RESUMEN

In order to elucidate the folding dynamics of protein, we have carried out numerical simulations of a heteropolymer model of self-interacting random chains. We find that folding propensity depends strongly on sequence and that both folding and nonfolding sequences exist. Furthermore we show that folding is a two-step process: the transition from coil state to unique folded state takes place through a globule phase. In addition to the continuous coil-globule transition, there exists an abrupt transition that separates the unique folded state from the globule state and ensures the stability of the native state.

Asunto(s)

RESUMEN

Native sulphur has had limited success as a medicinal agent. There is, however, hardly a class of drugs which does not contain compounds having sulphur in their structure. Sulphur-containing dyes have given rise to many clinically useful substances, others, such as the -lactam antibiotics, have been developed from naturally occurring molecules and yet others have been designed on the basis of a detailed understanding of physiological mechanisms. Sulphur occurs in drug molecules in all its oxidative states and in all its forms of organic combination. Organo-sulphur compounds, unquestionably form a major therapeutic resource and their potential remains to be further exploited.

Asunto(s)

Asunto(s)

RESUMEN

The pharmacokinetics of the reversible MAO-A inhibitor, cimoxatone, and its O-demethyl metabolite MD 770222 were investigated in eight healthy adult volunteers following single doses of 20- and 40-mg tablets, and 40-mg aqueous suspension. Cimoxatone plasma conc./time curves were fitted using a one-compartment open model, with absorption and elimination half-lives of about 0.5 and 12.0 h, respectively. Visual fittings, parameter estimates, and statistical analysis (Akaike information criterion) showed that data were better fitted by first-order than by zero-order absorption rate. A lag time of 20-25 min was observed for both formulations. MD 770222, which is also a selective and reversible inhibitor of MAO A although less potent than cimoxatone, is the major plasma metabolite and its plasma elimination half-life is about three times longer than cimoxatone. Although cimoxatone solubility in water is only 5 ppm, the drug appears to be well absorbed as indicated by the tight conformity of the pharmacokinetic parameters. Cmax and AUC values doubled from the 20- to the 40-mg dose. A statistical analysis showed that the systemic availability of cimoxatone from the 40-mg tablet is higher than from the suspension (p less than 0.05), and this difference is even more pronounced on analysis of the metabolite data (p less than 0.01). Particle size analysis of cimoxatone pronounced on analysis of the metabolite data (p less than 0.01). Particle size analysis of cimoxatone powder showed the formation of agglomerates for the suspension which, by reduction of surface area, could decrease the availability of the drug.

Asunto(s)

Asunto(s)

Asunto(s)

RESUMEN

Dilitazem, a coronary vasodilating agent, after oral administration of four different doses, was well and rapidly absorbed. The pharmacokinetics of the drug followed a two-compartment model, with a rapid distribution and an elimination with a half-life of 4-7 hours. After chronic treatment the pharmacokinetic parameters were practically unchanged and therefore no accumulation of the drug was observed. The comparison between capsule and tablet preparations showed that both forms had a similar bioavailability. Diltiazem was extensively metabilized and only a few percent of the drug was found in urine. Several metabolites, also present as conjugates, have been identified by means of gas chromatography-mass spectrometry.

Asunto(s)

RESUMEN

1. The serum profiles of chlorpropamide obtained following single doses of two tablet preparations and from a suspension formulation have been compared in healthy volunteers. The amounts of chlorpropamide absorbed from the three formulations were similar but the drug was absorbed more rapidly from the suspension than from either tablet formulation. There was a small but therapeutically insignificant difference in the rate of absorption of the drug from the two tablets. 2. Changes in blood glucose concentrations were found to be related to the drug serum profile characteristics of the formulations.

Asunto(s)

Asunto(s)

Asunto(s)

Asunto(s)

Asunto(s)

RESUMEN

A procedure is described for the determination of tiflorex and its metabolite nortiflorex in biological specimens. The compounds are converted into their trichoroacetyl derivatives, which are separated on a glass column packed with 3% OV-17 on Gas-Chrom Q, and measured with an electron-capture detector. The mechanism was investigated by gas chromatography-mass spectrometry. The method is rapid, sensitive for concentrations of 1 ng/ml and has been used to measure tiflorex and its metabolite in rat plasma after intravenous administration and in human volunteers after administration by the oral route.

Asunto(s)

Asunto(s)

RESUMEN

1 In a pharmacokinetic study in six volunteers serum fusidic acid concentrations were obtained after rapid intravenous administration of 100 mg. 2 Analysis of the data suggests that the serum concentration/time curve is biphasic and that the curve can be described by the following equation: cp=5.9e(-1.82t)+4.3e(-0.13t). 3 The disposition characteristics of sodium fusidate have been calculated from this relationship and a plasma half life for sodium fusidate of between 5 and 6 h obtained. 4 Subsequently plasma fusidic acid levels have been measured in the same volunteers on three occasions after sodium fusidate (500 mg) given either as a slow intravenous infusion, or orally as a capsule or as a suspension. 5 Serum levels and AUC after a capsule were about 75% of those obtained after the infusion (30 and 70 mg/1 at peak respectively) whereas levels and AUC after the suspension were only about 50%.

Asunto(s)

RESUMEN

A gas cromatographic method for the determination of the benzothiazepine diltiazem together with its major metabolite desacetydilitiazem, is described. Silylation of the desacetyl derivative separates the metabolite from the parent drug on a 1% OV-17 column and cyclopam is used as an internal reference standard. The compounds are analysed by means of a nitrogen detector which allows the determination of 10 ng/ml of both compounds in plasma. The method has been used to determine both diltiazem and its desacetyl derivative in plasma obtained from healthy volunteers after oral doses of 60-210 mg of diltiazem.

Asunto(s)

RESUMEN

Psychotropic drugs are prescribed to modify human behavior but they have persistent central sedative activity which may become a troublesome side-effect. Alcohol is known to interact with psychotropes, often to potentiate their central effects. We have previously shown that residues of some hypnotic drugs persist in the body for up to a week after a single therapeutic dose and have demonstrated that alcohol decreases the elimination rate of methaqualone even when taken 2 or 3 days after the drug. We have therefore looked at the influence of alcohol on the residual effects of Mandrax and nitrazepam on three measurements of human performance. The study was a double-blind, 3-way, cross-over study in which the following treatments were used: drug + alcohol, drug + alcohol placebo, and drug placebo + alcohol. In each case the alcohol or alcohol placebo was given 1, 2, and 3 days after the drug or placebo. The subject's kinetic visual acuity was measured 40 minutes after the alcohol had been taken. This was followed by a Stroop test. Changes in mental state and arousal were measured by an 18-item visual analogue scale. An interaction between alcohol and Mandrax was apparent in the results obtained from the Stroop and visual analogue scale on the third day. However, no interaction with nitrazepam could be clearly demonstrated by any of the tests on any occasion. The application of these results to the "real life" situation is discussed.

Asunto(s)

RESUMEN

Serum mecillinam concentrations have been obtained in 6 volunteers after intravenous injection of 200 mg mecillinam and two 200 mg tablets containing pivmecillinam hydrochloride. Initial concentrations were between 6 and 9 mg/1 and peak concentrations of about 2-0 mg/1 occurred at 1 to 1-5 h after the tablets. Analysis of the intravenous data shows the concentration/time curve to be biphasic and similar to that previously reported for penicillin G. The biexponential curves describing the data have been calculated using nonlin. Comparison of the areas under the serum mecillinam concentration/time curves suggests a bioavailability of 65 to 70% for the tablets. However, the two preparations contain therapeutically equivalent amounts of antibiotic, as two 200 mg tablets of pivmecillinam contain 30% more mecillinam than the 200 mg injection.

Asunto(s)

Asunto(s)

Asunto(s)