[Early prediction of lack of response to treatment with interferon and interferon plus ribavirin using biochemical and virological criteria in patients with chronic hepatitis C]. / Predicción precoz de no respuesta durante el tratamiento con interferón e interferón más ribavirina, mediante criterios bioquímicos y virológicos, en pacientes con hepatitis crónica C.

The objectives of this study were the following: 1) to evaluate the predictive value of the detection of RNA-HVC compared to GPT in the third month of treatment in patients with chronic hepatitis C treated with IFN, and at the first and third month in patients treated with IFN and ribavirin for 6 and 12 months. The study included: A) 80/132 patients treated with IFN (3 MU/3 times a week for 6-12 months), and B) 70/110 patients who had previously not responded to IFN, and who were treated with combination therapy (IFN: standard dose, ribavirin: 1200 mg/day) for 6 months (n = 40) and 12 months (n = 30). In group A, the positive predictive value (the probability of predicting the lack of response if the RNA-HVC was positive or if the GPT was elevated at the third month) was greater for RNA-HVC than for GPT (97.9% vs. 94.4%), although the response was not unequivocal (2.3% vs. 10.5%). The negative predictive value was 48.6% vs. 36.2%, respectively. The prediction level (odds ratio) of RNA-HVC and of GPT was 39.7 vs. 8.78 (p <0.000001 vs. p <0.002). The positive predictive value was 97.6% in patients with genotype 1, 4 and 5, and 100% in those with genotype 2 and 3. In group B, the positive predictive value was also greater for RNA-HVC than for GPT at the first month (100% vs. 94.4%) following six months of therapy, the odds ratio being infinite vs. 7.6. The positive predictive value was greater for RNA-HVC at the third month than at the first (100% vs. 91%), whereas it was similar for GPT (100%) with 12 months of therapy, the odds ratio being greater for GPT than for RNA-HVC at the first month (infinite and 7.27). The following was concluded: 1) detection of RNA-HVC at the third month of treatment with IFN predicts in advance a lack of response in patients, with a minimum risk of error; 2) in patients with six months of combined therapy, the detection of RNA-HVC at the first month is extremely reliable in the prediction of a lack of response, whereas after 12 months of combined therapy, elevated GPT values at the first month and the detection of RNA-HVC at the third are highly predictive of a lack of response.

Plasma butyrylcholinesterase activity and cocaine half-life differ significantly in rhesus and squirrel monkeys.

In vitro studies have implicated butyrylcholinesterase (BChE, E.C.3.1.1.8) as the major enzyme for metabolizing cocaine in humans, but little is known about endogenous BChE activity in monkeys and other animals often used in preclinical studies of cocaine. We compared BChE activity in 18 rhesus and 11 squirrel monkeys, using the colorimetric method of Ellman with butyrylthiocholine as substrate, and in vitro cocaine half-life in pooled plasma samples measuring cocaine concentrations over 60 minutes by GC-MS. Rhesus monkeys had a significantly higher plasma BChE activity than squirrel monkeys (8.2 +/- 0.5 U/L vs. 2.8 +/- 0.5 U/L), and a three-fold shorter in vitro cocaine half-life (20.1 min vs. 60.2 min). BChE activity in rhesus monkeys was comparable to the activity reported in humans. There was no significant influence of age, weight, or prior cocaine exposure. These results indicate that BChE level can vary between species of non-human primates, a factor that should be taken into account when studying drugs such as cocaine which are metabolized by BChE.

CuZn-superoxide dismutase (CuZnSOD) transgenic mice show resistance to the lethal effects of methylenedioxyamphetamine (MDA) and of methylenedioxymethamphetamine (MDMA).

We have used female and male transgenic (Tg) mice that carry the complete sequence of the human copper-zinc (CuZn) superoxide dismutase (SOD) gene in order to assess the lethal effects of methylenedioxyamphetamine (MDA) and methylenedioxymethamphetamine (MDMA). In contrast to non-Tg mice, both heterozygous and homozygous SOD-Tg mice showed resistance to the lethal effects of both drugs. Females of both SOD-Tg and non-Tg strains were somewhat more resistant to the effects of these drugs in comparison to males. In general, homozygous animals show greater resistance to the effects of the two drugs. These results suggest that the acute lethal effects of amphetamine-substituted analogs might involve the intracellular overproduction of the superoxide radicals secondary to hypoxic injury. The gender differences suggest that there might be hormonal-free radical scavenger interactions that offer better protection to female mice. This might be related both to the lifespan of and to the lower prevalence of Parkinson's disease in women. Future studies will need to address these issues further.

Comparison of the effects of cocaine and its metabolites on cardiovascular function in anesthetized rats.

Hemodynamic and cardiac-electrophysiologic effects of cocaine and its metabolites were measured in 18 groups (n = 6 each) of anesthetized, artificially ventilated rats during continuous intravenous (i.v.) infusions at three different doses (0.15, 0.45, and 1.5 mg/kg/min). At the highest dose, cocaine decreased blood pressure (BP) and heart rate (HR), while QRS duration, an index of cocaine's local anesthetic effect, was increased. Cocaethylene, a metabolite produced after coadministration of cocaine and ethanol, had effects comparable to those of cocaine. The cocaine metabolite norcocaine produced a decrease in BP at the lower dose that reversed to a small increase at the higher dose. The highest dose of norcocaine clearly decreased HR and increased QRS duration. The increases in QRS duration observed for cocaine, cocaethylene, and norcocaine were reversed by sodium bicarbonate. The cocaine metabolites benzoylecgonine and ecgonine methyl ester increased BP at the higher doses without affecting either HR or QRS duration. These results suggest that the spectrum of effects produced by cocaine are not necessarily mimicked by its metabolites. In particular, accumulation of the persistent, active metabolites benzoylecgonine and ecgonine methyl ester may contribute to delayed-onset, cocaine-related toxicity.