Females receive a life-span benefit from male ejaculates in a field cricket.

Mating has been found to be costly for females of some species because of toxic products that males transfer to females in their seminal fluid. Such mating costs seem paradoxical, particularly for species in which females mate more frequently than is necessary to fertilize their eggs. Indeed, some studies suggest that females may benefit from mating more frequently. The effect of male ejaculates on female life span and lifetime fecundity was experimentally tested in the variable field cricket, Gryllus lineaticeps. In field crickets, females will mate repeatedly with a given male and mate with multiple males. Females that were experimentally mated either repeatedly or multiply lived more than 32% longer than singly mated females. In addition, multiply mated females produced 98% more eggs than singly mated females. Because females received only sperm and seminal fluid from males in the experimental matings, these life-span and fecundity benefits may result from beneficial seminal fluid products that males transfer to females during mating. Mating benefits rather than mating costs may be common in many animals, particularly in species where female mate choice has a larger effect on male reproductive success than does the outcome of sperm competition.

Baseline serum and cerebrospinal fluid magnesium levels in normal pregnancy and preeclampsia.

OBJECTIVE: To determine whether baseline cerebrospinal fluid magnesium levels in preeclampsia differ from those in normal pregnancy, and to ascertain whether pre-treatment cerebrospinal fluid magnesium levels correlate with serum levels, which would suggest a baseline alteration in the blood-brain barrier in preeclampsia. METHODS: When spinal analgesia or anesthesia was administered for delivery, serum and cerebrospinal fluid magnesium levels were determined in 20 normal gravidas and 20 preeclamptic women not treated with magnesium sulfate. Data were analyzed by two-sided Student t test and regression analysis. RESULTS: Mean (+/- standard deviation) cerebrospinal fluid magnesium level for preeclamptic patients was 2.23 +/- 0.09 mEq/L, which was not significantly different from controls. Regression analysis revealed no significant correlation between cerebrospinal fluid and serum magnesium levels for either normal or preeclamptic gravidas. CONCLUSION: During the third trimester, there is no difference in baseline, pre-treatment cerebrospinal fluid magnesium levels in preeclamptic patients compared to normal subjects, and no correlation between cerebrospinal fluid and serum magnesium over the range of baseline values.

The use of vibroacoustic stimulation during the abnormal or equivocal biophysical profile.

OBJECTIVE: To determine whether vibroacoustic stimulation during the biophysical profile can change the fetal behavioral state and thus improve the score without increasing the false-negative rate of the test. METHODS: Eighty-one patients whose biophysical profile scores were 6 or lower after 15 minutes of observation had an electronic artificial larynx applied to the maternal abdomen in the region of the fetal head for 3 seconds, followed by continued observation for fetal movement, tone, and breathing for 15 minutes. We compared the obstetric and neonatal outcomes of 41 patients whose biophysical profile scores improved to normal after vibroacoustic stimulation with those of 283 patients whose scores were normal without vibroacoustic stimulation. RESULTS: Vibroacoustic stimulation did improve an abnormal or equivocal biophysical profile score to normal in 67 of 81 cases (82%). No antepartum stillbirths or perinatal deaths occurred. There was no increase in the obstetric and neonatal complication rates of cesarean delivery for fetal distress, meconium staining of the amniotic fluid, and the incidence of small for gestational age infants. CONCLUSION: Vibroacoustic stimulation improved the biophysical profile scores in most cases, an effect seen throughout the third trimester. Vibroacoustic stimulation did not appear to increase the false-negative rate of the biophysical profile and may reduce the incidence of unnecessary obstetric intervention.

Kinetics of potassium excretion following oral supplements: evidence of induced natriuresis.

Twenty-four healthy normal volunteers were given 40 mEq of three oral formulations of K+ as potassium chloride in a three-way Latin square design. Pharmacokinetic characteristics of potassium disposition were determined using urinary excretion data. Potassium was absorbed almost instantaneously from the 10% (w/v) solution, while a slow first-order absorption could explain the slow release of potassium from Slow-K and the new slow-release tablet. A biphasic elimination of potassium observed during the first 24 hr of urinary excretion suggested the body's adaptive process of changes in rates of elimination of potassium to maintain homeostasis. There was no significant difference (P = 0.25) in total recoveries of potassium in urine during 48 hr of urinary collection among the three formulations (mean +/- SE: solution, 35 +/- 7.1 mEq; Slow-K, 38.1 +/- 7.8 mEq; and new formulations, 33.5 +/- 6.8 mEq). An increased excretion of sodium was observed and correlated with increased potassium excretion following oral potassium administration which could not be explained by changes in urine flow rate. The clinical significance of such an increase in natriuresis is yet to be determined.

Asymmetries in mating preferences between species: female swordtails prefer heterospecific males.

In male swordtails ((Xiphophorus nigrensis)) there are three size classes that derive from allelic variation at the pituitary locus on the Y chromosome. Progeny analysis and preference tests suggest that females prefer to mate with larger males. In the closely related X. pygmaeus, there is no allelic variation at this locus; this species consists of males similar in size only to smaller X. nigrensis males. In addition to being smaller than most X. nigrensis males, these X.pygmaeus males also lack both the swordtail and a major component of the courtship display common in most X. nigrensis males. Usually, female X. pygmaeus prefer to mate with heterospecific males rather than conspecifics, regardless of body size and the presence of a swordtail. However, the smallest X. nigrensis males lack the same courtship component as do the X. pygmaeus males, and in this comparison female X. pygmaeus show no preference. Although sexual selection, through its action on divergence of courtship displays, has been implicated as a factor leading to speciation, in this case sexual selection could lead to the congealing of gene pools between heterospecifics.

Simultaneous first- and zero-order absorption of carbamazepine tablets in humans.

The absorption kinetics of carbamazepine (5H-dibenz[b,f]azepine-5-carboxamide) in healthy adult volunteers was investigated following a single 400-mg (2 X 200-mg) oral dose of commercially available conventional tablets (Tegretol). Wagner-Nelson plots of the data from all subjects (n = 10) showed that the fraction remaining to be absorbed declined in a biphasic manner, suggesting a mixed order of absorption. A model assuming the absorption of carbamazepine by simultaneous first-order and zero-order rates was used to describe the overall absorption process. Model parameters (and their mean +/- SD values) were: alpha, the fraction of the dose absorbed at a first-order rate (0.646 +/- 0.070); Ka, the first-order absorption rate constant (0.45 +/- 0.13 h-1); and tdur, the duration of the zero-order absorption component (36.0 +/- 4.4 h). If complete absorption can be assumed, then the corresponding average zero-order rate was 4.0 mg X h-1. The results indicate that 35% of the available dose is absorbed at a zero-order rate. These data suggest a prolonged constant rate of absorption due to continued delivery during its transit in the intestine. In addition, an assessment of the mean absorption time, based on the parameters from the model described above, compared closely (7.95 versus 8.44 h) with the mean absorption time estimated from an analysis of the fraction remaining to be absorbed versus time plot using a noncompartmental approach.

The pharmacokinetics of baclofen derived from intestinal infusion.

The pharmacokinetics of baclofen, a centrally acting muscle relaxant, have been elucidated in man. The pharmacokinetic disposition was determined form plasma concentration-time data and urinary recovery after the administration of rate-limiting intestinal infusions and an oral bolus dose. Based on comparisons between the plasma concentration-time profiles from the intestinal infusions and the oral bolus doses, relative regression parameter assignments were made. The intestinal absorption of baclofen after intestinal infusion was very rapid, such that baclofen disposition was well characterized by an open two-compartment pharmacokinetic model with zero-order input. Intravenous administration of baclofen was precluded from this study because of the potential for severe adverse reactions. The average distribution phase constant (alpha) was 1.29 hours-1 and the average elimination phase constant (beta) was 0.191 hours-1. Average volume of the central compartment (Vc/F), volume of the body compartment (Varea/F), systemic clearance (CL/F), and renal clearance were 28.8 L, 59.0 L, 180 ml/min, and 103 ml/min, respectively. Pharmacokinetics were dose proportional in the dose range studied. The use of these pharmacokinetic parameters as determined in normal subjects in therapeutic management is particularly relevant, because baclofen is targeted to a patient population subject to renal dysfunction.

Bioequivalence of carbamazepine chewable and conventional tablets: single-dose and steady-state studies.

Single-dose and steady-state studies were carried out on separate occasions to examine the bioequivalence of the newly formulated carbamazepine chewable tablet. In the single-dose study, the plasma levels resulting from 2 X 200-mg conventional tablets (CT), 4 X 100-mg chewable tablets swallowed whole (SW), and 4 X 100-mg chewable tablets chewed before swallowing (CHEW) were compared. A randomized 3 X 3 Latin-square design balanced for residual effects, with a 3-week washout period, was used (n = 6). Plasma samples were analyzed by a specific GC method for carbamazepine. The following parameters were used for evaluation: AUC, Cmax, tmax, and t1/2. None of the parameters were significantly different except Cmax and t1/2 values for CHEW and CT. The Cmax was 25% higher and t1/2 was 11% shorter for CHEW than CT. The impact of differences in the peak plasma levels at steady state were examined by pharmacokinetic projection (400 mg b.i.d.) based on the single-dose data and with simulated induction equal to a 50% reduction in t1/2. The projected steady-state CT and CHEW plasma concentrations were similar, with a difference of only 4%. The results demonstrate the bioequivalence of the dosage forms with respect to the extent of absorption, and similar steady-state concentrations of carbamazepine in plasma can be expected. To test the conclusion from the projected study, a separate bioequivalence study to compare CHEW relative to CT was performed at steady state in normal volunteers (200 mg b.i.d.).(ABSTRACT TRUNCATED AT 250 WORDS)

Kinetics of hydrochlorothiazide absorption in humans.

The kinetics of absorption of hydrochlorothiazide was studied in four adult male volunteers. Plasma levels were monitored for 48 h after a 100-mg dose. Food, electrolyte, and water intake were regulated as far as possible. The plasma level data were fitted to a two-compartment open model with either first-order or zero-order absorption, using the pharmacokinetic computer program AUTOAN. A better fit of the data, both graphically and statistically, was obtained with zero-order absorption kinetics. Additional confirmation of absorption kinetics was obtained by treating the plasma level results by the Loo-Riegelman method. Cartesian graphs of the amount absorbed verus time afforded linear plots, which indicate a zero-order process.

Oros controlled-release formulations of metoprolol: an approach to the development of a system for once daily administration.

A combined biopharmaceutical and haemodynamic approach to the development of a metoprolol Oros controlled-release delivery system for once daily administration is reported. Two studies, each involving 18 healthy volunteers, were performed in which twice daily administration of 100 mg conventional metoprolol tartrate tablets was compared with once daily administration of Oros systems containing 190 mg metoprolol fumarate but with different drug release rates. Plasma drug concentrations and beta-adrenoceptor blocking effects were measured over 24 h on days 1 and 5 of each treatment, and pre-dose in the interval between the main study days. The results of the first study with a 19 mg/h Oros system indicated that this rate was too rapid to provide the required response under steady-state dosing conditions. Theoretical calculations based on a one-compartment pharmacokinetic model and input functions for hypothetical Oros systems were then performed to define the optimal release rate for a once daily preparation. The results of the second study confirmed that a 14 mg/h system possessed the required characteristics in that it maintained more uniform beta-adrenoceptor blockade throughout 24 h, and produced pre-dosing plasma concentrations and haemodynamic effects which were identical to those for the conventional tablet twice daily regimen.

Absorption kinetics and model characteristics of orally administered pirprofen.

Pirprofen kinetics can be described by a linear two-compartment model. Absorption kinetics and model parameters were determined by the incremental method from 48 pirprofen plasma concentration-time profiles obtained after administration of single oral pirprofen doses. Statistical comparison of the results gave information on the influence of formulation, dose, and food on pirprofen absorption. The rate of absorption decreased significantly when pirprofen was administered as a capsule in comparison with a solution. The dose (200 mg compared with 100 mg) had no marked influence on the absorption rate. Food delayed absorption. Pirprofen model parameters, estimated as the median values of the results obtained from the 48 sets of data, permitted the plasma kinetics of the drug after single and repeated doses to be predicted.

Aminoglutethimide bioavailability, pharmacokinetics, and binding to blood constituents.

The bioavailability of aminoglutethimide tablets was examined using a spectrophotometric assay. For six subjects receiving 500 mg of aminoglutethimide as an oral solution, the average peak concentration was 6.2 micrograms/ml with a median time of 0.8 hr. The corresponding average peak concentration for tablet administration was 5.9 micrograms/ml with a median time of 1.5 hr. Average values for the area under the curve (AUC) extrapolated to infinity were 89.0 and 96.8 micrograms hr/ml for the solution and tablets, respectively. The tablets had a 9% larger mean for the AUC than the solution and a 5% lower value for the mean maximum concentration. The bioavailability of the tablets is considered equal to that of oral solution. Data for individual concentration versus time curves were treated by nonlinear least-squares curve fitting. A two-compartment model with first-order absorption gave an acceptable fit for most data sets, but the individual absorption rate coefficients were not reliably determined. Values were estimated for plasma clearance, renal clearance, and volume of distribution. The distribution of aminoglutethimide between plasma and cells of human blood was examined in vitro; the drug concentration in cells was 1.4-1.7 times the concentration in plasma. The binding of aminoglutethimide to plasma proteins of human blood was measured by equilibrium dialysis at starting concentrations of 5 and 10 micrograms/ml. The binding ranged from 21.3 to 25.0% without concentration dependence.

Bioavailability and kinetics of maprotiline.

Six male subjects received simultaneously single 50-mg oral doses of a maprotiline hydrochloride tablet and a trideuterated maprotiline hydrochloride aqueous solution. No side effects or other problems were encountered. The blood levels of unlabeled and isotope-labeled maprotiline for each subject were essentially superimposable. Peak levels, averaging about 50 ng/ml, were attained between 8 and 24 hr after drug. The biologic t1/2 (beta-phase) averaged 58 hr for the unlabeled and 60.5 hr for the labeled drug. The total areas under the curves (extended to time infinity) averaged 3,862 and 3,944 ng . hr/ml for maprotiline and trideuterated maprotiline, respectively (differences between the two are not significant). At the 95% degree of confidence the Westlake confidence limits show less than 10% differences between the formulations with respect to area under the curve data (calculated both to 168 hr and extended to time infinity), peak blood levels, and biologic t1/2s. There were no differences between formulations with respect to times of peak concentrations. Estimates were made for apparent volumes of distribution (about 1,000 l), apparent blood clearance (about 14 l/hr), lag times (about 1.42 hr for tablets and 1.31 hr for solution), and absorption rate constants (about 0.34 hr-1 for the tablets and 0.42 hr-1 for the solution).

Biological disposition of sodium dichloroacetate in animals and humans after intravenous administration.

Sodium dichloroacetate, a potential antidote for lactic acidosis, was administered intravenously to rats, dogs, and four humans. In three rats, maximum plasma sodium dichloroacetate concentrations were 120-164 microgram/ml after a 100-mg/kg dose and declined with half-lives of 2.1-4.4 hr. In two dogs, maximal concentrations of 447 and 508 microgram/ml were attained after a 100-mg/kg dose. The subsequent decline was relatively slow with approximate half-lives of 17.1 and 24.6 hr. An intravenous infusion of 10 mg/kg was administered over 20 min to two human subjects. Two other subjects received 20 mg/kg. After the infusion, maximum plasma concentrations of 19.9 and 24.7 microgram/ml were seen with the lower dose and 57.3 and 74.9 microgram/ml were achieved with the higher dose. Thereafter, concentrations declined rapidly with half-lives of 20-36 min. The observed large interspecies differences in half-lives could be explained in terms of differences in the apparent volume of distribution and/or clearance.

Determination of plasma hydrochlorothiazide levels in humans.

A method for determining plasma hydrochlorothiazide levels was developed with a sensitivity of 5 ng/ml. Accuracy and precision were demonstrated over the 5--648-ng/ml range by an overall recovery of 95 +/- 8%. The detector response was linear for the 5--250-ng/ml range. The method was sufficiently sensitive for hydrochlorothiazide bioavailability studies and also was applicable for the determination of whole blood drug levels. Plasma levels in two subjects reached peak levels of 428 and 450 ng/ml at 2.5 and 2 h, respectively, after a 50-mg dose. Whole blood levels at 3 hr after the same dose were 547 and 851 ng/ml and were approximately 2.5 times the 3-hr plasma levels.

Pharmacokinetics of phenformin in man.

Phenformin was assayed in urine, plasma, and sputum specimens, obtained from two healthy volunteers during the four-day period following oral administration of a single therapeutic dose. Approximately one third of the drug was excreted unchanged in the urine. Phenformin profiles were obtained for urinary excretion rates and for plasma and saliva concentrations. The terminal exponential declines indicate a half-life of approximately 11 hours. At 37 degrees C, plasma bound 19 per cent of added phenformin.