Mice were conditioned to respond for water reinforcements on a FR-5 schedule. Taurine, injected intraperitoneally at doses of 9.0, 13.8, and 21.3 mmole/kg 30 min prior to the experimental session, produced a dose-related decrease in both the initial response rate and total number of reinforcements received by mice deprived of water for 24 hr. The structural analogues of taurine (aminomethanesulfonic acid, 3-aminopropanesulfonic acid, beta-alanine, cysteamine, and glycine) also produced a hypodipsia. Doses of taurine which produced depression of responding for water reinforcements were used which produced no suppression of spontaneous motor activity, rotarod performance, Sidman avoidance, or shuttle-box avoidance. After intraperitoneal injection, the concentration of taurine increased in the hypothalamus and medulla, but not in other brain areas. We suggest that taurine might be acting by specifically depressing areas of the hypothalamus which stimulate drinking.

Animals↗

PubMedDate not supplied

Biochemical synthesis of stereospecifically hydrogen labeled compounds on a preparative scale, VI1-3 Synthesis of further substrates of NAD(P)-linked dehydrogenases of high specific tritium content.

The preparation of (R) and (S) [2(-3)H]lactate as well as (S) [2(-3)H] glutamate via the coupled exchange reaction catalyzed by NAD linked dehydrogenases and NADH: lipoamide oxidoreductase (diaphorase) is described. The specific radioactivity of the hydrogen ions of the 3HOH/H2O can be obtained in the substrates (100% exchange) if equilibrium isotope effects are disregarded. By the exchange procedure substrates with higher specific radioactivity are obtained from positionally [3H]labeled racemic mixtures prepared by chemical reductions with [3H]labeled hydrides. The tritium content of one of the enantiomeres is "washed out" into water. As examples are presented the preparation of (R) [2-3H] (S) [2-H]malate as well as the corresponding carnitine, glutamate and (R) and (S) lactate.

Alcohol Oxidoreductases↗

PubMedDate not supplied

Determination of the isotope effect of the enzymatic oxidation of (R)Carnitine by displacement of the equilibrium via mass action.

An isotope effect of the dehydrogenation of (R) Carnitine [(R) 3-hydroxy-4-trimethylaminobutyric acid hydrochloride] catalyzed by (R) carnitine dehydrogenase [(R) carnitine: NAD oxidoreductase E.C. 1.1.1.108] from Pseudomonas aeruginosa was measured at different temperatures. It was found that k1H/k3H does not vary greatly with changes of temperature. The value of 3 for k1H/k3H measured at small initial conversions strongly indicated that the rate limiting step of the oxidation of (R) carnitine is the cleavage of the C-H bond at C3.

Alcohol Oxidoreductases↗

PubMedDate not supplied

Drug therapy for geriatric depression.

Depression is a common problem in elderly patients. The identification and treatment of depression may be more complex in older than in younger patients because of co-existing illnesses and concurrent drug therapy. In addition, a variety of medical conditions and drugs can cause depression. The pharmacology and pharmacokinetics of the cyclic antidepressants have been extensively studied. These agents are hepatically metabolised, often to an active agent. The clearance of the parent compound and the active metabolite(s) may be reduced in elderly patients, causing drug accumulation and increased toxicity. The cyclic antidepressants interact with a variety of neurotransmitters and their receptors. While these effects explain many of the adverse effects of the cyclic antidepressants, it is not clear whether the noradrenergic and serotoninergic effects of such drugs explain their antidepressant effects. Cyclic antidepressant therapy is associated with a variety of adverse effects, including sedation, anticholinergic effects and effects caused by alpha-adrenergic blockade. The cyclic antidepressants differ in their relative ability to cause these adverse effects. The newer cyclic antidepressants such as the selective serotonin reuptake inhibitors are relatively free of sedative and anticholinergic effects, but cause insomnia, nausea and possibly cardiac arrhythmias. All cyclic antidepressants appear to be equally effective. Therefore, the choice of a cyclic antidepressant for a specific patient must be based on several factors, including the risk of adverse effects. In elderly patients, the initial dose of cyclic antidepressants should be lower than the usual dose recommended for younger adults, and titrated slowly. All antidepressants require at least 2 to 3 weeks for their antidepressant effects to be seen. Because depression is a relapsing disease, maintenance antidepressant therapy may be indicated to reduce the risk of recurrent depression. The monoamine oxidase (MAO) inhibitors are effective antidepressants, especially in atypical depression. However, the adverse effects and risk of potentially lethal drug interactions of the older agents preclude their routine use. However, the new reversible MAO inhibitors may prove to be a well tolerated alternative in older patients. Antidepressant therapy should not be avoided simply because of a patient's age. However, the clinician must be conservative in the use of cyclic antidepressants in elderly patients and monitor closely for adverse drug reactions.

Aged↗

PubMedDate not supplied

Pharmacokinetics of 14C-isotretinoin in healthy volunteers and volunteers with biliary T-tube drainage.

The pharmacokinetics of isotretinoin and 4-oxoisotretinoin in blood, as well as the blood concentrations and urinary, biliary, and fecal excretion of carbon-14 were studied using liquid scintillation counting techniques and reverse phase HPLC methods following a single 80-mg oral suspension dose of 14C-isotretinoin to four healthy male subjects and two patients with biliary T-tube drainage. Approximately 80% of the dose was recovered as 14C in excreta during the course of the study of which about equal fractions were in the urine and feces. Secondary peaks in blood concentrations of 14C were observed in the healthy subjects whereas they were not seen in the patients with T-tubes. The harmonic mean apparent half-life for isotretinoin in the blood of the healthy subjects was 13.6 hr, whereas the corresponding value for the 14C was 90 hr. Although a rigorous comparison of pharmacokinetic parameters between healthy subjects and T-tube patients was not feasible due to the limited number of subjects studied, comparisons of certain trends in the pharmacokinetic profiles gave some possible insights into the role of biliary excretion and enterohepatic cycling on the disposition of isotretinoin. The data for isotretinoin and 4-oxoisotretinoin coupled with the total carbon-14 data suggest that the oral dose of 14C-isotretinoin is absorbed to a similar extent by the healthy subjects and T-tube patients, whereas T-tube patients clear the drug more rapidly. The biliary excretion and possible enterohepatic circulation of isotretinoin and its metabolites may have significant impact on the pharmacokinetic profile of isotretinoin in man.

Adult↗

PubMedDate not supplied

The disposition and metabolic fate of 14C-cibenzoline in man.

The disposition and metabolic fate of cibenzoline (CBZ) following single oral 153-mg doses of 14C-CBZ succinate were studied in five healthy adult males. The mean maximum plasma radioactivity of 386 ng eq/ml occurred at 2.4 hr after administration. The mean half-life, determined from the 14C plasma concentration and urinary excretion rate data, was 13.1 and 14.8 hr, respectively. The mean maximum CBZ concentration was 196 ng/ml at 1.2 hr post-dose. The mean half-life, determined from the plasma concentration and urinary excretion rate data, was 7.2 and 7.3 hr, respectively. The mean total clearance of radioactivity and CBZ was 300 ml/min and 1224 ml/min, respectively, due to elimination via both renal and nonrenal pathways. The only unconjugated metabolite in the plasma was 4,5-dehydrocibenzoline which, together with other unidentified metabolites, is presumed responsible for the longer observed half-life for total radioactivity. Approximately 75% of the dose was recovered in the urine in the first 24 hr after dosing, 80% of which was present at CBZ and known metabolites. After 6 days, a mean of 85.7% of the dose was excreted in urine and 13.2% in feces. The predominant excreted compound was CBZ (55.7% of the dose) in the 0-72 hr urine. Although several metabolites were identified in urine samples, none were found in substantial amounts relative to the parent drug. Two of these substances showed slight antiarrhythmic activity, whereas the 4,5-dehydro metabolite, representing approximately 4% of radioactivity in urine, was inactive.

Adult↗