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Biomedical subjects

A N Chremos

Publications and source records attributed to A N Chremos.

At least 37 records · Page 2Linked to original sources
PubMed1987

The effects of intravenous famotidine on pentagastrin-stimulated gastric secretion in man.

Eight healthy male volunteers were each studied on four occasions in a 7 hour double-blind, placebo-controlled experiment. Three continuous 6 hour intravenous (i.v.) infusion rates of famotidine, calculated to achieve steady-state plasma concentrations of 10, 30 and 90 ng ml-1, were compared to placebo. Commencing at the third study hour, hourly incremental step-up i.v. infusions of pentagastrin 0.1, 0.2, 0.5, 1.0 and 2.0 micrograms kg-1. hour were administered on each of the four study days. Hourly blood samples were taken for the subsequent determination of plasma famotidine concentration. The three famotidine infusion rates inhibited basal gastric secretion. Pentagastrin-stimulated secretion was inhibited in a dose-dependent manner. The highest dose of famotidine (38.7 micrograms kg-1.hour) inhibited each infusion rate of pentagastrin-stimulated gastric secretion between 92 and 96%. The lowest dose of famotidine (4.3 micrograms kg-1.hour) inhibited pentagastrin 0.1 micrograms kg-1.hour stimulated secretion by 50% but, when stimulated with pentagastrin 2.0 micrograms kg-1.hour, gastric secretion was inhibited by only 25%. This study indicates that the intravenous preparation of famotidine is a potent inhibitor of pentagastrin-stimulated gastric acid secretion.

Adult↗
PubMed1987

The effect of famotidine on renal function in patients with renal insufficiency.

The effect of famotidine, a new histamine H2-receptor antagonist, on renal tubular creatinine secretion was evaluated in twelve patients with reduced renal function (creatinine clearance 10-60 ml min-1). Creatinine and inulin clearances were determined at baseline and for 4 h after a 10 mg intravenous dose of famotidine. Famotidine renal clearance exceeded inulin clearance by an average of 152%, indicating that renal tubular secretion of famotidine occurred. No significant changes in the clearances of creatinine or inulin, or the fractional clearance of creatinine were observed after famotidine administration. These data suggest that famotidine, unlike cimetidine, does not inhibit renal tubular secretion of creatinine. Thus, famotidine does not affect creatinine-dependent measurements of renal function and is unlikely to alter the renal elimination of basic drugs.

Adult↗
PubMed1987

Effects of antacids and food on absorption of famotidine.

The effect of a high potency antacid and food on the bioavailability of famotidine was studied in 17 healthy volunteers in an open randomized three-way cross-over trial. After an overnight fast, famotidine was administered to each subject as follows: 40 mg famotidine orally alone; 40 mg orally with antacid; and 40 mg orally with a standard breakfast. Coadministration of the antacid caused a small but significant reduction in the maximum plasma concentration (Cmax) of famotidine from 81.1 +/- 54.2 to 60.8 +/- 21.6 ng ml-1 (P less than 0.05) and a small decrease in the area under plasma concentration-time curve [AUC] from 443.3 +/- 249.2 to 355.0 +/- 125.1 ng ml-1 h (P greater than 0.05). However, there was only a minimal effect of food on these parameters; the Cmax and [AUC] were 81.6 +/- 29.6 ng ml-1 and 434.8 +/- 145.9 ng ml-1 h, respectively.

Antacids↗
PubMed1987

Comparative effect of famotidine and cimetidine on the pharmacokinetics of theophylline in normal volunteers.

The comparative effect of famotidine or cimetidine on theophylline disposition was determined in healthy volunteers. Cimetidine, but not famotidine, caused a reduction in the rate of elimination of theophylline. The mean total body clearance of theophylline was reduced from 57.6 ml min-1 before cimetidine to 39.5 ml min-1 during cimetidine; and the half-life was prolonged from 8.7 h before cimetidine to 12 h during cimetidine. The volume of distribution and renal excretion of theophylline were not affected by either famotidine or cimetidine.

Cimetidine↗
PubMed1986

Pharmacodynamics of famotidine in humans.

The physiologic role of histamine (H2) receptors and their involvement in pharmacologic responses have not been completely defined. To date, H2-receptor-specific pharmacologic actions of H2-receptor inhibitors in humans are primarily associated with effects on gastric acid secretion. Famotidine is a new potent competitive inhibitor of H2 receptors. During its development, in addition to studies defining its gastric acid antisecretory profile, famotidine was also examined for potential effects on other functions of the gastrointestinal tract and on other systems. Famotidine inhibits basal and stimulated gastric acid secretion in a dose-dependent manner after oral administration of 5 to 40 mg. Maximal effect is achieved by the 40-mg dose, with peak activity reached one to three hours after dosing and a duration of action lasting 10 to 12 hours. Gastric emptying times and exocrine pancreatic function are not affected after famotidine (40 mg twice daily) treatment. Blood pressure, heart rate, and electrocardiographic patterns remain unchanged after oral or intravenous administration of famotidine in doses up to 40 mg and 20 mg, respectively. Serum prolactin levels do not rise after intravenous administration of 20 mg of famotidine. The levels of prolactin, testosterone, dehydroepiandrosterone, follicle-stimulating hormone, luteinizing hormone, and other circulating hormones remain unchanged during four weeks of treatment with famotidine 40 mg daily. Renal inulin and creatinine clearances show no change after intravenous administration of 10 mg of famotidine, and tubular excretion of procainamide and its major metabolite is unchanged after administration of 40 mg of famotidine. No significant effects are found on the biologic disposition of theophylline, warfarin, and other compounds metabolized by the liver cytochrome P450 enzyme system when they are given concomitantly with famotidine.

Dose-Response Relationship, Drug↗
PubMed1986

Comparison of effects of oral and intravenous famotidine on inhibition of nocturnal gastric acid secretion.

In this double-blind, placebo-controlled, four-way crossover, randomized study, eight high-secretor (more than 5 meq per hour) volunteers received 20 mg of famotidine by mouth, 10 mg intravenously, and 20 mg intravenously at 9 P.M. Volume, acid content, and pH of continuous gastric aspirates were measured hourly from one to at least 12 hours after treatment. Plasma concentrations of famotidine were determined at specified intervals. All famotidine doses produced marked suppression of gastric secretion. The mean total output was 1,196.3, 526.8, 414.9, and 518.0 ml for placebo, the 10-mg intravenous famotidine dose, the 20-mg intravenous dose, and the 20-mg oral dose, respectively. The latter three values were significantly different from that of placebo at p less than 0.01. The mean total acid output was 105.3, 8.3, 2.3, and 6.2 meq, respectively, and the acid output for all three doses was significantly different from that of placebo at p less than 0.01. The onset of antisecretory effect was noted as early as one hour after dosing. The mean gastric aspirate pH values were 1.7, 5.5, 6.2, and 4.4 during the second hour after placebo, the 10-mg intravenous dose, the 20-mg intravenous dose, and the 20-mg oral dose, respectively, with the treatment pH values significantly different from the placebo pH value at p less than 0.01. Higher mean pH values were reached at seven, eight, and nine hours after the 20-mg intravenous dose than after the 10-mg intravenous dose (p less than 0.05). By the 12th hour after administration of the 10-mg intravenous dose, pH values had returned to baseline in all but one subject. After the 20-mg intravenous dose, a similar loss of effect occurred in one subject at 12 hours and in all subjects by 15 hours. Plasma concentrations of famotidine greater than 50 ng/ml were associated with an acid output inhibition of more than 80 percent, whereas high (more than 90 percent) as well as low (less than 50 percent) inhibition was observed at famotidine concentrations below 50 ng/ml.

Administration, Oral↗
PubMed1985

MK-208, a novel histamine H2-receptor inhibitor with prolonged antisecretory effect.

MK-208 is a guanidinothiazole derivative reported to be a potent H2 blocker devoid of antiandrogenic activity. Its potency and duration of action, in inhibiting pentagastrin-stimulated gastric secretion in man, was evaluated in this double-blind, five-way cross-over trial. Ten healthy male volunteers received single oral doses of placebo, cimetidine 300 mg, and MK-208 5, 10, and 20 mg. A continuous intravenous infusion of pentagastrin (1 microgram/kg/hr) was given 2-4 and 5-7 hr after each oral dose. Gastric contents were continuously aspirated and volumes and acid content determined every 30 min. Plasma levels for MK-208 and cimetidine were monitored over the 7 hr of the study. Cimetidine and all doses of MK-208 significantly inhibited gastric acid secretion in the initial 2-4 hr; however, 10- and 20-mg doses of MK-208 were significantly more potent than cimetidine. In the 5- to 7-hr period, cimetidine 300 mg was not different from placebo, while MK-208 in all doses studied continued to significantly suppress gastric secretion. Plasma levels for MK-208 showed dose-related increments. The results suggest that: (1) MK-208 is a potent inhibitor of gastric secretion in man, in a dose-related fashion at the doses tested; (2) under the study conditions, 5 mg MK-208 was equipotent to 300 mg cimetidine but with greater duration of action, extending at least 7 hr; and (3) these data suggest a future role for this new agent in therapy for acid-peptic disease in man.

Adult↗
PubMed1985

Famotidine, a new H2-receptor antagonist. Effect on parietal, nonparietal, and pepsin secretion in man.

We studied pentagastrin-stimulated acid and pepsin secretion with three doses (5, 10, and 20 mg) of a new H2-receptor antagonist (famotidine) administered orally to normal male volunteers. A dose response was identified: 2 hr after oral dosing, 5 mg famotidine suppressed stimulated acid secretion to 60% of control and was comparable to 300 mg cimetidine (55% suppression). Higher doses of famotidine yielded significantly more suppression of acid secretion (10 mg yielding 70% and 20 mg, 90%). Pentagastrin-stimulated acid secretion remained decreased (50% of control) 12 hr after oral dosing with 20 mg famotidine. The reduction in pepsin output paralleled the reduction in acid secretion and was primarily due to a reduction in the volume of secretion and not to a change in pepsin concentration. We calculated the components of gastric secretion (acid from parietal cells) and bicarbonate secretion (from nonparietal cells) and found that the primary effect of the H2-receptor antagonists was a dramatic reduction in parietal cell output without a significant decrease in nonparietal secretion. Famotidine proved to be a potent inhibitor of both the parietal component of gastric acid and pepsin output. Famotidine was significantly more potent than cimetidine; 5 mg of famotidine was comparable to 300 mg of cimetidine.

Adult↗
PubMed1985

Famotidine, a new, potent, long-acting histamine H2-receptor antagonist: comparison with cimetidine and ranitidine in the treatment of Zollinger-Ellison syndrome.

Famotidine, a new, potent, long-acting histamine H2-receptor antagonist was compared with cimetidine and ranitidine in 9 patients with Zollinger-Ellison syndrome. The mean minimum daily requirement of famotidine to control gastric acid hypersecretion was 0.24 g (range 0.08-0.48 g) compared with 2.1 g (range 0.6-3.6 g) for ranitidine and 7.8 g (range 1.2-13.2 g) for cimetidine. Equally potent doses of the three drugs had similar onsets of action, but the duration of action of famotidine was 30% longer than the duration of action of either ranitidine or cimetidine (p less than 0.05). Eight patients were treated for up to 9 mo (mean 6 mo) with good control of gastric acid hypersecretion and with no evidence of biochemical or hematologic toxicity. These studies demonstrate that famotidine is nine times more potent than ranitidine and 32 times more potent than cimetidine, has a longer duration of action than ranitidine or cimetidine, and is both safe and effective in the long-term therapy of Zollinger-Ellison syndrome.

Aged↗
PubMed1985

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. Similarly, differences among groups were not observed for creatinine clearance, urinary potassium and urinary chloride excretion. Mean basal plasma renin activity levels prior to furosemide administration on day 6 were significantly lower in the presence of ibuprofen (1.5 +/- 2.0 ng/ml/h;p less than 0.01) and sulindac (2,3 +/- 0.9 ng/ml/h; p less than 0.05), compared with placebo (3.3 +/- 1.1 ng/ml/h); the difference between the two NSAIDs was also significant (p less than 0.05). Mean plasma renin activity levels in the 4 h after furosemide increased significantly at all time points in comparison to basal values, but were significantly less for ibuprofen and sulindac groups in the first hour. Our data suggest that the natriuresis following intravenous furosemide in men consuming a normal sodium intake is not prostaglandin-dependent. Furthermore, the observation that sulindac suppressed basal and stimulated plasma renin activity levels, albeit to a lesser extent than ibuprofen, questions the claim that sulindac "spares' the kidney and compels further evaluation of this issue.

Adult↗
PubMed1984

Effects of sulindac and indomethacin on renal prostaglandin synthesis.

We compared the effects of sulindac and indomethacin, the effects of two nonsteroidal anti-inflammatory drugs, on renal prostaglandin synthesis and renal function. Sulindac, 200 mg twice daily, indomethacin, 25 mg four times a day, or placebo were taken by 15 normal female subjects (five in each of three treatment groups). Indomethacin decreased renal excretion of prostaglandins PGE2, PGF2 alpha, and 6-keto-PGF1 alpha, but sulindac and placebo had no effect on renal prostaglandin excretion. Concomitant with the reduction of renal prostaglandin synthesis in the indomethacin group, sodium and chloride excretion decreased; sulindac and placebo had no discernible effects on urine electrolytes. Extrarenal cyclooxygenase activity, as assessed by platelet thromboxane beta 2 release, was inhibited by both sulindac and indomethacin. Plasma renin activity and plasma aldosterone levels fell in all groups as a result of positive sodium balance, but the decrements of aldosterone were greater after indomethacin and sulindac. None of the treatments altered glomerular filtration rate or renal plasma flow in these normal women. We conclude that in normal women renal prostaglandin synthesis and prostaglandin-dependent tubular functions such as Na and Cl reabsorption are relatively unaffected by doses of sulindac (200 mg twice daily) that inhibit nonrenal cyclooxygenase. This may reflect the capacity of oxidative enzymes in the kidney to convert the active sulfide metabolite of sulindac to the inactive prodrug sulindac sulfoxide.

6-Ketoprostaglandin F1 alpha↗
PubMed1984

Comparison of the effects of sulindac with other cyclooxygenase inhibitors on prostaglandin excretion and renal function in normal and chronic bile duct-ligated dogs and swine.

Sulindac sulfoxide is a prodrug which must be converted to a reduced active metabolite, sulindac sulfide, in order to inhibit arachidonate cyclooxygenase. Oral administration of sulindac sulfoxide does not yield substantial amounts of sulindac sulfide in the urine. To determine whether sulindac sulfide inhibits renal prostaglandin (PG) synthesis, the active form of the drug, sulindac sulfide (5 mg/kg i.v.), was administered to four sham-ligated dogs and four dogs with liver disease induced by chronic (6 weeks) common bile duct ligation (CBDL). In both the sham and CBDL animals the sulindac sulfide caused a 60 to 90% reduction in PGE2, PGF2 alpha and 6-keto-PGF1 alpha excretion rates. In the same animals, subsequent treatment with another cyclooxygenase inhibitor, naproxen (10 mg/kg i.v.), did not result in any further decrease in PGE2 or PGF2 alpha excretion but did decrease 6-keto-PGF1 alpha excretion. In the CBDL animals, sulindac sulfide treatment decreased renal blood flow, glomerular filtration rate and urine volume and resulted in the urinary excretion of large amounts of the sulindac sulfide. Similar changes in PG excretion and renal function were observed in CBDL animals treated solely with naproxen (10 mg/kg i.v.) or with ibuprofen (20 mg/kg i.v.). In four normal and three CBDL animals, we determined that i.v. administration of the prodrug, sulindac sulfoxide (5-15 mg/kg), resulted in plasma levels of 2-5 micrograms/ml of the active drug, sulindac sulfide, only in the CBDL animals. In subsequent experiments, we gave sulindac sulfoxide, 5 mg/kg i.v., to five CBDL dogs and three CBDL miniature swine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1976

Time-dependent change in renal clearance of bethanidine in humans.

Blood levels and urinary excretion rates of bethanidine were determined in three normal human subjects following oral administration of a single dose of the drug. The postabsorptive decline of blood concentration with time was noticeably slower than the corresponding decline in the urinary excretion rate. The discrepancy can be attributed to a continual decrease in the renal clearance of bethanidine throughout the study. Therefore, pharmacokinetic modeling of urinary excretion data alone would lead to erroneous conclusions concerning the persistence of drug in the blood.

Bethanidine↗
PubMedDate not supplied

Single-dose pharmacokinetics and bioavailability of famotidine in man. Results of multicenter collaborative studies.

Pharmacokinetics and bioavailability of famotidine, a new H2-receptor antagonist, were investigated in healthy subjects in five clinical studies. Linear pharmacokinetics were observed following either intravenous or oral administration. Plasma clearance averaged 463 ml min-1. Renal clearance averaged 310 ml min-1, which exceeded the glomerular filtration rate. Renal excretion was the major route of elimination. Urinary recovery of unchanged drug following intravenous administration was about 67 per cent. Famotidine plasma half-life was approximately 2.6 h. Oral absorption was incomplete. The bioavailability averaged 43 per cent of the dose.

Administration, Oral↗
PubMedDate not supplied

An apomorphine-induced vomiting model for antiemetic studies in man.

Apomorphine-induced vomiting is often used for preclinical efficacy testing of putative antiemetics in normal volunteers. The usual technique of individual intravenous titration for finding the threshold emitic dose of apomorphine in each subject is slow and tedious. We used a uniform dose of 0.05 mg/kg apomorphine given subcutaneously to test the antiemetic action of metoclopramide and votracon in ten healthy, young male volunteers. All ten subjects vomited in response to this dose of apomorphine when pretreated with placebo. Pretreatment with metoclopramide prevented vomiting in all subjects, and votracon prevented vomiting in two. Apomorphine, 0.05 mg/kg, subcutaneously appears to be an appropriate challenge dose for testing compounds for antiemetic activity in normal human volunteers.

Adult↗
PubMedDate not supplied

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). The time to peak concentration was also longer after the single-dose regimen (2.5 +/- 0.8 vs 1.9 +/- 0.9 hr; p less than 0.05). The regimens were similar with respect to the mean 24-hour area under the plasma concentration-time curve at steady state (2839 +/- 612 vs 2782 +/- 778 micrograms.hr.ml-1), steady-state plasma concentrations (118 +/- 25 vs 116 +/- 32 micrograms/ml), trough plasma concentration (85 +/- 27 vs 92 +/- 28 micrograms/ml) as well as 24-hour urinary excretion (776 +/- 79 vs 771 +/- 89 mg) of diflunisal. Based on urinary recoveries, the bioequivalence ratio (once vs twice daily) was 1.01 +/- 0.08. These results indicate that diflunisal administered once daily might offer comparable therapeutic effects but be more convenient than a twice-daily regimen.

Adult↗