Biomedical subjects

J Demetriades

Publications and source records attributed to J Demetriades.

6 recordsLinked to original sources

PubMed1995

Effects of scopolamine on spatial working memory in rats pretreated with the serotonergic depleter p-chloroamphetamine.

The present study investigated the mnemonic consequences of muscarinic blockade in rats pretreated with the serotonergic depleter p-chloroamphetamine (PCA). Subjects were initially injected with either PCA (2.5 mg/kg) or saline (SAL) approximately 1 week prior to testing on a working memory version of the Morris water maze (four daily trials for 4 days). Fifteen minutes before each daily session, PCA- and SAL-pretreated subjects were injected either with SAL or with one of two doses of scopolamine (SCOP; 0.5, 1.0 mg/kg). Latency to find the platform on each trial served as the major dependent measure. The results indicated that SCOP increased escape latencies. However, the dose needed to produce this effect was dependent upon whether subjects were pretreated with PCA. Significant increases in escape latencies in SAL-pretreated rats were induced with 1.0 mg/kg SCOP (on Day 1), while 0.5 mg/kg SCOP produced the same effect in PCA-pretreated subjects (on Days 1-4). Thus, although it was clearly demonstrated that muscarinic blockade did impair spatial working memory, the present data indicated that the dose necessary to produce this effect was dependent upon the status of the serotonergic system. More generally, these results imply that the cholinergic and serotonergic systems interact in a functionally important, as yet undetermined manner.

Animals↗

PubMed1982

Pharmacokinetics of the pivaloyloxyethyl (POE) ester of methyldopa, a new prodrug of methyldopa.

A prodrug of methyldopa, the pivaloyloxyethyl (POE) ester, was administered orally to healthy human volunteers at doses equivalent to 500 and 1000 mg of methyldopa and was compared to oral and intravenous doses of methyldopa. The time courses of availability of methyldopa to the general circulation were compared and contrasted with the model-independent estimates of total systemic availability. The POE ester of methyldopa is completely hydrolyzed on the first pass; delivery of methyldopa to the general circulation was faster, more uniform, and more extensive compared to orally administered methyldopa. The systemic availability of methyldopa averaged 64% of the dose with a coefficient of variation (CV) of 15% for the prodrug treatments compared to 27% of the dose with a CV of 63% for methyldopa. First-pass metabolism of drug to the mono-O-sulfate conjugate of methyldopa was lower for the POE ester than for methyldopa.

Absorption↗

PubMed1982

Relationships among timolol doses, plasma concentrations and beta-adrenoceptor blocking activity.

1 We investigated the relationships among dose, plasma concentration and beta-adrenoceptor blockade after single and repeated doses (0.5-20 mg) of timolol and placebo in six normal men. 2 Maximal suppression of exercise-induced tachycardia (bicycle ergometry) was dose-dependent and greater at 2 than at 6 h after dosing; activity up to 12 h was evident on the last dosing day. 3 Attenuation of exercise-induced tachycardia was strongly correlated with the timolol dosage over the 0.5 to 5-10 mg range. 4 A plasma timolol concentration of 27 ng/ml was associated with maximal suppression of exercise-induced tachycardia. 5 Suppression of exercise-induced tachycardia and areas under the plasma concentration-time curves did not differ significantly on the first and last dosing days.

Adrenergic beta-Antagonists↗

PubMedDate not supplied

Evidence for route dependent biotransformation of cyclobenzaprine hydrochloride.

Cyclobenzaprine hydrochloride was administered to healthy volunteers as a 10 mg oral tablet, 10 mg and 20 mg intramuscular injections, and a 10 mg intravenous injection. Urinary excretion and plasma level data for cyclobenzaprine together provide evidence for route dependent biotransformation. Urinary excretion of total cyclobenzaprine (unchanged plus the glucuronide conjugate) was greater for the oral treatment than for the parenteral treatments (i.m. and i.v.). Area under the plasma concentration-time curve for unchanged cyclobenzaprine, however, was less for the oral treatment than for the parenteral treatments. Based on area calculations, the bioavailability of the 10 mg oral tablet, 10 mg i.m. and 20 mg i.m. injection was 0.33, 0.76, and 0.56, respectively, when compared to the 10 mg i.v. injection of cyclobenzaprine hydrochloride. The four treatments were well tolerated and no clinically adverse effects were observed.

Adult↗

PubMedDate not supplied

Urinary metabolites of amitriptyline in the dog.

Dogs excreted approximately 45% of an oral dose of 14C-amitriptyline (30 mg/kg) in the urine in 24 hr. Two new urinary metabolites of the drug were identified as dihydrodiol derivatives of amitriptyline and nortriptyline, respectively. The major metabolite in dog urine was 10-hydroxyamitriptyline, excreted mainly in conjugated form. Other metabolites were characterized as 10-hydroxynortriptyline, amitriptyline N-oxide, and nortriptyline. Together, these metabolites accounted for approximately 47% of the urinary radioactivity.

Amitriptyline↗

PubMedDate not supplied

Epoxide metabolites of protriptyline in rat urine.

Two epoxide metabolites of 5-(3-methylaminopropyl)-5H-dibenzo[a,d]cycloheptene (protriptyline) were identified in the urine of rats given 14-C-labeled drug. They were characterized by mass spectrometry, nuclear magnetic resonance spectrometry, and chemical reactivity as 10,11-dihydro-10,11-epoxy-5(3-methylaminopropyl)-5H-dibenzo[a,d]cycloheptene (I) and 10,11-dihydro-10,11-epoxy-5(3-aminopropyl)-5H-dibenzo[a,d]cycloheptene (II). Over twice as much I as II was excreted and together the two metabolites accounted for approximately 40% of the urinary radioactivity.

Animals↗