Genetic studies have elucidated mechanisms that regulate aging, but there has been little progress in identifying drugs that delay aging. Here, we report that ethosuximide, trimethadione, and 3,3-diethyl-2-pyrrolidinone increase mean and maximum life-span of Caenorhabditis elegans and delay age-related declines of physiological processes, indicating that these compounds retard the aging process. These compounds, two of which are approved for human use, are anticonvulsants that modulate neural activity. These compounds also regulated neuromuscular activity in nematodes. These findings suggest that the life-span-extending activity of these compounds is related to the anticonvulsant activity and implicate neural activity in the regulation of aging. (+info)
Prophylactic and therapeutic functions of T-type calcium blockers against noise-induced hearing loss.
Cochlear noise injury is the second most frequent cause of sensorineural hearing loss, after aging. Because calcium dysregulation is a widely recognized contributor to noise injury, we examined the potential of calcium channel blockers to reduce noise-induced hearing loss (NIHL) in mice. We focused on two T-type calcium blockers, trimethadione and ethosuximide, which are anti-epileptics approved by the Food and Drug Administration. Young C57BL/6 mice of either gender were divided into three groups: a 'prevention' group receiving the blocker via drinking water before noise exposure; a 'treatment' group receiving the blocker via drinking water after noise exposure; and controls receiving noise alone. Trimethadione significantly reduced NIHL when applied before noise exposure, as determined by auditory brainstem recording. Both ethosuximide and trimethadione were effective in reducing NIHL when applied after noise exposure. Results were influenced by gender, with males generally receiving greater benefit than females. Quantitation of hair cell and neuronal density suggested that preservation of outer hair cells could account for the observed protection. Immunocytochemistry and RT-PCR suggested that this protection involves direct action of T-type blockers on alpha1 subunits comprising one or more Ca(v)3 calcium channel types in the cochlea. Our findings provide a basis for clinical studies testing T-type calcium blockers both to prevent and treat NIHL. (+info)
The effects of diltiazem on hepatic drug metabolizing enzymes in man using antipyrine, trimethadione and debrisoquine as model substrates.
Six healthy male subjects were given single oral doses of antipyrine (7 mg kg-1), trimethadione (4 mg kg-1) and debrisoquine (10 mg) before and during diltiazem treatment (30 mg three times daily orally for 8 days). Antipyrine clearance decreased from 33.7 +/- 9.1 to 22.5 +/- 4.9 ml min-1 (P less than 0.05, mean +/- s.e. mean) after diltiazem treatment without any significant change in apparent volume of distribution (0.59 +/- 0.06 to 0.60 +/- 0.04 1 kg-1), resulting in an increase in antipyrine elimination half-life from 13.4 +/- 4.8 to 19.7 +/- 3.2 h (P less than 0.05). The formation clearance of antipyrine to 4-hydroxyantipyrine was decreased significantly from 10.8 +/- 2.7 to 6.6 +/- 2.7 ml min-1 (P less than 0.05), while that to 3-hydroxymethylantipyrine and norantipyrine was not altered by diltiazem. The metabolic ratio of debrisoquine (urinary excretion of debrisoquine/4-hydroxydebrisoquine) was increased significantly from 0.70 +/- 0.05 to 1.95 +/- 0.20 (P less than 0.05), while that of trimethadione (serum concentration of dimethadione/trimethadione) was not changed significantly (0.48 +/- 0.08 vs 0.41 +/- 0.06) after diltiazem treatment. Diltiazem selectively inhibits cytochrome P-450 isoenzymes. (+info)
The effect of roxatidine acetate and cimetidine on hepatic drug clearance assessed by simultaneous administration of three model substrates.
The effect of pretreatment for 7 days with either roxatidine acetate 75 mg twice daily or cimetidine 200 mg four times daily on the kinetics of antipyrine (AP), trimethadione (TMO) and indocyanine green (ICG) was studied in seven healthy, male, nonsmoking subjects. After pretreatment with cimetidine, the plasma clearances (CL) of AP and TMO were significantly lower and the elimination half-life (t1/2) of AP was significantly increased. The volumes of distribution (V) of AP and TMO were not affected. After roxatidine acetate, the pharmacokinetics of AP and TMO were unchanged. The cumulative renal excretion (% dose) and formation clearance of 3-hydroxymethyl-3-nor-antipyrine (NORA) were lowered by cimetidine treatment, but not following the administration of roxatidine acetate. ICG clearance was not changed significantly by either pretreatment. The results of this study show that roxatidine acetate does not impair the metabolism of three model substrates used to assess hepatic drug clearance. (+info)
Evaluation of the induction of hepatic drug-metabolizing enzymes in the rat and mouse treated with temazepam using trimethadione as the indicator.
In the present paper we report the effect of high doses of temazepam on drug-metabolism induction in rat and mouse. Temazepam induced a dose-dependent and reversible increase of hepatic microsomal drug-metabolizing enzymes in the rat, dose-correlated increase of dimethadione/trimethadione ratios in plasma of the rat, and dose-related shortening of hexobarbital-induced sleeping time in the mouse. In this study trimethadione is considered a good indicator for estimating the state of hepatic enzyme induction. (+info)
Species differences in pharmacokinetics and drug teratogenesis.
Interspecies differences in regard to the teratogenicity of drugs can be the result of differing pharmacokinetic processes that determine the crucial concentration-time relationships in the embryo. Maternal absorption, as well as distribution, of the drugs does not usually show great species differences. The first-pass effect after oral application is often more pronounced in animals than man (e.g., valproic acid, 13-cis-retinoic acid), although in some cases the reverse was found (e.g., hydrolysis of valpromide). Existing differences can be adjusted by appropriate choice of the administration route and measurements of drug levels. Many variables determine the placental transfer of drugs: developmental stage, type of placenta, properties of the drug. Even closely related drugs (e.g., retinoids) may differ greatly in regard to placental transfer. Maternal protein binding is an important determinant of placental transfer, since only the free concentration in maternal plasma can equilibrate with the embryo during organogenesis; this parameter differs greatly across species (e.g., valproic acid: five times higher free fractions in mouse and hamster than in monkey and man). The metabolic pattern has not yet been demonstrated to be a major cause of species differences, although recent evidence on phenytoin and thalidomide support the hypothesis that some species differences can be the result of differing activation/deactivation pathways. Laboratory animals usually have a much higher rate of drug elimination than man. Drastic drug level fluctuations are therefore present during teratogenicity testing in animals, but not to the same degree in human therapy. It must, therefore, be investigated if peak concentrations (such as for valproic acid and possibly caffeine) or the area under the concentration-time curve (AUC) (such as for cyclophosphamide and possibly retinoids) correlate with the teratogenic response. Only then is a rational and scientific basis for interspecies comparison possible. It is concluded that the prediction of the human response based on animal studies can be improved by consideration of the appropriate pharmacokinetic determinants. (+info)
Changes in sensitivity of mice to anticonvulsant drugs following bilateral olfactory bulb ablations.
Changes in sensitivity to anticonvulsant drugs were investigated after bilateral olfactory bulb ablations in mice. The sensitivity to benzodiazepines and acetazolamide increased, whereas that to phenylacetylurea and dipropylacetic acid decreased, and sensitivity to phenobarbital, diphenylhydantoin and trimethadion was not significantly changes after olfactory bulb ablations. Increase in sensitivity to benzodiazepines was the most significant in both electroshock and pentetrazol convulsions. It was suggested that altered activities and denervation supersensitivity in the limbic system, hypothalamus and midbrain might account for these changes in sensitivity to anticonvulsant drugs after olfactory bulb ablations. (+info)
Effect of anticonvulsants on thalamic afterdischarge in rats and cats.
Effects of anticonvulsants were determined on thalamic afterdischarge in gallamine-immobilized cats and d-tubocurarine-immobilized rats in order to clarify the participation of anticonvulsants in the thalamus. Thalamic afterdischarge was induced by electrical stimulation of cat nucleus centralis lateralis and rat nucleus reticularis at 50 Hz, 1 msec for 4 sec. In cats, diphenylhydantoin, carbamazepine, phenobarbital, and diazepam raised afterdischarge threshold, and shortened its duration induced at twice the threshold voltage. Trimethadione and dipropylacetate raised the threshold, but did not change the duration. In rats, diphenylhydantoin, phenobarbital, and diazepam raised the threshold, and shortened the duration with comparable dose ranges used for cats. Dipropylacetate and acetazolamide raised the threshold, although did not change the duration except for shortening action with a higher dose of dipropylacetate. Trimethadione was without effect. These results suggest that the depressive effect of anticonvulsants on the thalamus is, at least in part, associated with control of the epilepsies. (+info)