Timothy J. Hoon

Acute myocardial infarction associated with prostaglandin

Prostaglandin E2 is rarely associated with serious maternal side effects when used for second-trimester pregnancy termination. Acute myocardial infarction complicating therapeutic pregnancy termination with prostaglandin E2 in a patient with chronic glomerulosclerosis and severe hypertension is reported.

The pharmacodynamic and pharmacokinetic differences of the D- and L-isomers of verapamil: Implications in the treatment of paroxysmal supraventricular tachycardia

There is increasing interest in defining the pharmacodynamic and pharmacokinetic characteristics of drugs that are marketed as racemic mixtures. Verapamil is one such drug that is commercially available as a mixture of D- and L-isomers. The L-isomer of verapamil has a greater-negative inotropic, negative chronotropic, and negative dromotropic potency than the D-isomer. The values for fraction unbound in serum, distribution volume, and systemic clearance are substantially greater for the L-isomer after intravenous dosing. After oral dosing, the D-isomer achieves peak plasma concentrations five times greater than the L-isomer. The pharmacodynamic and pharmacokinetic characteristics of each isomer are reviewed. The differences in the concentrations of the D- and L-isomers after oral vs intravenous dosing may contribute to the relatively lower efficacy of orally administered verapamil in the treatment of PSVT.

Impact of food on the pharmacokinetics and electrocardiographic effects of sustained release verapamil in normal subjects

To evaluate the impact of food on the pharmacokinetics and electrocardiographic effects of sustained release (SR) verapamil tablets, 9 healthy men each received 3 single doses of verapamil in a randomized, crossover manner: 10 mg of intravenous verapamil, 240 mg SR verapamil on an empty stomach, and 240 mg SR verapamil with a standardized meal. PR intervals and racemic verapamil serum concentrations were measured serially over 30 hours after administration. The time to peak concentration was longer (7.5 +/- 3.0 vs 4.4 +/- 2.3 hours), resulting in a lower peak verapamil serum concentration (118 +/- 43 vs 175 +/- 50 ng/ml) when SR verapamil was administered with food (p < 0.05). Food tended to decrease the bioavailability of SR verapamil (34 +/- 12 vs 49 +/- 14%), although this difference did not reach statistical significance (p = 0.065). Precipitous or exaggerated release of verapamil from the SR tablet was not observed in any subject during the fasting state. Prolongation of the PR interval paralleled these alterations in serum concentration. The maximal change in the PR interval was greater (21 +/- 8 vs 14 +/- 5%; p < 0.05) when SR verapamil was given in the fasting state. Although an exaggerated verapamil release or effect was not observed, food significantly altered the absorption and electrocardiographic effects of a single dose of SR verapamil. Manipulation of the administration condition may be helpful in achieving desired outcomes.

Bioequivalence of a 17β‐Estradiol Hydroxypropyl‐β‐Cyclodextrin Complex in Postmenopausal Women

Five postmenopausal women received single doses of a 0.675 mg estradiol hydroxypropyl‐β‐cyclodextrin (estradiol‐HPβCD) sublingual tablet by the sublingual and oral route. A single dose of a 1 mg micronized estradiol tablet was given orally for comparison. Blood samples were obtained over 48 hours for measurement of estradiol, estrone, luteinizing hormone (LH) and follicle‐stimulating hormone (FSH) concentrations. Sublingual administration produced faster and significantly higher peak estradiol concentrations than after oral administration of either estradiol‐HPβCD or micronized estradiol. The concentration‐time area under the curve of estradiol after sublingual estradiol‐HPβCD was also significantly larger than after oral administration of either estradiol‐HPβCD or micronized estradiol, reflecting a larger estradiol bioavailability. The estradiol/estrone concentration ratio after sublingual estradiol‐HPβCD revealed a predominance of estradiol for the first 2 hours after the dose, followed by an estrone predominance. Both oral doses produced a predominant delivery of estrone to the systemic circulation. There was no difference in time‐averaged LH suppression between the three phases. However, estradiol‐HPβCD sublingually produced greater FSH suppression than oral micronized estradiol.

Evaluation of drug therapy for treatment of hypertensive urgencies in the emergency department

Oral nifedipine (N) and clonidine (C) are often used in the treatment of hypertensive urgencies; however, until recently, there were no comparative studies using the same patient population. The authors reviewed the records of hypertensive patients treated in the emergency department between October 1, 1987 and September 30, 1988. Selected patients had a diastolic blood pressure (DBP) of greater than 115 mm Hg without evidence of acute end organ damage. Patients were stratified into three treatment groups: N, C, and group 3 (G3). G3 received a variety of drug therapies but not exclusively N or C. Systolic blood pressure (SBP), DBP, mean arterial pressure (MAP), percent decrease in MAP (%MAP), time to lower blood pressure, admissions, and discharges were evaluated. Efficacy and safety were defined as reaching a DBP less than 110 mm Hg but %MAP of no greater than either 25% or 40%, respectively. Thirty-five N, 32 C, and 27 G3 patients were identified with no statistical difference between groups in race, gender, pretreatment SBP, DBP, or MAP. N, C, and G3 significantly reduced SBP, DBP, and MAP (P less than .01). Comparing N, C, and G3, no differences were observed in %MAP, admissions, discharges, efficacy, or safety. Time required to decrease blood pressure differed between all three groups (44 +/- 32 N v 77 +/- 57 C v 152 +/- 94 min G3) (p less than .05). These results indicate that N, C, and a variety of drug therapies are equally effective and safe in the treatment of hypertensive urgencies.

Angiotensin-converting enzyme inhibitor use in survivors of acute myocardial infarction

Abstract The present study found that a significant percentage of patients with myocardial infarction, who according to the results of large-scale clinical trials should benefit from ACE inhibitor therapy, did not receive such treatment at discharge.

Serum nifedipine concentrations and response of patients with pulmonary hypertension.

In patients with primary pulmonary hypertension who respond to nifedipine during acute drug testing, there is a significant linear correlation of serum nifedipine concentration with pulmonary artery pressure and resistance. Although most demonstrate an initial response at readily attainable nifedipine concentrations with conventional dosages, a subset of patients seem to display delayed or incomplete oral absorption; these results may facilitate the clinical use of nifedipine in patients with primary pulmonary hypertension.

Comparison of the Pharmacokinetics and Electrocardiographic Effects of Sublingual and Intravenous Verapamil

Using a dog model, a sublingual form of the free base of verapamil (SLV) was developed with the intent of avoiding stereoselective first‐pass metabolism and the necessity of intravenous administration. Intravenous verapamil (IVV) 5 mg and SLV 40 mg or 60 mg were sequentially administered to seven healthy human volunteers. Electrocardiograms and serum concentrations were obtained before and periodically from 5 to 480 minutes after each dose. The time to peak serum concentration (mean ± SD) was 77.6 ± 38.1 minutes after SLV. Bioavailability of SLV was 58.2 ± 36.9% compared to IVV. Verapamil half‐lives after IVV and SLV were 2.83 ± 0.93 and 2.28 ± 0.45 hours (NS), respectively. In one subject, the time to peak effect was delayed and overall change in PR interval was minimum. In the remaining six subjects, the maximum percentage increases in PR interval after IVV and SLV were 20.6 ± 6.4% and 14.8 ± 5.5% (p<0.05), respectively. Times to peak increase in PR interval were 28.3 ± 15.7 and 57.0 ± 17.5 minutes after IVV and SLV (p<0.05), respectively. Analysis of plots of percentage change in PR interval versus serum concentration revealed a shift to the right and therefore, lesser effect of SLV than of IVV in six subjects. All seven subjects complained of oral numbness and bitter taste. In conclusion, SLV is inferior to IVV in terms of rate and extent of absorption and pharmacologic effect in delaying atrioventricular nodal conduction. Probably SLV has little clinical utility because of its slow onset and poor tolerance.

EVALUATION OF THE PHARMACOKINETICS AND ELECTROCARDIOGRAPHIC EFFECTS OF INTRAVENOUS VERAPAMIL WITH INTRAVENOUS CALCIUM CHLORIDE PRETREATMENT IN NORMAL SUBJECTS

To evaluate the effects of calcium pretreatment on the disposition and electrocardiographic effects of verapamil, 8 healthy male volunteers received treatment in each of 3 phases in a randomized, double-blind, crossover manner. Phase I denoted 10 ml of 0.9% intravenous sodium chloride followed by 10 mg of intravenous verapamil; phase II denoted 10 ml of 10% intravenous calcium chloride followed by 4 ml of 0.9% intravenous sodium chloride; and phase III denoted 10 ml of 10% intravenous calcium chloride followed by 10 mg of intravenous verapamil. Blood samples for the determination of verapamil concentrations were drawn at 5, 10, 15, 20, 30, 45, 60 and 90 minutes, and at 2, 4, 6, 10 and 24 hours. Blood pressure, heart rate and PR intervals were also measured at these times. Pretreatment of verapamil with intravenous calcium did not alter the disposition of intravenous verapamil. Blood pressure was not significantly altered in any treatment phase, although calcium tended to increase mean arterial pressure and verapamil abolished this effect. Calcium had no significant affect on verapamil-induced PR prolongation (maximum percent change in PR interval: phase I = 19 +/- 11%, phase III = 18 +/- 7%; time to maximal prolongation: phase I = 0.38 +/- 0.21 hours, phase III = 0.37 +/- 0.26 hours; and area under the percent change in PR vs time curve: phase I = 15.5 +/- 10, phase III = 21 +/- 9). Verapamil caused a reflex increase in heart rate of similar magnitude in both phases I and III (24 +/- 10% and 21 +/- 7%, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Bioavailability of total and unbound disopyramide : implications for clinical use of the immediate and controlled-release dosage forms

This study further characterized the impact of concentration‐dependent protein binding on the bioavailability and clinical use of the immediate‐release (IR) and controlled‐release (CR) dosage forms of disopyramide after single doses and during steady‐state conditions in ten healthy volunteers. Consistent with the clinical use of these products, steady state has incorporated an IR to CR conversion step. Side effects and electrocardiographic actions were quantitated using a visual analog scale and serial Holter monitor recordings, respectively. Significant decreases resulted in area under the curve for total disopyramide between single dose and steady state: IR, 47.8 ± 13.6 versus 33.0 ± 6.4 mg/Lxh (P < .05); and CR, 46.9 ± 9.5 versus 31.7 ± 5.9 mg/Lxh (P < .05). In contrast, there were no differences in area under the curve for unbound disopyramide between phases or products. During conversion, the mean IR peak significantly decreased (P < .05) to the nadir before the first CR dose for total (37%) and unbound (60%) concentrations. There were no major differences in change in QT interval or side effects detected between products or phases. These findings indicate that, because of concentration‐dependent protein binding, unbound, not total, concentrations should be used to estimate the bioavailability of disopyramide. Also, although the previously recommended conversion method (first CR dose 6 hours after the last IR dose) should provide an adequate transition in most, an alternative method (combined first CR with last IR dose) is indicated in select patients.