimethylformamide, absolute ethanol, and benzyl alcohol in inbred mouse strains.

Acute intravenous toxicity of some solvents, i.e. dimethyl sulfoxide (DMSO), polyethylene glycol 400 (PEG 400), dimethylformamide (DMF), absolute ethanol (EtOH) and benzyl alcohol (BeOH), was determined in three inbred (CD2F1, B6D2F1 and C57BL/6N) mouse strains used in many preclinical tests, mainly in oncology and toxicology. Haemolytic and precipitation potential tests in vitro were performed to assess the blood compatibility of the investigated solvents and its relationship with the observed symptoms. The single tested solvents did not show any major differences in acute toxicity in the three tested strains with the exclusion of DMSO (less toxic in CD2F1) and BeOH and EtOH (less toxic in B6D2F1). The tested dose ranges in the three strains (in ml/kg) were 1.0-5.66 for DMSO, 2.0-8.0 for PEG 400, 1.0-4.0 for DMF, 0.75-4.24 for EtOH, 0.025-0.4 for BeOH. The lowest tested dose was a safe dose and the highest one was the dose causing mortality in no more than half the animals in each group. The in vitro results suggest avoiding the use of BeOH (which also is more toxic than the other solvents in the in vivo test) and DMSO and using PEG400, EtOH and DMF even though the latter induced a body weight decrease in the B6D2F1 mouse strain. As a general conclusion, dilution of these solvents in water is suggested to ameliorate their blood compatibility and the use of doses not higher than the lowest dose tested in this study is recommended.