Prolactin responsiveness to repeated decremental doses of sulpiride.

The variation in the prolactin response to sulpiride was studied in six normal men by repeating the same dose of the drug (50 mg) after 24 hours and on three subsequent occasions, repeating this 2 day test at an interval of 6 days with progressively halved doses of sulpiride. A similar PRL response occurred on the first day of each test period and the peak response was highly significant (P less than 0.001), occurring within 30 minutes. A gross blunting of the PRL response on the second day of each period was noted throughout the study. The difference in delta PRL between the first and second day of each period was highly significant (P less than 0.001). The delta PRL increment on the second day was inversely proportional to the dose of sulpiride; the differences in delta PRL between periods 1 and 3 and periods 1 and 4 being highly significant (P less than 0.001). This study suggests that a much lower dose of sulpiride than that normally used is adequate to stimulate PRL secretion and that care must be taken in the timing of repeat testing.

The metabolic fate of Sormodren (bornaprine hydrochloride) in animals and humans.

1. Single oral doses of the anticholinergic drug [14C]Sormodren to rats (1 mg/kg), dogs (0.3 mg/kg) and humans (0.03 mg/kg) were well absorbed. Excreted in urine and faeces were means of 31 and 70%, 53 and 39%, and 78 and 4% in rats, dogs, and humans, respectively, during five days: excretion was prolonged and still incomplete at five days in humans. 2. Peak plasma levels of 14C (scaled for dose) were generally reached within 1-2 h after oral doses in rats, 49 (ng/ml)/(mg/kg), dogs 290 (ng/ml)/(mg/kg) and humans 410 (ng/ml)/(mg/kg), and declined with half-lives of approx. 5, 12 and 30 h, in these species respectively. Repeated oral doses of [14C]Sormodren to dogs resulted in some accumulation of 14C in the plasma. 3. Tissue concn. of 14C in dogs were generally higher than those in rats, particularly in the brain, lungs and eyes. The tissue distribution of 14C in rats and dogs was consistent with that of a compound readily eliminated by both renal and hepatic routes. 4. Basic metabolites in dog and human, urine and plasma were investigated using a combination of h.p.l.c. and g.l.c.-mass spectrometry. Unchanged Sormodren was not detected in the dog samples and was only a minor component in human urine and plasma. Some metabolites were present as conjugates. 5. A basic extract of enzyme-hydrolysed dog urine (5 mg/kg dose) contained 42% of the urine 14C. The major metabolites in this fraction were identified as three isomers of monohydroxy-N-desethyl-Sormodren and three isomers of monohydroxy-Sormodren, resulting from hydroxylation in the bicyclic ring. The positions of oxidation were not determined. A similar extract from dog urine (0.3 mg/kg dose) contained 26% of the urine 14C and the major metabolites were identified as isomers of monohydroxy-N-desethyl-Sormodren. 6. A basic extract of enzyme-hydrolysed human urine (0.03 mg/kg dose) contained 23% of the urine 14C. The unchanged drug was only a minor component and most of the radioactivity was associated with five isomers of monohydroxy-Sormodren, hydroxylation having occurred in the bicyclic ring. 7. Basic extracts of dog and human plasma only contained about 10% of the plasma 14C. Metabolites were chromatographically similar to the hydroxylated metabolites identified in the corresponding urine samples.

Determination of the antispasmodic agent ethaverine in human plasma by high-performance liquid chromatography.

Ethaverine can be measured in the plasma of human subjects by reversed-phase high-performance liquid chromatography employing UV detection. The limit of detection was 2 ng/ml, and the precision was +/- 14, +/- 6 and +/- 2% at concentrations of 5, 25 and 50 ng/ml respectively. A peak mean plasma drug concentration of 20 ng/ml occurred at 1.5 h after single oral doses of a capsule formulation to human subjects, and declined with a half-life of 2.9 h.

Sleep-endocrine profile of the antidepressant mianserin.

The effects of mianserin, a tetracyclic antidepressant, on sleep stages and on the nocturnal secretion of cortisol, ACTH, growth hormone, prolactin and tryptophan were studied on 11 normal male volunteers in a double-blind, placebo-controlled study. Mianserin increased Stage 3 time (p less than 0.001) and Stage 4 time (p less than 0.01). It reduced the number of REM periods (p less than 0.001), the REM latency after sleep onset (p less than 0.01) and both the total and percentage REM time (p less than 0.05). A reduction in both the total sleep time (p less than 0.05) and the percentage of total time in bed (p less than 0.05) were the only significantly carry-over effects from the drug treatment period. No significant difference in any biochemical measurement was found between placebo and drug treatment.

Pharmacokinetics of isosorbide dinitrate after intravenous infusion in human subjects.

Plasma concentrations of isosorbide dinitrate have been measured after intravenous infusion of drug at a rate of 5.0 mg h-1 for 150 min and after single equal oral doses of 12.5 mg of drug in solution to two normal human subjects. During the infusion, uneven plateau concentrations were approached after 30 min. The calculated average steady-state plasma levels were 258 ng ml-1 and 514 ng ml-1 in the two subjects respectively. The half-life of elimination of isosorbide dinitrate after termination of the infusion was 9--10 min. After oral doses, peak plasma levels of 26.6 ng ml-1 and 12.7 ng ml-1 occurred at 10 min and 20 min in the two subjects respectively. The terminal half-life of drug after the oral doses was much longer than the elimination half-life (about 10 min), and was associated with the absorption phase. Fairly good agreement was obtained between the observed concentrations and those predicted by a one-compartment open model. The systemic availability of isosorbide dinitrate after the oral doses was up to only 3 per cent of the equal doses infused, indicating that presystemic elimination processes accounted for very large proportions of the oral doses. The systemic clearances of drug after infusion of 0.32 l min-1 and 0.16 l min-1 were unexpectedly low for a drug of reported high liver extraction ratio.

High-performance liquid chromatographic determination of the nitroimidazole azanidazole in human plasma and urine.

Azanidazole can be measured in plasma and urine by reversed-phase high-performance liquid chromatography employing UV detection. Peak mean plasma concentrations of azanidazole, of 267 ng/ml, occurred at 1.5 h after single oral doses to human subjects, and declined with a half-life of 0.8 h. Less than 0.5% of the dose was excreted in the urine as unchanged drug. Metabolites of azanidazole were also detected by the procedures used.

Plasma concentrations and pharmacokinetics of dihydralazine after single oral doses to human subjects.

After single oral doses of 20 mg of a suspension of dihydralazine sulphate to human subjects, the peak of mean plasma concentrations of dihydralazine of 47.0 ng ml-1 +/- 11.0 standard deviation (S.D.) (n = 7) was reached at 1 h. Mean concentrations declined biphasically with apparent half-lives of 0.57 and 4.96 h respectively. Dihydralazine was partly converted to hydralazine. The peak of mean plasma concentrations of the latter drug of 3.9 ng ml-1 +/- 1.7 S.D. (n = 7) occurred at 1-2 h after dosing with dihydralazine sulphate and declined to 1.5 ng ml-1 +/- 1.5 S.D. at 6 h. Of the seven subjects studied, three were classified as fast and four as slow acetylators. Mean clearances appeared to be slightly more rapid in fast acetylators (1.63 l min-1 +/- 0.32 S.D.) when compared to slow acetylators (1.31 l min-1 +/- 0.31 S.D.) but this difference and differences in plasma concentrations and in areas under the plasma drug concentration-time curves were not significant (p > 0.1).

Pituitary thyroid function and prolactin release following intravenous administration of TRH and pyroglutamyl-histidyl-prolyl-ß alanine amide to healthy volunteers.

The synthetic oligopeptide pyroglutamyl-histidyl-prolyl-ß-alanine amide, structurally related to thyrotrophin releasing hormone (TRH), has been investigated in healthy male volunteers for its effect on pituitary thyroid function and on serum prolactin levels. In an open randomised 2-way crossover study the peptide has been compared with TRH on an equal dose basis following intravenous administration at 4 dose levels. The synthetic material had significantly lower thyrotrophin (TSH)-releasing activity than TRH while the prolactin releasing potencies of the 2 peptides were about equal.

Plasma concentrations of isosorbide dinitrate after cutaneous and sublingual doses to human subjects.

After application of 100 mg (nominal dose) isosorbide dinitrate as an ointment to the skin of human subjects, mean drug concentrations were 1 to 2 ng/ml for 1.5 hour and reached a peak of 6.2 ng/ml at 6 hours. Thereafter, mean concentrations declined slowly to 2.9 ng/ml at 12 hours and 1.2 ng/ml at 24 hours. After a sublingual dose of 5 mg isosorbide dinitrate, mean drug concentrations reached a peak of 15.9 ng/ml at 0.5 hour and declined with a half-life of about 50 minutes. The mean bioavailability of isosorbide dinitrate from the ointment was estimated as 30 per cent of that from the sublingual tablet when corrected for differences in dose/body weight ratio. The results demonstrate that concentrations of isosorbide dinitrate in plasma can be maintained for relatively long periods when the drug is applied to the skin.

Pharmacokinetics of flunitrazepam following single- and multiple-dose oral administration to healthy human subjects.

Healthy human subjects received single and multiple oral doses of flunitrazepam. Absorption and disposition were first order and reproducible from administration. The oral doses were virtually completely available to the liver, and elimination from the body occurred entirely via metabolism. Assuming the liver to be the sole eliminating organ, hepatic blood clearance and extraction ratio were approximately 0.235 liter/hr/kg and 0.154, respectively. Steady-state blood volume of distribution averaged 3.76 liters/kg in the single-dose studies. Terminal exponential half-lives from the single- and multiple-dose studies (different subjects) averaged 13.5 and 19.2 hr, respectively; these differences were not due to clearance changes but were entirely attributable to variations in volumes of distribution.

Plasma concentrations of isosorbide dinitrate after administration of increasing doses of a sustained-release formulation to human subjects.

Plasma concentrations of isosorbide dinitrate have been measured after administration of increasing doses in the range 20--100 mg as sustained-release tablets (Isoket retard) containing 20 mg to human subjects. Means of peak concentrations of 4.2 ng/ml, 13.1 ng/ml, 20.7 ng/ml, 36.8 ng/ml, and 34.9 ng/ml were measured after doses of 20 mg, 40 mg, 60 mg, 80 mg and 100 mg, respectively. In the plasma of individual subjects, peak concentrations of isosorbide dinitrate increased in proportion to the dose administered. Areas under the plasma isosorbide dinitrate concentration-time curves also increased in proportion to the dose administered. Bioavailability parameters were better correlated to the dose over the range 20--60 mg than over the range 20--100 mg.

Restoration of fertility in prolactin induced premature menopause : A report of an eight year case study.

A case of infertility associated initially with amenorrhoea only and then with amenorrhoea and galactorrhoea following a successfully induced pregnancy is reported. In a period of eight years of continuous investigation and treatment this subject's infertility first responded to sequential clomiphene and human chorionic gonadotrophin (HCG) therapy resulting in a normal pregnancy. Subsequently she became refractory to this therapy. The availability of specific prolactin assays and a prolactin inhibitor (2-Br-α-ergocryptine, bromocriptine Sandoz) identified the aetiology of her amenorrhoea/galactorrhoea/infertility and provided a new mode of therapy. Planned conception has been achieved on three occasions, producing two normal males and a normal female child.