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Biomedical subjects

H Sevelius

Publications and source records attributed to H Sevelius.

At least 19 recordsLinked to original sources
PubMed1990

Ketorolac tromethamine pharmacokinetics and metabolism after intravenous, intramuscular, and oral administration in humans and animals.

In humans, ketorolac is completely bioavailable and its kinetics are linear. It is absorbed rapidly (half-life for absorption 3.8 min) after oral (fasting) and intramuscular administration; food delays but does not reduce its absorption. The drug is highly protein bound in humans (greater than 99%). The mean plasma elimination half-life is 5-6 hours, and ketorolac is not extensively distributed outside the vascular compartment (Vd beta 15 L). Virtually all of the drug-related material circulating in plasma is in the form of ketorolac (greater than 96%), with the only metabolite the pharmacologically inactive p-hydroxyketorolac (PHK). Humans excrete about 90% of the administered dose in urine. About 60% of drug-related material recovered from urine is ketorolac, about 12% is PHK, and 28% represents polar, glucuronide conjugates of ketorolac. The animal models in which ketorolac's metabolism and kinetics are most similar to those in humans are the mouse and monkey, respectively.

Administration, Oral↗
PubMed1989

Pharmacokinetics of ketorolac and p-hydroxyketorolac following oral and intramuscular administration of ketorolac tromethamine.

Ketorolac tromethamine (KT), a potent analgesic with cyclooxygenase inhibitory activity, was administered in an open, randomized, single-dose study of Latin-square design to 12 healthy male volunteers. Doses of 30 mg oral (po) and 30, 60, and 90 mg intramuscular (im) KT were administered in solution. Plasma samples were analyzed for ketorolac (K) and its inactive metabolite, p-hydroxyketorolac (PHK), by reversed-phase high-performance liquid chromatography (HPLC). The 30-mg im dose was found to be similar to the 30-mg po dose with respect to total AUC values for both K and PHK. The amount of PHK circulating in plasma was very low as judged by AUC ratios (PHK/K x 100) of 1.9 and 1.5% for the 30-mg po and im doses, respectively. The rate of absorption of K and formation of PHK, as determined by Cmax and Tmax values, was significantly slower following the im doses. Total AUC and Cmax for K and PHK increased linearly with dose after im administration of 30, 60, and 90 mg of KT. The mean plasma half-life of K was remarkably consistent between po and im administration and was independent of dose, ranging from 5.21 to 5.56 hr. The plasma metabolic profile was similar following both routes of administration and graded im doses.

Administration, Oral↗
PubMed1989

Effect of enprostil on gastric emptying, intestinal transit time and post-prandial release of gastro-intestinal peptides.

The effect of an oral dose of 70 micrograms enprostil (a prostaglandin E2 analogue) on the post-prandial hormone response to a test breakfast was examined in a double-blind, placebo-controlled, cross-over study in 10 healthy volunteers. Enprostil markedly reduced the post-prandial rises in insulin and glucose-dependent insulinotropic peptide (GIP) but plasma glucose remained unchanged. To study the effects on gut motility 8 healthy volunteers ingested a liquid meal containing 75 g glucose, 20 g lactulose and 99mTc colloid after taking placebo or 70 micrograms enprostil. Gastric emptying, measured using a gamma camera, was unchanged but mouth-to-caecum transit time was significantly longer on enprostil; time to half maximal breath hydrogen: placebo 119 min, enprostil 200 min (p less than 0.05). This delay was associated with a reduced and delayed post-prandial rise in GIP and insulin and with other changes in the gut hormone profile.

Adult↗
PubMed1988

Reduction of serum lipoproteins in man by the oral administration of a prostaglandin analogue (enprostil).

Retrospective analysis of ulcer healing trials utilizing enprostil, a synthetic dehydroprostaglandin E2 analogue, has demonstrated a 10% or greater reduction in total serum cholesterol in 64%, 64% and 67%, respectively, of hypercholesterolemic subjects receiving the drug in doses of 70 micrograms, 35 micrograms, and 7 micrograms bid, respectively. Only 16% of subjects receiving placebo exhibited a similar reduction (P less than 0.05). The median percent changes for hypercholesterolemic patients receiving enprostil 70 micrograms, 35 micrograms, or 7 micrograms bid, and placebo were -17%, -13%, -11%, respectively, while the median percent change for those on placebo was 0% (P less than 0.05). Eight normocholesterolemic subjects participated in a double-blind crossover study comparing enprostil 70 micrograms/d with its placebo. Nine days of enprostil administration was associated with reductions in total serum cholesterol (-16%) and apolipoprotein B (-16%) and with significant reductions from baseline for LDL-cholesterol (-22%), the LDL/HDL-cholesterol ratio (-13%), and the ratio of serum apolipoprotein B to apolipoprotein A-1 (-12%). Relative to placebo, mean HDL-cholesterol, total triglycerides, and apolipoprotein A-1 concentrations remained unchanged. Daily oral administration of microgram quantities of enprostil is associated with reductions in total cholesterol, LDL-cholesterol, and apolipoprotein B suggesting therapeutic potential of this synthetic prostaglandin for the treatment of hyperlipidemia.

Administration, Oral↗
PubMed1988

Suppression of postprandial glucose, insulin, C-peptide, and glucose-dependent insulinotropic peptide (GIP) in man by oral administration of a prostaglandin analogue (enprostil).

Enprostil, a long-acting, orally active dehydroprostaglandin E2 with cytoprotective and gastric antisecretory properties, is a potent inhibitor of meal-stimulated gastrin release. Recent data have suggested suppression of additional other gastrointestinal peptide hormones following single doses of enprostil. The current investigation was conducted to further clarify the effects of enprostil administration on gastrointestinal hormones and glucose metabolism under physiologic conditions and to determine whether these effects were present following multiple doses of the agent. Enprostil 70 mcg/d and its placebo were each administered for 7 1/2 days to eight normal male subjects in a study of crossover design, each treatment period lasting 7 1/2 days and separated by a 7 day washout period. Subjects received a test meal on days 1 and 8 and an oral glucose challenge on day 3 of each treatment period following enprostil or its placebo. Following the test meal, there was a delay and suppression of the maximum measured serum glucose levels. Mean overall peak glucose concentrations were lower during the enprostil phase compared to placebo (112 vs. 121 mg/dd, P = 0.025) with a trend toward delay in the time to achievement of peak glucose concentrations. Mean overall peak levels for insulin, C-peptide, and glucose-dependent insulinotropic peptide (GIP) were significantly suppressed by 36%, 16% and 60%, respectively by enprostil when compared to placebo. The overall integrated postprandial responses for insulin, C-peptide, and GIP were significantly reduced by 42%, 39% and 90%, respectively while that for glucose above baseline was reduced by 44% (P = 0.098). Similar effects were present following the oral glucose challenge.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1985

Antisecretory and serum gastrin lowering effect of enprostil in patients with duodenal ulcer disease.

This study was designed to compare the effects of enprostil, a synthetic dehydro-prostaglandin E2, on 24-h intragastric pH and serum gastrin profile in patients with duodenal ulcer disease. The dosing regimen included 3 enprostil groups: 35 microgram h.s. (at bedtime), 70 micrograms h.s., and 35 micrograms b.i.d., compared with cimetidine 600 mg b.i.d., and with placebo. Ten patients with inactive duodenal ulcer disease were randomly assigned to all five treatment regimens for 1 wk each according to a Latin Square design. There was a 1-wk washout period between each treatment. Intragastric pH and serum gastrin measurements were carried out on the last day of each treatment week. In placebo-treated patients, intragastric pH rose after each meal and fluctuated between 1.5 and 3.5. Enprostil 35 micrograms b.i.d. and cimetidine elevated pH after breakfast and during the night (p less than 0.05). The single nighttime dose of enprostil had a marked effect on pH only when given in the dose of 70 micrograms and this effect lasted over 13.5 h. The pH values during the night were similar in the groups treated with enprostil 35 micrograms b.i.d. and 70 micrograms h.s. During the daytime, the readings at or above pH 4 were placebo, 5%; cimetidine, 21%; enprostil 35 micrograms b.i.d., 34%. During the nighttime, the readings greater than or equal to 4 were placebo, 12%; cimetidine, 29%; enprostil 35 micrograms b.i.d., 39%; 35 micrograms h.s., 19%, and 70 micrograms h.s., 38%. The postprandial rise in serum gastrin was greatly enhanced by cimetidine, but the change after breakfast was dramatically blunted by enprostil 35 micrograms b.i.d. Gastrin concentration was increased with cimetidine during the night but there was no difference in gastrin concentration overnight between all regimens of enprostil and placebo. This study suggests that (a) enprostil 35 micrograms b.i.d. is as effective as cimetidine 600 mg b.i.d. in suppressing postprandial and nocturnal intragastric acidity; (b) enprostil 35 micrograms b.i.d. and 70 micrograms at night are similarly potent in suppressing nocturnal acidity; and (c) in addition to its cytoprotective effect, enprostil has potent antisecretory and antigastrin properties.

Adult↗
PubMed1985

Protection against aspirin-induced antral and duodenal damage with enprostil. A double-blind endoscopic study.

Prostaglandins protect against aspirin-induced damage to the gastrointestinal tract. This study tested the ability of enprostil, a synthetic analog of prostaglandin E2, given concurrently to prevent gastroduodenal injury. Twenty-four healthy subjects were randomly assigned to one of three groups. All received aspirin 650 mg q.i.d. for 5 days. One group received placebo and the other groups were given either 7 or 70 micrograms of enprostil b.i.d. for 5 days. Upper endoscopy was performed at entry and 2 h after the final dose of aspirin. Enprostil 70 micrograms b.i.d. afforded significant protection of both the antral and duodenal mucosa. The 7-micrograms dose protected only the antral mucosa. Side effects were not observed with the lower dose of enprostil. Serum salicylate levels did not differ significantly between the groups.

Adolescent↗
PubMed1985

The analgesic and anti-inflammatory profile of ketorolac and its tromethamine salt.

Ketorolac tromethamine[(+/-)-5(benzoyl)-2,3-dihydro-1N-pyrrolizine-1-carboxylic acid tris hydroxymethylaminomethane salt] is a highly potent member of a new class of compounds having analgesic and anti-inflammatory activity. When given orally in tests involving underlying inflammation it was a potent analgesic, whereas it was inactive in tests for narcotic activity. It was also highly active orally in rat models of acute and chronic inflammation and pyresis. These properties are mediated primarily via the compound's potent prostaglandin cyclooxygenase inhibitory activity. The agent elicited mild CNS and cardiovascular activity only at doses far in excess of those required for analgesic and anti-inflammatory activity. A single 10 mg tablet given orally to human volunteers following surgery provided pain relief equivalent to that provided by 10 mg of morphine given intramuscularly. When given intramuscularly to rabbits (0.25 ml of a 0.31-5% solution) or man (3 ml of a 1-3% solution), no drug-related irritation or changes in creatine phosphokinase were seen. Solutions (less than or equal to 0.5%) applied to the eyes of animals and man were not irritating. When applied topically in rat and rabbit models of ocular inflammation, less than or equal to 0.5% solutions of ketorolac tromethamine inhibited the inflammatory response.

Administration, Oral↗
PubMed1976

Pharmacokinetics of naproxen overdoses.

In earlier safety studies, naproxen, 600 mg three times daily, was administered to healthy subject without significant adverse effects. Another study demonstrated that single doses of 500 to 900 mg resulted in accelerated renal clearance and a nonlinear naproxen plasma level response after the higher doses. Our report describes the pharmacokinetics of naproxen when administered in single doses of 1, 2, 3, or 4 gm (up to eight times the clinically effective dose in rheumatoid arthritis) to healthy subjects. An increase in urinary excretion rate and continuation of the previously documented nonlinear plasma level response were observed. There were no signs that capacity to conjugate or to excrete the drug was exceeded. There were no adverse effects.

Adolescent↗