Pharmacokinetics and pharmacodynamics of zolmitriptan in patients with mild to moderate hypertension: a double-blind, placebo-controlled study.

Zolmitriptan is a potent selective 5HT1B/1D receptor agonist for acute migraine therapy. Zolmitriptan has vasoconstrictor activity in cerebral vessels and may cause slight elevations of blood pressure in subjects without hypertension. Therefore, the pharmacokinetics and pharmacodynamics of zolmitriptan (5, 10, and 20 mg) were evaluated in 16 patients with mild to moderate hypertension (controlled by hydrochlorothiazide 50 mg once daily) and 17 healthy age- and sex-matched control subjects in a randomized, placebo-controlled, double-blind, four-period crossover study. The pharmacokinetics of zolmitriptan and its metabolites were dose proportional. Although area under the concentration-time curve (AUC0-infinity) and maximum concentration (Cmax) were slightly higher in patients with hypertension at all doses, this was only statistically significant for AUC at the 20-mg dose. Differences between subjects with and without hypertension were not clinically significant. Zolmitriptan produced a small increase in blood pressure, but this was similar in subjects with and without hypertension and was of no clinical significance. Zolmitriptan was well tolerated in both groups. Zolmitriptan plasma concentrations were higher in women than in men, with higher values of AUC and Cmax and lower total clearance in women. These results indicate that zolmitriptan can be administered for treatment of migraine in patients with controlled hypertension without dose adjustment.

Zolmitriptan (311C90) does not interact with fluoxetine in healthy volunteers.

Zolmitriptan (Zomig, formerly 311C90) is a selective 5-hydroxytryptamine (5-HT)1B/1D-receptor agonist with central and peripheral activity for the acute treatment of migraine. This randomized, placebo-controlled, crossover study investigated the effects of fluoxetine administration on the pharmacokinetics and pharmacodynamics of zolmitriptan. Twenty volunteers were given single doses of fluoxetine 20 mg or an identical placebo daily for 28 days prior to receiving a single 10 mg oral dose of zolmitriptan. Sixteen volunteers completed the two treatment phases. The pharmacokinetic parameters of zolmitriptan and its metabolites were not significantly affected by fluoxetine pretreatment. The pharmacodynamic effects of zolmitriptan were also unaffected by fluoxetine pretreatment. There were small, clinically insignificant increases in blood pressure following zolmitriptan which were unaltered by fluoxetine. Zolmitriptan was well tolerated when given alone or concomitantly with fluoxetine. These results indicate that there is no contraindication to the use of zolmitriptan in patients treated concurrently with selective serotonin reuptake inhibitors and that no adjustment of the zolmitriptan dose is required in these circumstances.

Early transvaginal ultrasound following an accurately dated pregnancy: the importance of finding a yolk sac or fetal heart motion.

Our goals were to determine the prognostic value of a yolk sac or fetal heart motion seen during an early accurately dated transvaginal ultrasound (TVU). We reviewed 225 consecutive pregnancies for fetal heart motion data. Furthermore, 63 pregnancies following in-vitro fertilization were reviewed for yolk sac information. The TVU was performed between 5 and 6 weeks following presumed conception (heart motion data) and between 22 and 32 days following in-vitro fertilization (yolk sac data). Pregnancies were followed until an ongoing pregnancy or spontaneous abortion was documented. The presence of a yolk sac between 22 and 32 days from fertilization was associated with the development of fetal heart motion in 94% of cases. The absence of the yolk sac by 32 days after fertilization was always associated with a poor outcome. In women < 36 years of age, the presence of fetal heart motion was associated with a spontaneous abortion in only 4.5% of the cases. However, the incidence of spontaneous abortion following fetal heart motion increased to 10% in women 36-39 years and 29% in women > or = 40 years of age. The presence of heart motion should not be considered a reassuring sign in the older woman. These data have implications regarding early embryology and the counselling of infertility patients.

Pituitary response to early follicular-phase minidose gonadotropin releasing hormone agonist (GnRHa) therapy: evidence for a second flare.

PURPOSE: Our purpose was to determine the pituitary response to minidose follicular-phase GnRHa and see if a second flare can be achieved. METHOD: A prospective, consecutive series of 12 couples with tubal-factor infertility underwent 14 cycles of minidose GnRHa. Women were given a 25- or 50-migrograms dose of leuprolide acetate (LA) on cycle days 2 and 5. On cycle days 3 and 4 no LA was given but 2 ampoules of pure follicle stimulating hormone (FSH) was administered. Beginning day 6, a combination of LA and FSH was administered. RESULTS: Following a dose of only 25 micrograms of LA on cycle day 2, mean FSH, LH, and E2 levels were significantly elevated over the baseline levels. Following no LA on cycle day 3 or 4, a repeat dose of 25 micrograms LA caused a second flare of LH and E2 on cycle day 6. Of the 14 cycles, 6 were canceled because of poor stimulation. Two of the eight patients who underwent retrieval delivered a live birth. CONCLUSIONS: This is the first study to examine both the pituitary response and the recovery time from minidose follicular-phase GnRHa. An extremely small dose of LA is needed to cause a pituitary flare of gonadotropins. Following a flare from 25 micrograms of LA on cycle day 2, the pituitary is able to recover and respond with a repeat flare on cycle day 5.

Population pharmacodynamics of doxacurium.

The nonlinear mixed-effects modeling (NONMEM) computer program was used to investigate the variability in the duration of doxacurium-induced neuromuscular block in 408 patients enrolled in phase II and phase III clinical trials of doxacurium. Spontaneous recovery data in the 10% to 90% block range from all patients were pooled and fitted to a linear model. Two parameters were estimated: (1) the slope, which is related to the pharmacokinetics and to the steepness of the dose-response curve, and (2) the intercept, which is linearly related to dose but has no physiologic meaning. The primary goal was to determine the factors affecting the slope by use of univariate and multivariate analyses techniques. Estimates of the slope ranged from 0.67% to 1.1% block/min (interindividual variability, 39%). Factors with clinically significant effects on the slope included the following: age, obesity, and anesthesia type. Thus these factors influence the time course of doxacurium-induced block and may require individualization of dose.

A comparison of pharmacokinetic versus empirical lithium dosing techniques.

Three methods for estimating maintenance dosage requirements of lithium carbonate were retrospectively evaluated in 20 inpatients who met criteria of the Diagnostic and Statistical Manual, Third Edition, for "bipolar disorder, manic phase." Dosing methods evaluated included a pharmacokinetic method, the single-point method of Perry et al.; a population-based nomogram approach, the Zetin et al. method; and a physician-based empirical dosing procedure. The ability of each dosing procedure to produce dosing recommendations that resulted in a targeted steady-state serum lithium concentration was evaluated. The empirical dosing procedure demonstrated a significant tendency (bias) to underestimate the dose necessary to produce a desired steady-state serum lithium concentration. Comparison of the predictive accuracy of the various dosing methods failed to demonstrate any statistically significant differences among the dosing procedures. There was a strong trend, however, for the Perry method to produce predictions of steady-state lithium levels that were more frequently within 0.2 mEq/L of actual levels.

Comparison of pharmacokinetic procedures for dosing lithium based on analysis of prediction error.

Five pharmacokinetic methods for estimating maintenance dosage requirements of lithium carbonate were compared retrospectively in 20 inpatients with acute bipolar illness. Specific pharmacokinetic methods tested included the method of Cooper, the multiple-point method of Perry, the single-point method of Perry, the method of Zetin, and the method of Pepin. Data analysis was based on evaluation of prediction error or the difference between the predicted steady-state lithium concentration and the measured steady-state lithium concentration at equivalent daily doses. Each dosing method was assessed in regard to accuracy and bias of predicted steady-state serum lithium concentrations. Bias was assessed by comparison of the median value of the prediction error with zero. The dosing recommendation based on the Cooper nomogram resulted in a significant positive bias (p less than or equal to 0.05). Intermethod accuracy was assessed by comparison of the absolute prediction errors of each dosing method. Significant differences in accuracy were observed between the method of Pepin when compared with the single-point method of Perry (p less than or equal to 0.05, k-sample sign test). All other comparisons were nonsignificant.