Comparative bioavailability evaluation of two cyclosporine oral formulations in healthy Mexican volunteers.

BACKGROUND: The use of conventional cyclosporine (Sandimmune) requires great care, as this drug exhibits a narrow therapeutic index and wide interindividual variability in its pharmacokinetics. Recently, a new microemulsion formulation (Neoral) was developed. With this formulation, cyclosporine is absorbed at the small intestine without the presence of bile. Therefore, the objective of this study was to compare the bioavailability of cyclosporine after the administration of conventional and microemulsion formulations in healthy Mexican volunteers in order to approach the optimal dosage regimen of microemulsion in the Mexican population. METHODS: The trial was conducted using 23 healthy volunteers according to a randomized crossover design. Volunteers received one 7.5-mg/kg dose as each formulation, with a 1-week washout period between treatments. Blood samples of 0.5 mL were obtained according to the following schedule: 0, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 h after medication. RESULTS: These indicated that Cmax and AUC0-24 values were higher with the microemulsion than with the conventional formulation. CONCLUSIONS: The microemulsion had a better absorption profile than the conventional formulation, because plasma levels with the conventional formulation demonstrated oscillations rather than reflecting an erratic absorption. Lower doses of the microemulsion are required to obtain Cmax values similar to those obtained with conventional cyclosporine.

Bioavailability of oral cyclosporine in healthy Mexican volunteers: evidence for interethnic variability.

The existence of population variations in cyclosporine pharmacokinetics could be expected, as this drug, similar to nifedipine, is biotransformed by cytochrome P-450 subfamily 3A4, and the existence of interethnic variability in nifedipine disposition has been demonstrated previously. The bioavailability of oral cyclosporine was studied in 23 healthy Mexican volunteers receiving 7.5-mg/kg doses of cyclosporine. Blood samples were drawn over 24 hours, and concentration of cyclosporine in whole blood was determined by a radioimmunoassay using monoclonal antibodies specific for the unchanged drug. The bioavailability of cyclosporine exhibited wide interindividual variability. Maximum concentration (Cmax) ranged from 528 ng/mL to 2,689 ng/mL, area under the concentration-time curve (AUC) ranged from 6,550 ng.hr/mL to 18,562 ng.hr/mL, and time to reach Cmax (tmax) ranged from 1 to 8 hours. Half-life (t1/2) exhibited less important variations, ranging from 4.4 to 9.1 hours. The bioavailability of oral cyclosporine in Mexicans was higher than that reported for white populations under similar conditions. The present results suggest the existence of interethnic variability in the pharmacokinetics of cyclosporine, as is the case with nifedipine.

Discrepancy between Bioavailability and Hypotensive Effect of Oral and Sublingual Nifedipine.

Nifedipine, 10-mg capsules, were given orally and sublingually to six healthy volunteers according to a randomized crossover design. Nifedipine plasma levels, blood pressure, and heart rate were determined at several times after medication. C(max) was higher (134 plus minus 17 vs. 93 plus minus 2 ng ml(minus sign1), mean plus minus SD, P < 0.01) and occurred earlier (0.5 vs. 1 h) with oral than with sublingual nifedipine. However, there was no significant difference in AUC (268 plus minus 56 vs. 288 plus minus 35 ng h ml(minus sign1)) nor in t(1/2) (1.8 plus minus 0.2 vs. 1.9 plus minus 0.3 h), indicating that sublingual administration decreased the rate but not the extent of nifedipine absorption. Notwithstanding the difference in C(max), both routes yielded a similar reduction in diastolic blood pressure of 13 plus minus 1 mm Hg. Heart rate increase, which reflects the activation of homeostatic mechanisms, was greater with oral than with sublingual nifedipine, that is, 18 plus minus 1 vs. 13 plus minus 1 beats min(minus sign1), P < 0.01. It is concluded that slower absorption after sublingual administration increases nifedipine hypotensive efficiency by producing less counteracting homeostatic responses than the more rapidly absorbed oral nifedipine.

Pharmacokinetics of oral nifedipine in different populations.

Nifedipine disposition varies among populations. Reports on oral nifedipine pharmacokinetics show that peak plasma levels and AUC values are higher in Mexican and Japanese than in European and North American subjects. Increased nifedipine bioavailability in the nonwhite populations is likely due to nutritional habits. Certain flavonoids that inhibit the first-pass metabolism of dihydropyridines are present in the diets of both Mexican and Japanese. Differences in phenotypes may play a role in interethnic variability.

[Nifedipine in gynecology and obstetrics]. / Nifedipina en ginecología y obstetricia.

Nifedipine has both vasodilator and relaxant actions in arterial smooth muscle and other tissues, like uterus. The goal of this review is describe the potential uses of this calcium antagonist in two clinical features in pregnancy. First, in premature labor, nifedipine is an appropriate alternative related with beta-mimetic or prostaglandin synthetase inhibitors agents, with good tocolytic properties and safe for both mother and baby. Second, in the treatment of hypertension in pregnancy or preeclampsia, where, according literature, nifedipine would be a valuable therapeutic gun. It is exposed the nifedipine advantages and disadvantages in pregnancy found by the authors from the reports reviewed here. It is analyzed the ethics of nifedipine use in pregnancy. Moreover, it is pointed out the nifedipine clinical usefulness in the treatment of primary dysmenorrhea and it is analyzed some nifedipine hemodynamic aspects on uterine blood flow.

[The clinical importance of pharmacokinetics]. / Importancia clínica de la farmacocinética.

An overall review about the main concepts of pharmacokinetics and its importance in the clinical arena is presented. The goal of this manuscript is the comprehension of this matter, described with a clear language, without mathematical formulas, considering that they are widely explained in the publications of the well-known journals of clinical pharmacology.

[Relation between dose, plasma concentration and therapeutic effect of theophylline in children with sleep apnea]. / Relación entre la dosis, concentración plasmática y efecto terapéutico de teofilina en niños con apnea del sueño.

The plasma concentration of theophylline was determined in twelve children with infantile sleep apnea (average age 48.5 days). The purpose of the study was to correlate concentrations with the dosages given, the therapeutic response and any adverse effects which could arise. In addition, other pharmacokinetic values were found, half-life (t 1/2) and clearance concentrations (Clss). The oral maintenance dose used was 4 mg/kg/24 h. The serum concentration of theophylline was determined by a homogeneous immunoassay enzyme technique (EMIT). A bad correlation was found (r = 0.45) between the oral dosage given and the plasma concentrations found. This was probably due to variations in the clearance of the drug. Yet, plasma concentrations fell between 3.0 and 12.6 micrograms/mL, enough to satisfactorily control apneic episodes in all the children included in the study without undesirable side-effects. Only one patient had some trouble in falling asleep and showed signs of irritability. The half-life was 13.30 +/- 7.46 hours and Clss was 36.64 +/- 12.98 mL/h/kg. In general, our results correlate with those reported in the literature. The accuracy of the pharmacokinetic parameters with two samples is reliable, therefore avoiding the use of multiple sampling in this group of children.

Bioavailability and pharmacokinetics of nifedipine administered by different routes in healthy volunteers.

Absolute bioavailability (F) of 10 mg nifedipine capsules was studied in six adult healthy male volunteers. The drug was given swallowed and sublingual and the results compared with data obtained when the drug was administered intravenously (0.015 mg/k). The pharmacokinetic profile of nifedipine was performed from venous blood samples obtained over a period of 8 hours, with a specific gas chromatographic assay. Besides bioavailability (F), also were calculated the peak plasma concentration (Cmax), the time to reach Cmax, (tmax), the clearance of the drug (CL), the apparent volume of distribution (V1), the elimination half-life (t1/2 beta), and the area under the curve (AUC). The F value was 44.5 + 7.5% and 48.7 + 8.3% for the swallowed and sublingual routes respectively; however, during the sublingual administration the mean Cmax was larger (92.9 +/- ng/ml), and mean tmax greater (1 h), than the data obtained following the swallowed administration (134.1 +/- 17.7 ng/ml and 0.5 h respectively; p less than 0.05). When nifedipine was administered intravenously the mean t1/2 beta was 2.063 +/- 0.24 h, the mean CL was 0.234 + 0.017 l/h.kg, and the mean V1 was 0.278 + 0.027 l/kg; these data did nat show the great individual variability reported by other authors. Due to the mean AUC, less than 450 ng.h/ml, the group of volunteers of this trial could be classified as rapid metabolizers. Finally, there was a significant linear correlation between nifedipine plasma concentrations and the changes observed in the heart rate blood pressure (r = 0.85; p less than 0.05).

[Indications and contraindications for analgesics and antibiotics in pediatric dentistry]. / Indicaciones y contraindicaciones de analgésicos y antibióticos en odontología pediátrica.

A general overview upon most used products in odontopediatrics is presented; the factors which influence the determination of the adequate doses in children and some useful recommendations in dental clinical practice are described. The most prescribed products in pediatric odontology are summarized into two groups: a) benzodiazepine, for anxiety and lidocaine, aspirin and acetaminophen, dipirone and naproxen, for pain; and b) penicillin, erythromycin, for treatment of infections. Doses, pharmacologic effects, clinical indications, side effects and contraindications of the chemicals mentioned are described. Also, the article presents some of the aspects which justify the use, in our country, of certain medicaments prescribed in other nations reporting, the recommendations in order to prevent the use of other chemicals because of their lack of therapeutical advantages over the ones of first choice.