[Survival of HIV women and HAART therapy]. / Supervivencia de las mujeres infectadas por el VIH tras la aparición del TARGA.

OBJECTIVES: To assess antiretroviral treatment in women with HIV infection, to evaluate the evolution of the disease and to establish the survival rate of these patients. DESIGN: A retrospective study performed from 1985 to December, 2004. Seventy-five women, chosen randomly from all patients attending the Out-patients Department, Arnau de Vilanova Hospital, Spain. All patients were over 18 years of age, with HIV infection and undergoing antiretroviral treatment. Patients were divided into two groups according to the starting date of therapy, before or after the year 1997 when a significant change in antiretroviral therapy took place, referring both to the number of drugs used and their potency. METHODS: A comparison was made regarding the epidemiological and demographic profile, the initial and final treatment, the efficacy of antiretroviral treatment, the evolution of the HIV infection and the survival rate between both groups of patients. RESULTS: Sixty-six point seven per cent (66.7%) of the patients in the first group and 85.2% of patients in the second had negative viral loads at study end. Forty-seven point nine per cent (47.9%) of patients starting treatment before 1997, maintained CD4 lymphocyte counts above 500 cells/mL compared with 59.3% of the patients who started treatment after 1997. There were only 6 deaths, which corresponded to the first group of patients. CONCLUSIONS: The data obtained from our study suggests that antiretroviral treatment is effective in both groups of patients, and has enabled good evolution and lengthened the survival rate.

[Effect of the concomitant administration of indomethacin or ibuprofen on amikacin pharmacokinetics in premature newborns]. / Efecto de la administración concomitante de indometacina o ibuprofeno en la farmacocinética de amikacina en neonatos prematuros.

OBJECTIVE: To evaluate whether the concomitant administration of ibuprofen or indomethacin plus amikacin may alter the latter drug s pharmacokinetic parameters, and hence amikacin plasma levels. METHOD: Retrospective cohort study performed by reviewing the medical records of premature children with persistent ductus arteriosus receiving amikacin and ibuprofen, or amikacin and indomethacin. They were divided up into three groups: group 1: treatment with amikacin went before indomethacin or ibuprofen; group 2: simultaneously treated with amikacin and indomethacin; group 3: simultaneously treated with amikacin and ibuprofen. Pharmacokinetic parameters, distribution volume, and amikacin clearance were measured using the PKS program (a non-linear regression method). Half life was determined from previous parameters. RESULTS: Twenty-eight patients were included. No statistically significant differences were found among pharmacokinetic parameters corresponding to each study group. CONCLUSIONS: Further studies are needed with a greater number of patients and currently recommended doses to assess the influence of indomethacin and ibuprofen in the pharmacokinetics of amikacin in premature children with persistent ductus arteriosus.

Pharmacological studies of the two new hypoglycaemic compounds 4-(3-methyl-5-oxo-2-pyrazolin-1-yl)benzoic acid and 1-(mesitylen-2-sulfonyl)-1H-1,2,4-triazole.

New compounds showing hypoglycaemic activity have been designed through a computer-aided method based on QSAR (quantitative structure activity relationship) and molecular connectivity. The pharmacological tests carried out on the newly designed compounds demonstrated the existence of notable activity for two of them, namely: 4-(3-methyl-5-oxo-2-pyrazolin-1-yl) benzoic acid (CAS 60875-16-3) and 1-(mesitylen-2-sulfonyl)-1H-1,2,4-triazole, (CAS 54230-59-0). Both substances mainly follow a mechanism based on the response to the oral glucose overcharge, decreasing the glycemia to lower levels as compared with tolbutamide, which is used as a standard drug, and reaching normal glycaemia at a similar time.

Nonlinear pharmacokinetics of cefadroxil in the rat.

The pharmacokinetics and bioavailability of cefadroxil in the rat were examined after intravenous and oral administration at three doses (2.5, 10, and 15 mg). Cefadroxil disposition kinetics was clearly nonlinear, with an increase in plasma clearance as the dose increased (2.65 +/- 0.55, 3.17 +/- 0.48, and 3.82 +/- 0.39 ml/min for the three doses assayed). This phenomenon was attributed to a saturable renal tubular reabsorption of the antibiotic. After oral administration, the normalized Cmax was lower for the largest dose (4.6 +/- 0.7 micrograms/ml) than for the other two doses (5.5 +/- 0.5 and 5.4 +/- 0.7 micrograms/ml). Renal excretion of cefadroxil in the rat after intravenous and oral administration was investigated at two level doses (2.5 and 15 mg). No significant differences were found between doses or administration routes, and the mean percentage of dose recovered in the urine for the intravenous and oral routes was 80.7 +/- 6.1% and 76.4 +/- 3.7%, respectively. Cefadroxil bioavailability estimated from plasma levels or from the amounts of drug excreted in the urine was high and ranged from 90% to 100%.

Influence of permanent cannulation of the jugular vein on pharmacokinetics of amoxycillin and antipyrine in the rat.

The effect of chronic cannulation of the rat jugular vein on the pharmacokinetics of amoxycillin and antipyrine administered by the i.v. and oral routes has been evaluated. Animals that received the i.v. dose of amoxycillin on the eighth day after jugular vein cannulation showed decreased clearance (4.0 +/- 0.3 ml/min) and steady-state volume of distribution (105 +/- 8 ml) compared to animals that received the i.v. dose on the fourth day (5.5 +/- 1.1 ml/min and 155 +/- 17 ml, respectively). Rats first dosed by the i.v. route showed an oral bioavailability of 54 +/- 12%, whereas for those first dosed by the oral route the calculated bioavailability was 31 +/- 6%. Antipyrine was administered to rats by the i.v. and oral routes on the first and fourth days after jugular vein cannulation. Animals intravenously dosed on the fourth day showed a decreased clearance (1.9 +/- 0.3 ml/min) compared to rats intravenously dosed on the 1st day (2.7 +/- 0.6 ml/min). Antipyrine bioavailability was larger in animals first dosed by the i.v. route than in animals first dosed by the oral route (173 +/- 43 and 74 +/- 15%, respectively). These results argue against the use of crossover studies in rats with permanently implanted cannulas since kinetic changes induced by cannulation can be larger than previously proposed.

General treatment of the enterohepatic recirculation of drugs and its influence on the area under the plasma level curves, bioavailability, and clearance.

A general treatment of enterohepatic recirculation of drugs has been developed based on the fraction of drug in systemic circulation that is excreted in the bile and the fraction of drug reabsorbed from the gut that reaches systemic circulation in each enterohepatic cycle. The deduced equations make it possible to establish mathematical relationships between the areas under the blood level curves (AUC) of a drug when administered to normal and bile duct-cannulated animals and to predict the effect of enterohepatic recycling on bioavailability and clearance. The results were compared with those obtained by other authors using different approaches to enterohepatic recirculation, and some discrepancies were found in the equations describing the effect of enterohepatic recycling on AUC and bioavailability of drugs. The cause of such discrepancies and the problems associated with the prediction of hepatic extraction ratio from in vitro studies are discussed.

Nonlinearities in amoxycillin pharmacokinetics. I. Disposition studies in the rat.

Several features of amoxycillin pharmacokinetics in man are not well known in spite of the extensive clinical use of the antibiotic. In this paper it is demonstrated that amoxycillin disposition kinetics in rats is clearly nonlinear, and that this may be due mainly to its elimination mechanisms. At different intravenous bolus dose levels, and in steady-state perfusion studies, the most striking feature is an increased renal clearance as dose increases (from 3.5 to 7.0 mg kg-1 for intravenous bolus, and from 4.6 to 20.0 micrograms min-1 for intravenous perfusions). This phenomenon has been attributed to a saturation of the active renal tubular reabsorption of the antibiotic. When the intravenous dose is substantially increased (28.0 mg kg-1 bolus), plasma clearance tends to stabilize, probably because saturation of the active tubular secretion of amoxycillin takes place at these doses. Extrarenal clearance seems to remain linear throughout the entire dose range. On the basis of these observations and a review of selected bibliography, an interpretation of the kinetic disposition behaviour of amoxycillin in man is attempted.

Nonlinearities in amoxycillin pharmacokinetics. II. Absorption studies in the rat.

Most factors influencing amoxycillin oral absorption are, even today, unknown. Since many dosage schedules have been shown to lead to incomplete absorption, it would be desirable to find a suitable animal model where these factors could be studied in depth. In this paper, it is shown that, in the rat, plasma level curves obtained after oral doses of 7 and 28 mg kg-1 are poorly fitted using first-order absorption kinetics and that the best fit is obtained through the use of an input equation combining zero and first-order kinetics. In contrast, plasma level curves found after intraduodenal administration of amoxycillin solutions (7 mg kg-1) are well fitted by first-order input kinetics. It would seem that precipitation of some dose fraction of the orally administered antibiotic may occur in proximal gastrointestinal areas; this plays an important role in absorption profiles and prevents any possible saturation phenomena associated with active intestinal transport of the antibiotic. A comparative study of available human oral data revealed close similarities with those found in rats. As a result, the plasma level curve fitting was greatly improved by the use of the input function described here for the rat. Although oral bioavailability (as assessed from urinary excretion data) is lower in this latter species, the use of suitable correction factors led to superimposable plasma level curves in the two species, as occurred in previously reported disposition studies.

Pharmacokinetics and bioavailability of diclofenac in the rat.

Diclofenac sodium is a widely used drug with interesting absorption and disposition features when administered to laboratory animals. The present study was undertaken to assess the pharmacokinetics of the drug after iv and gastrointestinal dosing to rats. Renal excretion of unchanged drug was negligible, but biliary excretion of the drug (unchanged and conjugated) was detected in bile duct-cannulated rats; it accounted for 27.2 and 31.2% of the total dose following iv and intraduodenal administration, respectively. Most of the drug excreted in the bile was conjugated diclofenac; unchanged drug accounted for only 4.7 and 5.4% of total diclofenac excreted in the bile after iv and intraduodenal dosing, respectively. In normal animals, intestinal absorption of the drug excreted in the bile resulted in higher drug concentrations in plasma than those obtained in bile duct-cannulated rats, but only after 60 min of dosing. When administered directly into the duodenum, diclofenac absorption was extremely fast and the maximum plasma diclofenac concentration was reached within 2 min. After oral dosing, an early peak was also observed, but it was lower than that obtained after intraduodenal dosing: 71% diclofenac bioavailability was found in bile duct-cannulated rats intraduodenally dosed, whereas in normal animals dosed by mouth a bioavailability of 79% was obtained. In normal animals intraduodenally dosed, an apparent bioavailability of 106% was observed. All of these features, particularly the influence of enterohepatic circulation on drug bioavailability, are discussed.

Dose-dependent absorption and elimination of cefadroxil in man.

The pharmacokinetic behaviour of cefadroxil was dose-dependent in healthy male volunteers following the oral administration of single doses of 5, 15, and 30 mg.kg-1. As the dose of cefadroxil increased from 5 to 15 and 30 mg.kg-1, the peak plasma concentrations, normalized to 5 mg.kg-1, decreased significantly from 15.1 to 10.7 and 7.6 mg.l-1, while the corresponding normalized areas under the plasma concentration-time curves from 0 to 2 h decreased significantly from 1258 to 946 and 801 min.mg.l-1. When the same subjects were given 5 mg.kg-1 of cefadroxil together with 45 mg.kg-1 of cephalexin, the absorption of cefadroxil was slowed to a similar or greater extent than with the high dose of cefadroxil. Although the absorption rate decreased as the dose increased, the systemic availability of cefadroxil was essentially complete at all doses, as judged by the 24 h urinary recoveries of the antibiotic. Kinetic analysis of the plasma concentration-time curves gave the best fit with a zero-order followed by a first-order absorption process, consistent with saturable intestinal absorption of cefadroxil. The elimination rate of cefadroxil was directly related to dose and plasma concentrations, and the clearance at the dose of 5 mg.kg-1 was significantly increased by the simultaneous administration of high-dose cephalexin. The renal clearance of cefadroxil ranged from 98 ml.min.l-1 at total plasma cephalosporin (cefadroxil + cephalexin) concentrations less than 2.5 mg.l-1 to 156 mg.l-1 at concentrations greater than 40 mg.l-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Kinetics of the intestinal uptake of zinc acexamate in normal and zinc-depleted rats.

The uptake of zinc as acexamic acid salt in the small intestine of the anaesthetized rat was shown to be a two-phase process in normal animals. The first phase is rapid mucosal binding which satisfies the Freundlich isotherm equation and which involves about 30 per cent of the initially perfused zinc. The second phase was characterized as an apparent absorption step which obeys Michaelis-Menten and first-order combined kinetics, with the following parameters: Vm = 6.51 mg h-1; Km = 2.96 mg; ka = 0.306 h-1. In largely non-saturated conditions, an apparent global rate constant of about 2.50 h-1 was calculated. No significant interference due to endogenous zinc excretion into the small intestine was observed during the absorption period. In zinc-deficient animals, the two phases were not so well characterized. Binding was non-linear and apparent absorption efficiency was much greater at high zinc concentrations, so no evidence of saturable kinetics was found, thus confirming the hypothesis of a homeostatic zinc regulation mechanism.

Absorption kinetics of beta-alanine as model compound in rat small intestine.

Contradictory results have been reported on intestinal beta-alanine absorption, although a generalized view is that it could be a passive, nonmediated process. Since previous data from our laboratory suggested that some competition arises between intestinal absorption of the gamma-amino acidic drug baclofen and beta-alanine, a rat jejunum in situ study was undertaken in order to gain insight into the mechanism of beta-alanine absorption. Perfusion solutions with initial beta-alanine concentrations ranging from 0.3 to 56 mM were used. The beta-alanine absorption was clearly identified as a saturable process which obeys Michaelis-Menten equation kinetics, as assessed through two computer-assisted procedures based on differential and integrated forms of this equation. Parameter values found were: Vm = 3.88-4.72 mg.ml-1.h-1 (43.6-52.9 mM.h-1), and Km = 0.97-1.13 mg.ml-1 (10.9-12.7 mM). Statistical analysis does not account for the existence of significant parallel passive diffusion pathways (less than 0.2 h-1).

Evidence of a specialized transport mechanism for the intestinal absorption of baclofen.

Absorption of the spasmolytic drug baclofen in three selected intestinal segments of living anaesthetized rats in situ, is shown to be a specialized transport mechanism obeying Michaelis-Menten kinetics. Equation parameters were calculated through different procedures, whose features are discussed. A computer method based on the integrated form of Michaelis-Menten equation which reproduces the entire time course of drug absorption from the data found in three intestinal perfusion series at different initial concentrations, yielded Vm and Km values of 12.0 mg h-1 and 8.0 mg, respectively, in the mean segment of the small intestine, a rather selective absorption site for baclofen. Lesser but comparable absorption rates were found in the proximal and distal segments of the small intestine, whereas in colon, drug absorption was negligible. Baclofen transport was significantly reduced in the presence of the enzymatic inhibitor sodium azide. If these results were extrapolated to humans, they would explain the excellent bioavailability profiles reported for baclofen at normal doses in spite of its physicochemical properties, which do not favour passive diffusion. Based on the same principle, the administration of usual doses at shorter time intervals could be recommended, instead of high, when higher plasma levels at steady-state are needed. On the other hand, more than 8-h sustained-release preparations of baclofen should, probably, be avoided.

Non-linear intestinal absorption kinetics of cefadroxil in the rat.

Absorption of cefadroxil in a selective intestinal absorption area (the proximal third of the small intestine) of the anaesthetized rat, at seven initial perfusion concentrations, ranging from 0.01 to 10.0 mg mL-1, is shown to be a non-linear transport mechanism. With the aid of computer-fitting procedures based on differential and integrated forms of Michaelis-Menten equation, Vm and Km values of 36.7-37.3 mg h-1 and 12.0-13.0 mg, respectively, were found. The statistical parameters were better than those obtained both for first-order and for combined Michaelis-Menten and first-order kinetics. There is no evidence for substantial passive diffusion processes. The results reported here, together with allometric considerations and literature data analysis, may help to explain some particular non-linear features of plasma level curves associated with the administration of fairly high oral doses of cefadroxil to humans.