The influence of heparin on the prothrombin time.

We studied the effect of known concentrations of heparin on the prothrombin time (PT) in patients receiving warfarin and in controls who were not anticoagulated. Plasma from the subjects and controls was serially diluted with known concentrations of heparin, and PT was measured. Linear regression of heparin concentration versus percentage change in PT resulted in r = 0.86 in the warfarin group and r = 0.72 in the control group. The warfarin group was more sensitive to the effects of heparin than the control group, as manifested by a steeper slope of the regression line (p less than 0.001). Over the therapeutic range of heparin concentration (0.2-0.4 units/ml), the 95% prediction interval of the percentage change in PT was -6-12% at 0.2 units/ml, and 2-20% at 0.4 units/ml in the warfarin group. These results demonstrate a strong relationship between the heparin concentration in plasma and the percentage change in the PT. This effect should be considered when adding warfarin to the regime of patients receiving heparin therapy.

Norepinephrine is a possible neurotransmitter stimulating pulsatile release of luteinizing hormone-releasing hormone in the rhesus monkey.

The hypothesis that norepinephrine (NE) plays a facilitatory role in controlling the pulsatile release of LHRH was tested with a modified push-pull perfusion technique in conscious rhesus monkeys. The in vivo LHRH release in perfusate samples collected from the stalk-median eminence of ovariectomized females was pulsatile and synchronous with pulsatile LH release. Catecholamines measured in aliquots of perfusate samples revealed that in vivo NE release was also pulsatile and was synchronous with LHRH release. Local infusion of NE or methoxamine (an alpha 1-adrenergic stimulant) through a push cannula stimulated LHRH release, while iv injection of prazosin (an alpha 1-adrenergic blocker) suppressed LHRH release. It is concluded that NE is a possible neurotransmitter stimulating pulsatile LHRH release.

Posterior hypothalamic lesions advance the time of the pubertal changes in luteinizing hormone release in ovariectomized female rhesus monkeys.

To examine further the relationship between developmental changes in LH release and the onset of puberty, effects of posterior hypothalamic lesions were tested in ovariectomized (OVX), sexually immature female monkeys. In OVX females (n = 3) with sham hypothalamic lesions basal LH levels were suppressed during the prepubertal period until 25 months of age, when LH levels started to increase. The increase in basal LH continued; a 100% elevation from prepubertal levels was attained at 26.0 +/- 0 months of age, and a 200% elevation was attained at 31.0 +/- 3.2 months of age. A consistent appearance of LH circadian fluctuation (nocturnal LH increase) with a large amplitude accompanied the initial LH increase. Lesions of the posterior hypothalamus (PH) in OVX animals (n = 6) at 17-18 months of age, which we previously reported to be effective in advancing the onset of puberty by several months in ovarian intact monkeys, resulted in an early 100% increase in basal LH levels and the circadian LH fluctuation (19.5 +/- 1.0 months of age). Basal LH levels in these animals further increased, reaching a 200% elevation of prelesion levels at 24.2 +/- 0.7 months of age. All of these LH changes with PH lesions occurred significantly (P less than 0.01) earlier than those in sham-lesioned animals. Lesion of the PH in OVX animals (n = 4) at 13-14 months of age resulted in an increase in LH and the circadian LH fluctuation within 1 month postoperatively. However, 100% and 200% LH elevations did not occur until 20.8 +/- 1.0 and 24.8 +/- 1.4 months of age, respectively. These ages were similar to those of animals receiving lesions at 17-18 months of age, but much younger than those of sham controls (P less than 0.01). PH lesions in animals at 13-14 months of age also advanced the time of the first positive feedback effects of estrogen. In animals (n = 4) with PH lesions, estradiol benzoate induced a first LH response at 21.5 +/- 1.6 months of age, when basal LH was 276 +/- 83% increased from prelesion levels. This age was significantly (P less than 0.05) younger than that (29.3 +/- 1.9 months; n = 6) of the first LH surge induced by estrogen in control animals when basal LH levels attained 248 +/- 18% of prepubertal levels.(ABSTRACT TRUNCATED AT 400 WORDS)

Esmolol hydrochloride: an ultrashort-acting, beta-adrenergic blocking agent.

The chemistry, pharmacology, pharmacokinetics, hemodynamic and electrophysiologic effects, clinical efficacy, adverse effects, drug interactions, compatibility and stability, dosage, and administration of esmolol hydrochloride are reviewed. Esmolol produces competitive blockade of beta receptors in both animals and humans. It does not possess membrane-stabilizing, intrinsic sympathomimetic, or alpha-adrenergic blocking activity. The relative cardioselectivity of esmolol is similar to that of metoprolol. Esterase metabolism accounts for the rapid total body clearance of 285 mL/kg/min and elimination half-life of 9.2 minutes. Its rapid metabolism following continuous intravenous infusion results in the rapid offset of pharmacologic effect after drug administration is discontinued. In patients with supraventricular tachyarrhythmias, esmolol produces rapid control of heart rate in an average effective dosage range from 97.2 to 115.0 micrograms/kg/min and effects that are similar to propranolol. Esmolol is effective and safe in managing tachycardia and hypertension during surgical stress and may be useful in postoperative hypertension or elevated heart rates during myocardial ischemia. Esmolol does not appear to interact with digoxin, morphine, warfarin, or succinylcholine to any clinically important extent. The most frequent adverse effects associated with esmolol infusion are hypotension and phlebitis. Hypotension can be avoided by careful titration, and if encountered, it can be rapidly resolved by dosage adjustment or discontinuation of the infusion. The ultrashort half-life and duration of action of esmolol may allow safer application of beta blockade in critically ill patients.

Factors influencing the progesterone-induced luteinizing hormone surge in rhesus monkeys: diurnal influence and time interval after estrogen.

In the rhesus monkey, progesterone (P) given after a small dose of estradiol benzoate (EB) induces a luteinizing hormone (LH) surge with a short latency and short duration (Terasawa et al., 1982). In the present study, effects of P injection in relation to the interval after EB and to the time of day were investigated. Nine long-term ovariectomized female rhesus monkeys (which were implanted with an estradiol-17 beta (E2) capsule 2 wk prior to the experiments) were injected with EB (10 micrograms) and P (2.5 mg). In order to determine the period of estrogen priming necessary to induce the facilitatory effects of P, P was injected at 30, 24, 12 or 0 h after EB in the first four experiments. The time of EB injections was fixed at 0830 h. To determine whether there is any diurnal influence on the action of P, the EB injection was moved to 2030 h, followed by P 30 h later. Administration of P 30 h after EB induced a typical LH surge with peak latency (6.7 +/- 0.5 h) and duration (16.0 +/- 1.4 h) in all animals. Similarly, P injection 24 h after EB induced a LH surge with peak latency (7.4 +/- 0.4 h) and duration (18.0 +/- 1.2 h) in all animals. The amplitudes of the P-induced LH surges at both 30 h and 24 h after EB were also similar (P 30 h; 65.0 +/- 18.7 ng/ml, P 24 h; 59.8 +/- 24.4 ng/ml). In contrast, administration of P 12 h or 0 h after EB resulted in a LH surge in only 4 and 3 of 9 animals, respectively, and these numbers of responders were significantly less (P 12 h: P=0.0147, P 0 h: P=0.0045) than those of P 30 h and P 24 h. The amplitudes of the LH surge in animals responding to P 12 h and P 0 h after EB were much smaller than those of P 30 and P 24 h after EB (P less than 0.01), although the peak latency and duration of the response were similar. Overall responses to P 12 h and P 0 h after EB were significantly (P less than 0.005) different from those of P 30 h and P 24 h after EB. A 12-h shift of the injection time of both EB and P did not alter the LH response. Reversed timing of EB and P injections induced a LH surge with peak latency, 7.7 +/- 0.5 h; duration, 16.3 +/- 1.7 h; and amplitude, 59.2 +/- 20.7 ng/ml. These results indicate that 1) P injection 24 h or 30 h after EB reliably induces a LH surge with a short latency and duration, 2) P injection 12 h or 0 h after EB is not effective in inducing a LH surge, and 3) there is no diurnal influence on the P-induced LH surge. Therefore, the time interval of estrogen priming required for progesterone action in the rhesus monkey is similar to that required in rodents for LH release as well as for lordosis behavior.(ABSTRACT TRUNCATED AT 400 WORDS)