Sex differences in the intramuscular absorption and bioavailability of cephradine.

Six male and six female volunteers each received a single intramuscular injection of cephradine, a new cephalosporin antibiotic, once weekly for 3 consecutive weeks. The drug was injected into the gluteus maximus, vastus lateralis, or deltoid muscle groups. Injection sites were rotated each week so that each subject received an injection into each muscle. Pharmacokinetic evaluation of serum concentrations and urinary excretion data indicated a sex difference with respect to the rate and extent of cephradine absorption from the three injection sites. Smaller areas under the curve and absorption rate constants were observed for females after injection into each muscle group. The most striking difference was observed when cephradine was injected into the gluteus maximus muscle, where the exponential function describing the alpha phase was observed to be 1.16 +/- 0.17 hr(-1) for females and 2.70 +/- 0.34 hr(-1) for males. Total area under the mean serum concentration-time curves, mean time to peak, and peak height parameters consistent with the slower rate of absorption and lesser bioavailability in females were observed. These results show that the vastus lateralis or deltoid muscle groups are preferable to the gluteus maximus as injection sites because of the more rapid rates of drug absorption from those muscles.

Angiotensin converting enzyme inhibitors. (Mercaptoaroyl)amino acids.

A series of (mercaptoaroyl)amino acids and related compounds was synthesized and tested for ability to inhibit angiotensin converting enzyme (ACE). The most active compound was N-(3-chloro-2-mercaptobenzoyl)-N-cyclopentylglycine, having an in vitro I50 = 0.28 microM. Substitution of the aromatic 3-position by small polar groups enhanced ACE inhibitory activity, whereas bulky groups diminished it. Alteration of the beta relationship between the mercaptan and amide carbonyl or masking of the thiol by acylation reduced activity. Replacement of the thiol by nitro, hydroxy, or carboxy gave compounds lacking ACE inhibitory activity.

Synthesis and antiallergic activities of 1,3-oxazolo[4,5-h]quinolines.

A series of new 1,3-oxazolo[4,5-h]quinolines has been prepared. These compounds were tested as inhibitors of antigen-induced release of histamine (AIR) in vitro from rat peritoneal mast cells (RMC) and as inhibitors of IgE-mediated passive cutaneous anaphylaxis in the rat (PCA). After several modifications of the original lead, the most potent compound of the series was determined to be 5-chloro-1,3-oxazolo[4,5-h]quinoline-2-carboxylic acid methyl ester (4a). It has an IC50 of 0.3 microM in the RMC assay and an ED50 (intraperitoneal) of 0.1 mg/kg in the PCA test, which is 10 times and 60 times more potent than disodium cromoglycate (DSCG), respectively. Of greater importance, it is orally active (ED50 = 0.5 mg/kg) as an inhibitor of the PCA test.

Angiotensin-converting enzyme inhibitors: new orally active 1,4-thiazepine-2,5-diones, 1,4-thiazine-2,5-diones, and 1,4-benzothiazepine-2,5-diones possessing antihypertensive activity.

The preparation of a series of 1,4-thiazepine-2,5-diones, 1,4-thiazine-2,5-diones, and 1,4-benzothiazepine-2,5-diones and their ability in inhibiting the activity of angiotensin-converting enzyme (ACE) in vitro and in vivo were examined. These compounds are assumed to act as prodrugs since they undergo rapid ring-opening reactions to give the corresponding biologically active free SH compounds when incubated with rat plasma or when treated with aqueous 0.1 N HCl or phosphate buffer (pH 7.4). The thiazepines 23-25 and 30 are potent inhibitors of ACE when administered po to rats and are comparable in potency to captopril (1). The most active thiazines in rats, po, were 42 and 45. Of the benzothiazepines studied, 22a was the most active in inhibiting ACE in the conscious normotensive rat, ID50 = 0.15 mg/kg, po. The acute antihypertensive effects of oral administration of a number of these compounds on mean arterial pressure and heart rate were studied in spontaneously hypertensive rats (SHR) maintained on a sodium-deficient diet.

Angiotensin-converting enzyme inhibitors. New orally active antihypertensive (mercaptoalkanoyl)- and [(acylthio)alkanoyl]glycine derivatives.

A variety of N-substituted (mercaptoalkanoyl)- and [(acylthio)alkanoyl]glycine derivatives was synthesized and their ability in inhibiting the activity of angiotensin-converting enzyme (ACE) was examined in vitro and in vivo. The acylthio derivatives prepared are assumed to act as prodrugs since they are much less active than the corresponding free SH compounds in vitro and can be expected to act in vivo only after conversion to the free sulfhydryl compounds. A number of these compounds are potent ACE inhibitors that lowered blood pressure in Na-deficient, conscious spontaneously hypertensive rats (SHR), a high renin model. One of the most active members of the series was (S)-N-cyclopentyl-N-[3-[(2,2-dimethyl-1-oxopropyl)thio]-2-methyl-1 -oxopropyl]glycine (REV 3659-(S), pivopril). Structure-activity relationships are discussed.

Substituted arylmethyl phenyl ethers. 1. A novel series of 5-lipoxygenase inhibitors and leukotriene antagonists.

A series of new substituted arylmethyl phenyl ethers has been prepared. These compounds were tested as inhibitors of 5-lipoxygenase (5-LO) in rat neutrophils, in vitro antagonists of leukotriene-induced contraction of guinea pig (GP) lung parenchymal strips, and inhibitors of slow reacting substance of anaphylaxis (SRS-A) mediated bronchospasm in the GP in vivo. Most representatives of this new class of potential antiallergic/antiinflammatory agents showed potent inhibition of 5-LO activity in rat PMNs. The most potent compound, 2-[[3-(1-hydroxyhexyl)phenoxy]-methyl]quinoline (33), had an I50 of 0.12 microM in the rat PMN 5-LO assay and an I50 of 3.6 microM in the leukotriene-induced contraction of GP lung parenchymal strips, and it also showed 91% inhibition of SRS-A-mediated bronchospasm in the GP in vivo at 10 mg/kg, administered intraduodenally. Some of the compounds in this series were also leukotriene antagonists in vitro, and several of them showed in vivo activity against SRS-A-mediated bronchospasm in the GP.

Angiotensin converting enzyme inhibitors. 10. Aryl sulfonamide substituted N-[1-carboxy-3-phenylpropyl]-L-alanyl-L-proline derivatives as novel antihypertensives.

Compounds 1a-g consisting of enalaprilat covalently bonded to aryl sulfonamides, including several known thiazide diuretics, were synthesized and tested for ACE inhibitory and diuretic and overall antihypertensive effects. All compounds were potent ACE inhibitors in vitro, with IC50 = 6.5-85 nM. At 10 mg/kg iv or ip in the rat, 1a-g inhibited the AI pressor response by 76-100%; inhibition declined significantly upon oral dosing. Compounds 1a and 1f at 100 mg/kg ip in the sodium-depleted, spontaneously hypertensive rats reduced blood pressure 28-35% and 41-42%, respectively. Compounds 1a and 1f elicited natriuresis and kaliuresis without accompanying volume increases in the rat; 1c at 25 mg/kg iv induced delayed diuresis. Compound 1f has been chosen for further development.

The disposition of 14C-indapamide in man.

The metabolism of 14C-indapamide labeled in the indoline ring was determined after a single oral administration of a solution (4.99 mg, 90.47 microCi) to four fasted adult male volunteers. 14C-Indapamide was rapidly absorbed, and peak blood concentrations of radioactivity occurred by 0.5 hour in three subjects and at 2 hours in one subject. The mean elimination half-lives of total radioactivity were 27.0 hours in blood and 24.5 hours in plasma. The concentration of total radioactivity in blood was 5.7 times greater than in plasma, indicating extensive binding to red blood cells. Unchanged drug, as analyzed in one subject, reached a peak concentration by 0.5 hour, and had a blood half-life of 15.8 hours. Radioactivity was primarily excreted in the urine, and more than 50 per cent of the administered radioactivity was eliminated by this route in 48 hours. By eight days, 92.8 per cent of the radioactivity was recovered, with 70.3 per cent in the urine and 22.5 per cent in the feces. 14C-Indapamide was shown to be extensively metabolized, with only 7.3 per cent of the dose excreted as unchanged drug in the urine. Systemic and renal clearances of total radioactivity were 12.8 +/- 1.3 and 8.6 +/- 0.8 ml/min, respectively, while the renal clearance of unchanged indapamide, determined for one subject, was substantially lower (1.71 ml/min).

The bronchosparing effect of celiprolol, a new beta 1- alpha 2-receptor antagonist on pulmonary function of propranolol-sensitive asthmatics.

Twelve normotensive asthmatics who demonstrated bronchoconstriction after a single oral dose of 80 mg of propranolol received (according to a double-blind, randomized, crossover design) placebo, celiprolol 200 mg, and celiprolol 400 mg at intervals of at least three days. Pulmonary function parameters were measured by whole body plethysmography just before treatment and hourly for three hours. Thereafter, terbutaline (0.5 mg), a beta2 agonist, was administered in aerosol form at 15-minute intervals for a total of five doses. This design permitted a safety assessment of the effect of placebo and celiprolol on resting pulmonary function and the evaluation of any interaction between this beta blocker and terbutaline. Propranolol 80 mg produced a statistically significant decrease in a forced one second expiratory volume and forced vital capacity, and a pronounced rise in airways resistance as compared with either dose of celiprolol or with placebo (P less than .001). The effect of celiprolol was not statistically distinguishable from placebo. Terbutaline caused further net bronchodilation after administration of celiprolol and placebo but, even at supratherapeutic doses, failed to restore pulmonary function parameters to baseline levels after treatment with propranolol. The bronchosparing effect of celiprolol may be due to its unique pharmacologic profile, which includes cardioselectivity, modest beta 2-agonist activity, and alpha 2-receptor blockade.

Multicenter dose-response study of the effect of indapamide in the treatment of patients with mild to moderate hypertension.

This study, carried out in three centers in the United States, investigated the antihypertensive effect of three dosages of indapamide in 87 patients with mild to moderate hypertension. The dosages studied were 1 mg, 2.5 mg, and 5 mg daily. A double-blind, parallel study design was used with a six-week placebo run-in period followed by an eight-week treatment period and a two-week follow-up period. Compared with placebo, all dosages caused a significant decrease (P less than 0.05) in blood pressure, with an average decrease of approximately 6 mmHg diastolic and 13 mmHg systolic. The antihypertensive effect seemed to be fully manifest after six weeks of treatment. At all dosage levels, indapamide produced markedly greater therapeutic success rates than did the placebo. Success was defined as either a standing phase-5 diastolic blood pressure of less than 90 mmHg or a decrease by at least 10 mmHg from baseline. Although the decrease in mean serum potassium concentration was dose-related, the decrease was not clinically significant with any dose. A reduction in serum chloride and increases in serum uric acid and glucose were also observed. These changes were slight and did not cause the discontinuation of treatment for any patient. The most frequently observed side effects were mild to moderately severe dizziness, weakness, and headaches.

Multi-centre clinical investigation of indapamide in the United States: a review.

Indapamide, a new indoline antihypertensive agent, has been the subject of a worldwide programme to develop this drug for general clinical use. The results are described of the multi-centre U.S. clinical programme demonstrating the effectiveness and tolerance of indapamide for the treatment of hypertension. All work was conducted under U.S. Federal Food and Drug Administration guidelines, and resulted recently in a New Drug Application. A total of 1891 subjects or patients participated in 27 separate studies conducted by 91 investigators. In controlled clinical trials comparing 2.5 mg indapamide once daily with 50 mg hydrochlorothiazide once daily for 40 weeks in patients with mild to moderate essential hypertension, indapamide produced a reduction of supine blood pressure of -9.5/-14.3 mmHg as compared with -7.6/-11.4 mmHg for hydrochlorothiazide. In combination with methyldopa, propranolol, clonidine, guanethidine and hydralazine, indapamide consistently produced a greater decrease in arterial pressure than did those agents given alone. Indapamide added to these step-care agents did not result in a meaningful increase in adverse reactions. Indapamide has been the subject of a long-term safety study in which over 100 hypertensive patients have been followed up for 2 years or longer. During this period of time, indapamide was well tolerated and remained effective. No biochemical, electrocardiographic or ophthalmological changes were associated with its use. Other studies with indapamide are discussed describing the systemic and renal haemodynamic effects, pharmacokinetic properties and special safety studies conducted with this agent. The use of indapamide in patients with hepatic or renal impairment is reviewed in detail.

Indapamide in the stepped-care treatment of obese hypertensive patients.

A double-blind study was carried out in obese patients with moderately severe hypertension to assess the efficacy and tolerability of 2.5 mg indapamide as a once-a-day Step 1 drug compared to 50 mg hydrochlorothiazide also as a once-a-day Step 1 drug; to assess the efficacy and tolerability of a fixed daily dose of 2.5 mg indapamide administered concomitantly with methyldopa starting at 500 mg daily; and to compare the findings of efficacy and tolerability of 2.5 mg indapamide daily with those of 50 mg hydrochlorothiazide daily as Step 1 agents when methyldopa is the Step 2 drug. Twenty-nine patients completed the study and were evaluated. Nine patients achieved the study criterion of reduction of average standing diastolic pressure to 90 mmHg or less when treated with Step 1 medication only. Twenty patients required the addition of methyldopa to their Step 1 medication: 10 patients took 2.5 mg indapamide with an average constant daily dose of 1100 mg methyldopa and 10 patients took 50 mg hydrochlorothiazide with an average constant daily dose of 1575 mg methyldopa to achieve blood pressure control. All groups had mean diastolic pressure controlled at or below the 90 mmHg criterion during the period of constant methyldopa dosage for those patients who required Step 2 therapy. There were no significant differences between groups with respect to diastolic pressure during the constant dosage period. The indapamide patients required significantly (p less than 0.05) less methyldopa than did the hydrochlorothiazide patients in order to maintain satisfactory control of diastolic blood pressure. The number of responders was greater in the 2.5 mg indapamide + methyldopa group than it was in the 50 mg hydrochlorothiazide + methyldopa group, and responses were achieved more rapidly in the former group than in the latter. Indapamide (2.5 mg per day) was effective and well tolerated when used alone or as Step 1 medication in combination with methyldopa as Step 2 medication, and it compared favourably in this regard with hydrochlorothiazide.

Cephradine and epicillin in body fluids of lactating and pregnant women.

The passage of two antibiotics, cephradine and epicillin, into the milk of 12 lactating women and the amniotic fluid of 48 pregnant women was investigated. All women were given a 500-mg capsule every six hours for at least two days prior to our taking multiple biologic samples from them. Constant levels of both antibiotics were reached in the milk of lactating women as well as in the amniotic fluid of mid-term and full-term pregnant women during the sample period. The ratio of drug concentrations in serum to that in milk was about 5.0 for each antibiotic. In the midtrimester women, the ratio of concentrations in serum to amniotic fluid of both antibiotics was approximately 1.0, suggesting the development of an equilibrium between these two compartments. This ratio was 0.2 for both drugs in the full-term women, demonstrating that the antibiotics concentrated in the amniotic fluid compartment.

Chlorthalidone-triamterene: a potassium-sparing diuretic combination for the treatment of oedema.

The efficacy of a once-daily combination of chlorthalidone 50 mg plus triamterene 50 mg or chlorthalidone 100 mg plus triamterene 100 mg was compared to that of chlorthalidone 50 mg or 100 mg. This double-blind study was carried out in eighty-eight patients over a treatment period of 12 weeks. All patients entered the active medication period of 12 weeks after a placebo run-in period of 3 to 7 days, during which pretibial or malleolar pitting oedema averaging 2 to 4 mm developed. All patients started at the lower doses, i.e. forty-one started on chlorthalidone 50 mg plus triamterene 50 mg and forty-seven started on chlorthalidone 50 mg. The protocol provided for doubling the dose (but not for reducing it thereafter) at any time during the 12-week period when control of oedema was deemed inadequate. Eight of the combination therapy patients and sixteen of those on chlorthalidone required the higher doses. By Week 12, 96% of the chlorthalidone plus triamterene patients and 100% of the chlorthalidone patients had shown a reduction of at least 2 mm in depth of pits, and 92% and 72%, respectively, had complete disappearance of oedema. The decreases in pitting oedema were paralleled by mean weight losses of 2.4 kg and 3.1 kg, respectively, for the combination treatment group and the chlorthalidone group. Average serum potassium levels throughout the 12-week treatment period were 3.70 mEq/L for the patients taking the combination compared to 3.41 mEq/L of those taking chlorthalidone.(ABSTRACT TRUNCATED AT 250 WORDS)

The efficacy of a potassium-sparing combination of chlorthalidone and triamterene in the control of mild and moderate hypertension. I.

Chlorthalidone 25 mg/triamterene 50 mg in once-daily oral doses was as effective in reducing blood pressure as chlorthalidone 25 mg alone. The decrease in serum potassium was statistically significantly less with the combination than for chlorthalidone. There were no notable differences between the treatments in any other measure of laboratory safety or adverse reactions.

The efficacy of a potassium-sparing combination of chlorthalidone and triamterene in the control of mild and moderate hypertension. II.

Chlorthalidone 50 mg/triamterene 50 mg in once-daily oral doses was as effective in reducing blood pressure as chlorthalidone 50 mg alone. The decrease in serum potassium was statistically significantly less with the combination than for chlorthalidone. There were no notable differences between the treatments in any other measure of laboratory safety or adverse reaction.

Clinical pharmacology of SQ 10,996, a potential antidepressive agent.

Single oral doses of SQ 10,996 ranging from 500 to 1000 mg (0.34 to 15.3 mg/kg), given once daily for 3 consecutive days to groups of healthy volunteers, were well tolerated. One of three subjects given 1250 mg (17.1 mg/kg) and two of three subjects given 1500 mg (15.6 and 21.4 mg/kg) became drowsy on the second and third days; this symptom disappeared within 24 hrs after cessation of dosage. A short-term, multiple-dose tolerance study was carried out with a formulation of SQ 10,996, the bioavailability of which was comparable to that of the formulation used earlier in the ascending-dose tolerance study. When 200-mg doses were administered every 12, 8, or 6 hrs over a 6-day period, mean steady-state serum concentrations of approximately 4, 7, and 8 mug/ml were attained within 48 hrs; unexpectedly, no subject showed any sign of drowsiness. The half-life for SQ 10,996 in serum, estimated from concentrations in serum after the last dose, was approximately 13 hrs, significantly shorter than the half-life found previously after the administration of single 10-mg doses. These clinical pharmacology studies in healthy volunteers have shown SQ 10,996 to be biologically available and well tolerated. Future studies will test its antidepressive potential in patients.