Pharmacologic effects in man of a potent, long-acting dopamine receptor agonist.

Single-dose administration of pergolide mesylate (100 to 400 micrograms) results in a dose-related inhibition of prolactin secretion which persists for more than 24 hours. During multiple-dose administration of pergolide, plasma prolactin concentrations remain markedly reduced (greater than 80 percnet) and gradually return to control levels several days after drug administration is discontinued.

11-hydroxy- 9 -tetrahydrocannabinol: pharmacology, disposition, and metabolism of a major metabolite of marihuana in man.

11-Hydroxy-Delta(9)-tetrahydrocannabinol, administered intravenously to man, produces psychologic and pharmacologic effects that persist for several hours. The drug and its metabolites are excreted in urine and feces for more than 1 week. The pharmacology, disposition, and metabolism of 11-hydroxy-Delta(9)-tetra-hydrocannabinol mimic that of Delta(9)-tetrahydrocannabinol, thus providing evidence that Delta(9)-tetrahydrocannabinol (the major active component of marihuana) is converted to the 11-hydroxy compound in man, the latter compound being responsible for the effects.

Physiologic disposition of nabilone, a cannabinol derivative, in man.

Nabilone is a cannabinoid that is being evaluated in man as a potentially useful psychoactive drug. We found that nabilone was readily absorbed from the human gastrointestinal tract when administered orally as a coprecipitate with polyvinyl-pyrrolidone. The absorbed drug disappeared from plasma rather rapidly (half-life, approximately 2 hr), evidently due to extensive tissue distribution and rapid metabolism. The metabolites of nabilone persist in plasma for extended periods (half-life of total radioactivity exceeds 20 hr). Circulating metabolites include isomeric carbinols formed by reduction of the ketone in the 9-position of nabilone. Nabilone is eliminated in feces (about 65% of dose) and urine (20%). The excretory products in urine have not been identified, but metabolites that are labile to hydrolysis by beta-glucuronidase or sulfatase do not appear to be formed in significant amounts. A metabolite of nabilone in feces has been identified as a diol formed by reduction of the 9-keto group plus oxidation at the penultimate carbon of the dimethylheptyl side chain. The long duration of action of nabilone in the face of rapid and extensive metabolic elimination suggests that the pharmacologic effects, at least in part, may be exerted by one or more active metabolites.

Physiologic disposition of lergotrile.

Lergotrile, an ergot alkaloid, has been shown to be effective in treating disorders associated with elevated serum prolactin levels (e.g., galactorrhea-amenorrhea). Lergotrile has also been found to be a potent dopaminergic agonist and thus to be effective in Parkinson's disease. This study describes the physiologic disposition of lergotrile after administration to human volunteers. N-14CH3-lergotrile was rapidly absorbed from the gastrointestinal tract. Lergotrile was detected at low concentrations in plasma when subjects received large doses over extended periods of time. The major portion of radioactivity in plasma was attributed to the presence of circulating metabolites of lergotrile. Lergotrile metabolities were eliminated in the feces (ca. 60%), urine (ca. 20%), and breath (ca. 7% as 14CO2). A metabolite in feces was identified as 13-OH-lergotrile (up to 30% of the dose). A metabolite in urine was formed by conversion of the C8-acetonitrile group of lergotrile to a carboxyl group (about 10% of the dose). The presence of 14CO2 in the expired air after administering N-14C-methyl-lergotrile indicated that the drug was N-demethylated to form norlergotrile.

The evolutionary enigma of bonefishes (Albula spp.): cryptic species and ancient separations in a globally distributed shorefish.

Many examples of cryptic marine species have been demonstrated with biochemical and molecular studies. In most cases, a broadly distributed taxon is actually a group of sibling species that can be distinguished (upon closer examination) by ecological or morphological characters. Fishes of the family Albulidae constitute a notable exception. Bonefish (Albula spp.) morphology and ecology are highly conserved around the globe, and their extended pelagic larval stage could allow population connections on a vast geographic scale. Based on this perceived homogeneity, bonefishes were classified as a single pantropical species, A. vulpes. However, allozyme studies of Hawaiian populations indicated that two sympatric species (A. glossodonta and A. neoguinaica) are included in the synonymy of A. vulpes. To ascertain the number and distribution of evolutionary partitions in Albula, we surveyed 564 bp of mitochondrial DNA (mtDNA) cytochrome b from 174 individuals collected at 26 locations. Sequence comparisons reveal eight deep lineages (d = 5.56-30.6%) and significant population structure within three of the four lineages that could be tested (phiST = 0.047-0.678). These findings confirm the genetic distinctiveness of the three species noted above and invoke the possibility of five additional species. Clock estimates for mtDNA indicate that these putative species arose 4-20 million years ago. Distinct evolutionary lineages coexist in several sample locations, yet show little morphological or ecological differentiation in sympatry. Thus, bonefish species seem to defy the evolutionary conventions of morphological differentiation over time and ecological displacement in sympatry. Despite multiple cases of sympatry, sister-taxa relationships inferred from mtDNA indicate that divergence in allopatry has been the predominant speciation mechanism in Albula. Stabilizing selection in the homogeneous habitat occupied by bonefishes (tropical sand flats) could promote the retention of highly conserved morphology and ecology.

Gastrointestinal microbleeding: comparisons between benoxaprofen and other nonsteroidal antiinflammatory agents.

Unlike other nonsteroidal antiinflammatory agents, benoxaprofen has only minor antiprostaglandin synthetase activity. This property may explain the lack of gastric irritation seen in animal studies. To evaluate gastric irritation in man, benoxaprofen was compared with aspirin, naproxen, ibuprofen, sulindac, and indomethacin by measuring fecal blood loss with chromium-51 tagged red blood cells in randomized double-blind crossover and parallel studies. Benoxaprofen produced significantly less blood loss than aspirin, naproxen, or indomethacin, and less blood loss than ibuprofen or sulindac. Benoxaprofen also caused the fewest gastrointestinal complaints.

Tracer microspheres as compliance markers in clinical research.

Tracer microspheres are small, ceramic-like particles (50 micron) containing one of several radionuclide markers. We have utilized them over a period of 9 years as quantitative fecal markers for recovery measurements in metabolic studies. The markers have been administered daily for up to 2 weeks, during which time the marker concentration per unit dry weight of feces remains fairly constant. Data on the markers and our experience with them are presented along with the concerns that must be addressed in considering them as compliance markers.

The disposition of l-3-[(dimethylamino)-(m-dioxan-5-yl)methyl]pyridine in man.

l-3-[(Dimethylamino)-(m-dioxan-5-yl)methyl]pyridine hydrochloride (LY 108380) is being evaluated in man as a potentially useful, nonaddicting analgesic agent. This substituted dioxane is structurally different from any currently known analgesic. Following im administration of the 14C-labeled compound to healthy volunteers, the drug was absorbed rapidly (t1/2(abs) = 2--20 min). Pharmacokinetic analyses suggested that LY 108380 was widely distributed and extensively bound in tissues. The drug was not bound to plasma proteins in vitro or in vivo. In the blood, radioactivity was distributed in both red cells and plasma; a cell/plasma radioactivity ratio of 0.5 was maintained for about 1 hr. The t1/2 for elimination of LY 108380-14C from plasma was about 1.3 hr, although radioactivity persisted in plasma for over 100 hr. At the time of peak radioactivity, the parent compound was the major constituent in plasma; quaternary N-glucuronide and N-desmethylated metabolites were also detected in plasma. Levels of radioactivity in saliva were 2--5 times higher than those in plasma shortly after drug administration. About 82% of the radioactivity was eliminated in the urine, 6% in expired air (as 14CO2), and 1% in feces. The major metabolite of LY 108380 (55% of the dose) was a quaternary amine formed by glucuronidation at the pyridine nitrogen. Less than 10% of the dose was N-demethylated to secondary and primary amines, and about 2% was excreted unchanged.

Metabolism of propionyl erythromycin lauryl sulfate. II. Fate of the lauryl sulfate moiety in the rat and man.

The absorption, excretion, and metabolism of [1-14C]lauryl sulfate as either the sodium or propionyl erythromycin salt has been studied in the rat and man. In the rat 88% of the radiolabel from propionyl erythromycin [1-14C]lauryl sulfate was excreted in the urine in the 24-hr period following a single oral dose. More than 95% of the radiolabel was excreted as the metabolite butyric acid 4-sulfate. This metabolite was shown to be derived from carbons 1-4 of the lauryl sulfate moiety. There was no evidence of sulfate cleavage in the rat. In man 51-59% of the administered ratioactivity was recovered in the urine. The major excretion product was butyric acid 4-sulfate accounting for approximately 95% of urinary radioactivity. The remainder was unchanged lauryl sulfate. A significant portion of the radiolabeled propionyl erythromycin lauryl sulfate was converted to 14CO2 indicating that the sulfate linkage was cleaved. A minimum value of 9-16% of the dose was metabolized in this manner.