Prostaglandin receptor site: evidence for an essential role in the action of luteinizing hormone.

A dose-response relation was established between prostaglandins and formation of adenosine 3',5'-monophosphate in the mouse ovary. The prostaglandin antagonist, 7-oxa-13-prostynoic acid, blocked the stimulatory effect of prostaglandin E(1), prostaglandin E(2), and luteinizing hormone on adenosine 3',5'-monophosphate formation in a competitive manner. Kinetic studies made it possible to suggest that there is a single luteinizing-hormone-related prostaglandin receptor in mouse ovaries, and that activation of this prostaglandin receptor is an essential requirement in the action of luteinizing hormone to stimulate adenosine 3',5'-monophosphate formation and steroidogenesis.

Enhancement of uricosuric properties of indacrinone by manipulation of the enantiomer ratio.

Racemic indacrinone is a high-ceiling, relatively long-acting diuretic. Both enantiomers have uricosuric activity, but the diuretic activity resides predominantly in the (-) enantiomer. Usual therapeutic doses of racemic indacrinone have only transient uricosuric activity, so that, as with other diuretics, hyperuricemia occurs. Sixty-five healthy men participated in a multicenter, double-blind, randomized, balanced, incomplete-block study comparing the effects on plasma urate and urate clearance of indacrinone (-) enantiomer 10 mg given concomitantly with 0, 10, 20, 40, and 80 mg (+) enantiomer (10/0, 10/10, 10/20, 10/40, 10/80), as single daily doses for 7 days. Hydrochlorothiazide (HCTZ) 50 mg daily and ticrynafen (T) 250 mg daily were controls. Each subject received two of the seven treatments, so that there were 18 subjects per treatment. On days 7 to 8, morning (mean of 0-hr values on days 7 and 8), HCTZ, 10/0, 10/10, and 10/20 elevated plasma urate by 8% to 16%. 10/40 was approximately isouricemic, and 10/80 and T lowered plasma urate by 13% and 41%. There were corresponding changes in urate clearance.

Enalapril: a review of human pharmacology.

Enalapril, an orally-active, long-acting, nonsulphydryl angiotensin-converting enzyme (ACE) inhibitor, is extensively hydrolysed in vivo to enalaprilat, its bioactive form. Bioactivation probably occurs in the liver. Metabolism beyond activation to enalaprilat is not observed in man. Administration with food does not affect the bioavailability of enalapril; excretion of enalapril and enalaprilat is primarily renal. Peak serum enalaprilat concentrations are reached 4 hours post-dose, and the profile is polyphasic with a prolonged terminal half-life (greater than 30 hours) due to the binding of enalaprilat to ACE. Steady-state is achieved by the fourth daily dose, with no evidence of accumulation. The effective accumulation half-life following multiple dosing is 11 hours. Higher serum concentrations and delayed urinary excretion occur in patients with severe renal insufficiency. Enalapril reduces blood pressure in hypertensive patients by decreasing systemic vascular resistance. The blood pressure reduction is not accompanied by an increase in heart rate. Furthermore, cardiac output is slightly increased and cardiovascular reflexes are not impaired. Once- and twice-daily dosage regimens reduce blood pressure to a similar extent. Enalapril increases renal blood flow and decreases renal vascular resistance. Enalapril also augments the glomerular filtration rate in patients with a glomerular filtration rate less than 80 ml/min. Enalapril reduces left ventricular mass, and does not affect cardiac function or myocardial perfusion during exercise. There is no rebound hypertension after enalapril therapy is stopped. Enalapril does not produce hypokalaemia, hyperglycaemia, hyperuricaemia or hypercholesterolaemia. When combined with hydrochlorothiazide, enalapril attenuates the undesirable diuretic-induced metabolic changes. Therapeutic doses of enalapril do not affect serum prolactin and plasma cortisol in healthy volunteers or T3, rT3, T4 and TSH in hypertensive patients. Enalapril has natriuretic and uricosuric properties. The antihypertensive effect of enalapril is potentiated by hydrochlorothiazide, timolol and methyldopa, but unaffected by indomethacin and sulindac. No interactions occur between enalapril and frusemide, hydrochlorothiazide, digoxin and warfarin. The bioavailability of enalapril is slightly reduced when propranolol is coadministered, but this does not appear to be of any clinical significance. Enalapril increases cardiac output and stroke volume and decreases pulmonary capillary wedge pressure in patients with congestive heart failure refractory to conventional treatment with digitalis and diuretics.(ABSTRACT TRUNCATED AT 400 WORDS)

The chemistry, pharmacology and clinical pharmacology of diflunisal.

Studies are reviewed on diflunisal, a new analgesic agent with an improved therapeutic index, compared with acetylsalicylic acid, in animals and humans. Pharmacokinetic data indicate that a twice-daily dosage regimen of diflunisal is adequate for therapeutic purposes. Diflunisal inhibits prostaglandin E synthesis, but in humans at clinically effective doses it does not alter bleeding time or platelet aggregation. Diflunisal is uricosuric at clinically effective doses. No clinically important drug interactions with diflunisal have been found to date, although some slight alterations in blood and urine drug levels have been noted. The slight increase in prothrombin time seen when diflunisal and acenocoumarol were co-administered is not considered to be of major clinical importance.

Enalapril in congestive heart failure: acute and chronic invasive hemodynamic evaluation.

Following hemodynamic evaluation using invasive and noninvasive methods, 73 patients were treated in an open, uncontrolled, multicenter study with single oral doses of enalapril maleate 1.25 to 40 mg until the optimal dose for each patient (based upon hemodynamic response) was achieved. Diuretics were withheld and reinstituted only if necessary. Hemodynamic measurements were made at 0 (predrug), 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours postdrug. Patients were discharged on their optimal dose, treated 1 to 4 months and then rehospitalized for repeat hemodynamic measurements. The optimal enalapril single dose was associated with the following mean peak responses: increased cardiac index 42% (SE = 6) and decreased pulmonary capillary wedge pressure 40% (SE = 3), systemic vascular resistance 39% (SE = 2), and mean arterial pressure 23% (SE = 1.5). These changes persisted during chronic therapy. Chronic treatment with enalapril also improved exercise capacity 40% (P less than 0.01), ejection fraction 18% (P less than 0.05) and clinical status (N.Y.H.A. functional class, P less than 0.01). Ten and 20 mg/day, taken as once- or twice-daily regimens, were the most commonly effective doses.

The clinical pharmacology of enalapril.

Enalapril, a long-acting, non-sulfhydryl, angiotensin converting enzyme (ACE) inhibitor, is well absorbed after oral administration, and hydrolised to its bioactive form, enalaprilic acid (EA). Administration with food does not affect its bioavailability; elimination is predominantly renal. Peak serum EA concentrations occur 4 h after an oral dose; its serum half-life is approximately 35 h, and steady state is achieved by the fourth day of treatment. Enalapril controls blood pressure in essential and renovascular hypertension without affecting heart rate or cardiovascular reflexes. It also decreases serum concentrations of ACE (for greater than 24 h), angiotensin II and aldosterone, and increases plasma renin activity. Once and twice-daily regimens are equally effective. In patients with congestive heart failure refractory to digitalis and diuretics, enalapril increases cardiac output and decreases pulmonary capillary wedge pressure. Long-term treatment produces improvement in NYHA functional classification, exercise capacity and ejection fraction. Human experience to date indicates that enalapril is safe and well tolerated.

Birth control in nineteenth-century America: a view from three contemporaries.

Social, philosophical and technical aspects of birth control in nineteenth-century America are examined through the lives and thoughts of three men who lived and worked at that time: John Humphrey Noyes, Anthony Comstock and Edward Bliss Foote.

Pharmacology and therapeutic use of antihistamines.

The classes of antihistaminic agents, their pharmacology and therapeutic uses, adverse effects, drug interactions, toxic overdoses and abuse are reviewed. It is concluded that antihistamines are valuable drugs for treating a number of conditions and diseases (e.g. allergic rhinitis, motion sickness and parkinsonism), but proof of efficacy has not been established for the treatment of cardiac arrhythmias, peptic ulcers, insomnia and headaches. Because responses to antihistamines may vary, titration of each patient's dose is recommended.

The clinical pharmacology of lisinopril.

Lisinopril is an orally active, nonsulfhydryl angiotensin-converting-enzyme (ACE) inhibitor that is not metabolized or bound to protein. Peak serum concentrations occur 6-8 h after oral dosing. Lisinopril bioavailability (approximately 25%) is not significantly affected by food, age, or coadministration of hydrochlorothiazide (HCTZ), propranolol, digoxin, and glibenclamide. Lisinopril is excreted unchanged in the urine. Steady state is achieved in 2-3 days with little accumulation. Significant accumulation occurs in patients with severe renal impairment (creatinine clearance less than or equal to 30 ml/min). Lisinopril inhibits ACE activity, thereby reducing plasma angiotensin II and aldosterone and increasing plasma renin activity. Lisinopril produces a smooth, gradual blood pressure (BP) reduction in hypertensive patients without affecting heart rate or cardiovascular reflexes. The antihypertensive effect begins within 2 h, peaks around 6 h, and lasts for at least 24 h. Lisinopril produces greater systolic and diastolic BP reductions than HCTZ. Lisinopril is similar to atenolol and metoprolol in reducing diastolic BP, but superior in systolic BP reduction. Lisinopril and nifedipine produce comparable reductions in systolic and diastolic BP. When lisinopril is given once daily as monotherapy, the range of BP reductions is 11-15% in systolic and 13-17% in diastolic. HCTZ addition enhances its antihypertensive effect. Lisinopril does not produce hypokalemia, hyperglycemia, hyperuricemia, or hypercholesterolemia. Lisinopril has natriuretic properties; renal blood flow remains stable or increases. Lisinopril increases cardiac output, and decreases pulmonary capillary wedge pressure and mean arterial pressure in patients with congestive heart failure refractory to conventional treatment with digitalis and diuretics. Human experience to date (2,800 patients/subjects) indicates that lisinopril is well tolerated and has a good safety profile.

Enalapril: benefit-to-risk ratio in hypertensive patients.

Enalapril is an effective agent in the treatment of mild to severe hypertension. It is equally effective in elderly and young adult patients but appears to be more effective in white than in black hypertensive patients. Following treatment with enalapril, an assessment of maximum exercise performance found a decrease in total peripheral resistance without significant changes in cardiac output, heart rate, or stroke volume compared with pretreatment values. In addition, there have been reports of reversal of left ventricular hypertrophy in enalapril-treated hypertensive patients. Enalapril is also effective and well tolerated in hypertensive patients with renal impairment of varying etiology. The most common adverse experiences reported in controlled clinical trials were headache (5.2%), dizziness (4.3%), and fatigue (3.0%). In high-risk hypertensive patients, no enalapril-treated neutropenia, proteinuria, dysgeusia, or ageusia were reported. It may be concluded that the benefit-to-risk ratio of enalapril is among the best of the antihypertensive therapies currently available.

A comparison of hypotensive responses after oral and intravenous administration of enalapril and lisinopril in chronic heart failure.

The acute hypotensive response to oral and parenteral enalapril (E) and lisinopril (LI) was assessed in 24 patients with chronic congestive heart failure in two open, randomized, balanced, crossover studies. In the E study, 12 patients received each of three treatments: a single oral dose of 10 mg E, a single intravenous bolus of 5 mg E, and a single intravenous bolus of 5 mg enalaprilat (ET). In the LI study, 12 patients received each of two treatments: a single oral dose of 10 mg LI and a single intravenous bolus of 5 mg LI. Intraarterial blood pressure was measured continuously. Significant decreases from baseline in mean arterial pressure (MAP) were observed in all cases, starting at 15 min. The maximal hypotensive effect (MAP; mean +/- SD) was greatest and the nadir earliest for intravenous ET (-30 +/- 7 mm Hg at 75 min) compared with oral E (-25 +/- 10 mm Hg at 210 min) and intravenous E (-19 +/- 10 mm Hg at 195 min). Oral E and intravenous E had similar onsets of action. The maximal reduction following oral LI (-19 +/- 13 mm Hg at 210 min) was similar to oral E and intravenous E. The effect of intravenous LI (-25 +/- 9 mm Hg at 105 min) was similar to that of intravenous ET. Among the parenteral treatments, E produced the most gradual and least pronounced reduction in blood pressure, and may be best suited for use in the acute situation to minimize the risk of abrupt hypotension.(ABSTRACT TRUNCATED AT 250 WORDS)

Estrogen-directed synthesis of specific prostaglandins in uterus.

Endogenous uterine prostaglandin levels were monitored in the cycling rat and prostaglandins of the F-type were found to rise at proestrus when estrogen levels have been shown to be maximal. Evidence that this is an estrogen-induced event is furnished by the finding that estradiol-17beta caused a similar rise in prostaglandin F levels in uteri of ovariectomized rats, an action blocked by coadministration of progesterone. Examination of in vitro prostaglandin synthetase by uterine microsomal fractions from cycling rats and estrogen-treated ovariectomized rats revealed that the action of estrogen to control prostaglandin synthesis in a directional manner is accomplished, at least in part, by regulation of the prostaglandin synthetase complex, resulting in a patterned alteration in the ratio of prostaglandin F to prostaglandin E. These results demonstrate that prostaglandins are involved in the expression of estrogen action in the rat uterus.

Absence of a pharmacokinetic interaction between enalapril and frusemide.

Single doses of enalapril maleate 10 mg and frusemide 80 mg do not significantly affect the pharmacokinetics of each other when taken concomitantly. Their concomitant use may be associated with more adverse effects than with the individual entities.

The regulatory role of steroid hormones on the PGF/PGE ratio in target tissues.

Estrogen has been found to regulate cyclic nucleotide and prostaglandin levels in the rat uterus. This action of estrogen is associated with a simultaneous rise in cyclic GMP and PFG levels. Alterations in PG levels are either independent of or secondary to the formation of cyclic GMP. The mechanism by which estrogen induces the rise in uterine PGFs, although not precisely defined, is associated with alterations of the enzymes rather than of the substrates involved with prostglandin synthesis.

Lisinopril: dose-peak effect relationship in essential hypertension.

1. The dose-peak effect relationship of lisinopril was evaluated in a double-blind, parallel study in 83 patients with mild to moderate essential hypertension (supine diastolic blood pressure = 95-115 mm Hg). 2. After a 4 week placebo washout, patients were randomly assigned to one of four treatments: lisinopril 2.5, 10, 20 or 80 mg day-1 for 1 week. 3. Lisinopril 10 and 20 mg day-1 produced similar peak antihypertensive effects which were greater than that produced by 2.5 mg day-1, but less than that of 80 mg day-1. If the incidence of first-dose symptomatic hypotension is related to the peak effect, then an initial lisinopril dose of 20 mg should not pose any greater risk than a 10 mg dose. 4. The magnitude of antihypertensive response at 24 h postdrug appeared to be dose related across the 2.5 to 80 mg day-1 range.

Effective dose range of enalapril in mild to moderate essential hypertension.

The dose-response relationship of enalapril was evaluated in a double-blind, balanced, two-period, incomplete-block study in 91 patients with mild to moderate essential hypertension. Patients were randomly assigned to two of six treatments: placebo, 2.5, 5, 10, 20 and 40 mg/day of enalapril maleate. There were two 3-week treatment periods, each preceded by a 4-week, single-blind placebo washout. Each dose of enalapril produced significant decreases in standing and supine systolic and diastolic blood pressure after 2 and 3 weeks of treatment. There were no significant changes on placebo. There was a significant linear dose response relationship for both mean blood pressure and mean change from baseline in blood pressure (P less than 0.01 for systolic and mean arterial pressure, and P less than 0.05 for diastolic pressure). Enalapril was associated with an increasing dose-response relationship across the 2.5-40 mg/day range. The 2.5 mg/dose is effective in some patients; however, doses greater than or equal to 10 mg/day may be necessary to achieve satisfactory blood pressure control.

The effect of enalapril on serum prolactin.

Twelve healthy male volunteers received single daily oral doses of enalapril (EN) 10 mg for 8 consecutive days. Serum samples for prolactin (PRL) assay were taken on day 0 (baseline) at 12.00 h and 16.00 h, and on days 1 and 8 at 08.00 h (pre-drug), 12.00 h and 16.00 h. The 08.00 h values on day 1 served as the pre-drug baseline. There were no significant changes from baseline in serum PRL levels on days 1 and 8. All mean serum PRL levels on day 8 were significantly (P less than 0.01) lower than the upper limit of the normal range (2-15 ng/ml) found for healthy males in this laboratory. It is concluded that therapeutic doses of EN (10 mg/day, p.o.) for 8 consecutive days do not raise mean serum PRL levels above the normal range in healthy male volunteers.

Lisinopril dose-response relationship in essential hypertension.

1. This was a multicentre, double-blind, parallel study in 216 patients with mild to moderate (supine diastolic blood pressure = 95-115 mm Hg) essential hypertension. 2. After a 4-week placebo washout, patients were randomized to placebo or lisinopril 1.25, 5.20 or 80 mg once daily for 6 consecutive weeks. Supine and erect blood pressure was measured 24 h postdose at the end of weeks -2, 0, 2, 4, and 6. 3. There was a linear dose-response relationship for both supine and erect blood pressure. Diastolic blood pressure reductions in the lisinopril 20 and 80 mg day-1 groups were significantly greater than in the placebo or lisinopril 1.25 and 5 mg day-1 groups. 4. Lisinopril, at doses up to 80 mg day-1, was well tolerated.

A double-blind comparison of a novel indanone diuretic (MK-196) with hydrochlorothiazide in the treatment of essential hypertension.

1 The antihypertensive effect and tolerability of MK-196 (10 mg and 15 mg daily) was compared to hydrochlorothiazide (HCT; 50 mg daily) in a 4-week multiclinic, double-blind study involving 42 patients with mild to moderate, essential hypertension. 2 Both doses of MK-196 were as effective and sometimes more effective than HCT in lowering standing and supine systolic and diastolic blood pressures. 3 HCT consistently brought about significant increases in serum uric acid and significant decreases in serum potassium; both doses of MK-196 produced similar but less frequent and smaller changes in both of these parameters. 4 Both doses of MK-196 brought about significant decreases in body weight at Weeks 3 and 4 of drug treatment. 5 Patients taking MK-196 reported fewer adverse clinical reactions (10 mg = 15%; 15 mg = 13% than those taking HCT (21%). 6 MK-196 may offer a therapeutic advantage over HCT as an antihypertensive agent for use in the treatment of mild to moderate, essential hypertension.