Stereoselective disposition of methadone in man.

Stable isotope labeled methadone (pentadeuteromethadone) has been used in conjunction with gas chromatography-chemical ionization mass spectrometry to study plasma disappearance rates and urinary excretion of pharmacologically active R-(?)-methadone (l-methadone) and inactive S-(+)-methadone (d-methadone) in three adult methadone maintenance patients. In all three cases, the analgesically active enantiomeric form of the drug had a significantly longer elimination half-life ($\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext><mtext>\beta </mtext>}}$) when studied in a steady state than did the inactive form ($\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext><mtext>\beta </mtext>}}$ for active R-(?)-methadone, 51.7 to 61.8 hours; $\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext><mtext>\beta </mtext>}}$ for inactive S-(+)-methadone, 31.8 to 37.0 hours). The ratio of drug elimination half-lives } R-(?)-/S-(+)- ranged between 1.40 and 1.94. In the two cases so studied, slower plasma disappearance of active R-(?)-enatiomer than the inactive S-(+)-enantiomer was also observed ($\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2\beta </mtext>}}$ R-(?)-, 42.8 and 52.5 hours; $\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2\beta </mtext>}}$ S-(+)-, 38.3 and 41.3 hours).     

The physiologic disposition of marihuana in man

Marihuana and hashish are the most widely used illicit drugs. They are derived from the hemp plant, $\text{Cannabis sativa}$. Among the diverse chemicals in the plant, more than 20 so-called cannabinoids have been isolated and their chemical structures elucidated (1). In 1965, Mechoulam and coworkers (2,3) isolated △⁹- tetrahydrocannabinol (△⁹-THC) from cannabis extract and demonstrated that it was responsible for the psychopharmacologic effects of cannabis in animals. Later, Isbell (4) and Hollister $\text{et al.}$ (5) confirmed these findings in man. This paper reviews the physiologic disposition of △⁹-THC in man; the disposition of △⁹-THC in animals has been reviewed elsewhere (6, 7, 8).     

Response of plasma adrenal steroids to synthetic ACTH under ketoconazole in man

We have investigated the effect of a single oral administration of 600 mg ketoconazole, an imidazole derivative used in clinical practice as an antimycotic agent, on the response of plasma adrenocortical steroids to 1-24 ACTH in 5 normal male subjects pretreated with dexamethasone. The 2 mg of dexamethasone was administered orally at 2300 h on the preceding night, and then a rapid ACTH test was started at 0830 h. After a 1 week interval, the ACTH test was repeated in the same manner under the same dexamethasone pretreatment, but 600 mg of ketoconazole was given orally at 0500 h. The absolute plasma concentration and the increase over the basal level of each steroid after ACTH were evaluated and compared in both conditions with and without ketoconazole administration. A single ingestion of ketoconazole caused a decrease in both indices of the responsiveness of plasma dehydroepiandrosterone and a rise in the plasma level of 17 alpha-hydroxypregnenolone. The response of plasma aldosterone was clearly blunted by ketoconazole administration, whereas that of plasma corticosterone was clearly increased. Ketoconazole also blocked the response of plasma cortisol with concomitantly increased responses of plasma 11-deoxycortisol and 11-deoxycorticosterone. The increased response of plasma corticosterone seemed to be likely due to the severe inhibitory action of ketoconazole on the conversion of corticosterone to aldosterone. These results imply the inhibitory effect of ketoconazole on C17-20-lyase activity and on the conversion of corticosterone to aldosterone, and suggest an inhibitory action on 11 beta-hydroxylase activity. The effects of ketoconazole on the other enzyme activities in adrenal steroid biosynthesis were also discussed.     

Gonadal steroids deficiency and prolactin response to a met-enkephalin analog in man

The aim of this study was to ascertain whether there is a correlation between gonadal steroids and opioid control of prolactin (PRL) secretion. Four castrated men, aged 18 to 24 years were submitted to intravenous injection of 250 ug of a met-enkephalin analog (D-Ala2-Mephe4-Met-(o)-ol-Enkephalin, FK 33824) (DAMME). In normal men DAMME injection was also performed on the 6th day after treatment with clomiphene citrate (CC) (200 mg/day for 5 days), a specific nonsteroidal estrogen receptor blocker. In castrated men and in normal men after CC treatment, there was a lower PRL response to DAMME than in controls (P less than 0.0005). These results suggest that gonadal steroid deficiency seems to cause a change in the opioid system and/or dopaminergic control of prolactin secretion.     

Effect of parenteral steroids on edema in replanted rat legs

The experiments described demonstrate that parenteral steroid therapy will decrease the amount of postoperative edema in the replanted leg of a rat.