The prevention and reversibility of tissue non-enzymatic glycosylation in diabetes.

The time course of non-enzymatic glycosylation (NEG) of liver, kidney, tail collagen, and haemoglobin was studied in diabetic rats. Increased NEG of liver, kidney, and collagen was detectable within 4 weeks of diabetes. The abnormal NEG of liver, kidney, and haemoglobin present after 4 weeks of untreated diabetes could be normalized by 4-8 weeks of intensive insulin therapy given by continuous subcutaneous infusion.

Effect of renal failure or biliary stasis on the pharmacokinetics of amiodarone in the rat.

The single dose intravenous pharmacokinetics of amiodarone (50 mg/kg) were examined in rats with 72 h of biliary stasis secondary to bile duct ligation compared with paired control animals; and in rats with uranyl nitrate induced acute renal failure compared with paired control animals. Plasma and tissue levels (liver, kidney, heart, and lung) of amiodarone (1) and its N-deethyl metabolite 2 were obtained at 4 and 24 h following drug administration. Pharmacokinetic parameters were derived from plasma samples obtained over a 24-h period.

Steady-state disposition of diflunisal: once- versus twice-daily administration.

To evaluate the steady-state bioequivalence of the nonsteroidal antiinflammatory analgesic agent, diflunisal, administered once versus twice daily, 13 healthy volunteers received diflunisal as follows: 1000 mg at 8:00 AM and 500 mg at 8:00 AM and 8:00 PM, each for 14 days in a randomized crossover study. The mean (+/- SD) steady-state peak plasma concentrations were significantly greater after once-daily dosing (186 +/- 25 micrograms/ml vs 150 +/- 37 micrograms/ml; p less than 0.01).

Effect of phenobarbitone on the pharmacokinetics and tissue levels of amiodarone in the rat.

Phenobarbitone pretreatment has been shown to increase amiodarone total clearance and decrease amiodarone elimination half-life after a single intravenous amiodarone dose in the rat. Coadministration of phenobarbitone with amiodarone for 7 days resulted in decreased tissue amiodarone levels compared to controls. These results may have implications for patients undergoing therapy with amiodarone and concomitant potent enzyme inducing drugs.

Radioenzymatic assay of angiotensin-converting enzyme inhibitors in plasma and urine.

A rapid, sensitive assay for angiotensin-converting enzyme (ACE) inhibitors is described. Biological samples were diluted with methanol to precipitate endogenous ACE and centrifuged. Supernatants were further diluted with 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid buffer, pH 8.

Regulation of growth of an interleukin 2 (IL-2)-dependent murine T-cell clone (HT-2) in a defined serum-free medium.

In this study, we demonstrate that an IL-2-dependent T-cell clone (HT-2) can be grown in a serum-free medium (HB101) with defined additives at rates comparable to those which can be obtained in serum-containing medium. Further, we show that cells cultured in the serum-free medium in the absence of IL-2 arrest growth in the G1 portion of the cell cycle, and that these arrested cells can be stimulated to reenter the cell cycle upon the addition of IL-2 to the culture medium. Growth of these cells in the absence of serum requires the presence of IL-2 as well as other hormones and growth factors and 2-mercaptoethanol.

Medical use of dimethyl sulfoxide (DMSO).

DMSO is a clear odorless liquid, inexpensively produced as a by-product of the paper industry. It is widely available in the USA as a solvent but its medical use is currently restricted by the FDA to the palliative treatment of interstitial cystitis and to certain experimental applications. Cutaneous manifestations of scleroderma appear to resolve (albeit equivocally) following topical applications of high concentrations of DMSO.

Sulindac and ibuprofen inhibit furosemide-stimulated renin release but not natriuresis in men on a normal sodium diet.

We compared the effect of two commonly prescribed nonsteroidal anti-inflammatory drugs, ibuprofen and sulindac, and placebo on intravenous furosemide-induced natriuresis and renin stimulation in 11 healthy male volunteers, consuming a 100 mEq sodium, 80 mEq potassium diet. Chronic (6-day) therapy with each agent was followed by a 1-week washout period. There were no significant treatment-related differences in either urine volume or sodium excretion for any of the designated collection periods or for the cumulative value for the 4 h after furosemide administration.

Effect of captopril and hydrochlorothiazide on the response to pressor agents in hypertensives.

The effect on arterial pressure of incremental doses of norepinephrine (2 to 10 micrograms/min) and angiotensin II (50 to 800 ng/min) administered over 10 min periods was studied in sodium-replete hypertensive patients after crossover oral treatments with placebo, captopril 50 mg in a single dose, captopril 50 mg three times daily for one week and hydrochlorothiazide 50 mg daily for a week. Neither captopril nor hydrochlorothiazide affected the dose response to infusions of angiotensin II. In comparison to placebo responses, however, both single and multiple-dose captopril therapy, and hydrochlorothiazide attenuated the pressor responses to infusions of norepinephrine.

Influence of food on the bioavailability of enalapril.

In a randomized, two-period crossover study in 12 normal volunteers, serum and urine concentrations of the angiotensin-converting enzyme inhibitor enalapril and its active metabolite enalaprilat were determined following administration of a single 40-mg tablet of enalapril maleate administered both in the fasting state and with a standard breakfast. A 7-d interval separated the two treatment periods. Area under the serum concentration-time curves for enalaprilat and urinary recoveries for enalaprilat and total drug did not differ significantly between the fed and fasted conditions.

Relationship of morphine-induced miosis to plasma concentration in normal subjects.

The relationship between morphine plasma concentration and pupil diameter was evaluated 2-10 h following intravenous administration of morphine sulfate (10 mg). Seven healthy male volunteers received 10 mg of morphine intravenously following pretreatment for 4 d with either cimetidine (300 mg po four times a day) or placebo in a single blind, balanced crossover study. Pupil diameters were measured directly from contact prints using calipers and a photographed millimeter scale.

Steady-state serum amiodarone concentrations: relationships with antiarrhythmic efficacy and toxicity.

The relationship of apparent steady-state serum concentrations of amiodarone and its metabolite, desethylamiodarone, to therapeutic and toxic effects was assessed in 127 patients who had treatment-resistant ventricular or supraventricular arrhythmias or were intolerant to other agents. After at least 2 months (mean, 9.8) of treatment with daily maintenance doses of 200 to 600 mg, arrhythmias were effectively suppressed in 78% of patients.

Indacrinone: natriuretic and uricosuric effects of various ratios of its enantiomers in healthy men.

Indacrinone is an investigational loop-acting diuretic. To evaluate the natriuretic and uricosuric effects of varying ratios of its enantiomers, 10 healthy men, on a controlled Na+ (100 mEq) and K+ (80 mEq) diet, participated in a double-blind, randomized, balanced incomplete block, multiple-dose (one week) study of a fixed daily dose (10 mg) of (-) enantiomer combined with increasing doses (40, 90 and 140 mg) of (+) enantiomer versus 50 mg hydrochlorothiazide and placebo. On day 1, mean 24-h urinary Na+ increased (p less than 0.

Methyldopa does not alter the disposition of digoxin.

To investigate whether methyldopa alters digoxin disposition, eight healthy subjects received methyldopa titrated to 250 mg t.i.d.

Bucindolol, a beta-adrenoceptor blocker with vasodilatory action: its effect in systemic hypertension.

Bucindolol is a newly developed, nonselective beta-adrenergic blocking agent with intrinsic sympathomimetic activity and direct vasodilator properties. In 14 patients with mild to moderate essential hypertension, the effects of bucindolol, hydrochlorothiazide and their combination on blood pressure (BP), heart rate (HR) and parameters of the renin-aldosterone system were compared with those after placebo. Bucindolol's antihypertensive effect was evident within the first hour after drug administration, maximal at 2 to 3 hours, and lasted for as long as 12 hours.

Initial evaluation of the non-sulfhydryl-containing converting enzyme inhibitor MK-521 in hypertensive humans.

MK-521 is a new orally active, nonsulfhydryl angiotensin-converting enzyme (ACE) inhibitor. Single doses of 2.5, 5.

Enalapril, a new nonsulfhydryl angiotensin converting enzyme inhibitor, does not potentiate morphine analgesia.

Sprague-Dawley rats received oral doses of enalapril maleate (5 mg/kg), a potent, nonsulfhydryl, angiotensin converting enzyme inhibitor, or saline. Sixty min later, morphine sulfate, 5 mg/kg, or saline was injected subcutaneously. Response to a thermal stimulus was monitored before and up to 5 h ter morphine injection using the rat tail flick test.

Weight gain and feed efficiency of chicks fed sucrose fatty acid esters.

Day-old Hubbard X Hubbard broilers (mixed sexes) were fed for 2 weeks with a basal diet containing 5% experimental carbohydrate. The experimental carbohydrates were one of the following: sucrose fatty acid esters (SFE)-high monoesters (SFE 1670), SFE-low monoesters (SFE 370), sucrose, glucose, or cellulose. Feed efficiency, weight gain, and growth performance were compared among treatments.

Temperature dependence of the resonance Raman spectra of plastocyanin and azurin between cryogenic and ambient conditions.

Resonance Raman spectra of spinach plastocyanin and Pseudomonas aeruginosa azurin were studied as a function of temperature between 10 K and 300 K. The spectra are markedly improved both in signal/noise ratio and in resolution at low temperatures. The assignments of the resonance Raman-active vibrations are reinterpreted in view of the number and intensities of peaks observed in the low-temperature spectra.

Antihypertensive efficacy of once daily MK-521, a new nonsulfhydryl angiotensin-converting enzyme inhibitor.

The effects of the new nonsulfhydryl-containing oral converting-enzyme inhibitor MK-521 on blood pressure, heart rate, angiotensin-converting enzyme activity, plasma renin activity and plasma aldosterone concentration were assessed in 10 hypertensive patients. After a 2-week no-treatment period, patients received placebo and then 14 days each: MK-521 20 mg once daily, hydrochlorothiazide 50 mg once daily and the latter 2 in combination. During the last day of each treatment, the mean (+/- standard deviation) time-averaged (1- to 12-hour) standing diastolic blood pressure decreased from 106 +/- 8 (placebo) to 95 +/- 10 mm Hg with MK-521, 95 +/- 13 mm Hg with hydrochlorothiazide (p less than 0.

Hemodynamic and humoral responses to enalapril and nifedipine in the rat.

The hemodynamic and humoral effects of enalapril, an angiotensin converting enzyme (ACE) inhibitor, and nifedipine, a calcium-entry blocker, were evaluated in conscious spontaneously hypertensive rats (SHR). Rats received enalapril (5 mg/kg, po) or vehicle, followed in one hour by nifedipine (2.5 mg/kg, ip) or its vehicle.

Amiodarone: individualizing dosage with serum concentrations.

The purpose of the present report is to review the available pharmacokinetic information on amiodarone with an emphasis on our own experience in monitoring serum amiodarone concentrations. We have found that 400 mg should be the maximal maintenance dose; if that treatment fails, careful addition of other antiarrhythmic agents is preferable over an increase in amiodarone dosage. Serum concentrations below 2.