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Biomedical subjects

D K Luscombe

Publications and source records attributed to D K Luscombe.

At least 37 records · Page 2Linked to original sources
PubMed1984

Lormetazepam--plasma concentrations in volunteers following sublingual and oral dosing.

The plasma profile of lormetazepam has been determined in sixteen clinically healthy, adult male volunteers following 1 mg lormetazepam, administered either sublingually or by the oral route. Absorption of lormetazepam was found to be rapid following both sublingual and oral administration. While a trend was observed towards a more rapid rate of absorption after sublingual dosing, statistically, there was no significant difference (p greater than 0.05) between the speed with which lormetazepam was absorbed following sublingual and oral dosing. After absorption, plasma lormetazepam levels rapidly reached mean (+/- s.d.) peak concentrations of 4.9 +/- 0.9 ng/ml and 5.2 +/- 1.7 ng/ml for the sublingual and oral routes, respectively, there being no significant difference (p greater than 0.05) between these values. Likewise, there was no significant difference (p greater than 0.05) in the times at which peak plasma levels were attained in the two groups. Furthermore, measurement of the area under each plasma concentration-time curve showed that the bioavailability of lormetazepam was the same for the two routes of administration. Elimination of lormetazepam followed a similar pattern following sublingual and oral dosing, the mean terminal half-lives being 13.0 h and 13.8 h, respectively. The findings in the present study clearly indicate that the plasma profiles of lormetazepam attained on sublingual and oral dosing are similar, indeed the pharmacokinetic characteristics of this drug appear identical being independent of its route of administration.

Administration, Oral↗
PubMed1983

Influence of the antidepressant binodaline on biogenic amine uptake and brain levels in the rat.

The influence of 1-(omega-dimethylaminoethylmethyl)-amino-3-phenylindole hydrochloride (binodaline, Sgd-Scha 1059) on the uptake of noradrenaline (norepinephrine, NA), 5-hydroxytryptamine (5-HT) and dopamine (DA) into pre-synaptic nerve endings has been studied using purified synaptosomal preparations from various regions of rat brain. Binodaline was found to be an effective inhibitor of biogenic amine uptake the IC50 values being 5.0 X 10(-6) mol/l (NA), 2.3 X 10(-7) mol/l (5-HT) and 1.5 X 10(-6) mol/l (DA). The desmethyl analogue of binodaline (Sgd 20578) also inhibited transmitter uptake into cerebral nerve endings, being more potent than the parent compound in inhibiting NA uptake (8.5 X 10 mol/l), of a similar potency with respect to 5-HT (3.2 X 10(-7) mol/l) and slightly less potent against DA (8.3 X 10(-6) mol/l). Neither binodaline nor the desmethyl derivative was found to influence cerebral levels of NA, 5-HT and DA following acute dosing in rats. Brain concentrations of the related metabolites 5-hydroxyindolacetic acid, dihydroxyphenylacetic acid and homovanillinic acid were also unchanged. It is concluded that binodaline owes its antidepressant activity at least in part to its ability to inhibit monoamine uptake into pre-synaptic cerebral nerve endings.

Animals↗
PubMed1980

Clomipramine and exposure for compulsive rituals: II. Plasma levels, side effects and outcome.

Forty obsessive-compulsive ritualizers received nightly placebo or clomipramine up to 225 mgs nocte for 8 months, and received behavioural treatment (exposure to vivo) from weeks 4 to 10. Plasma concentrations of clomipramine and its primary metabolite N-desmethylclomipramine steadily increased over the first 4 weeks of treatment after which they remained relatively steady. Plasma levels correlated significantly with dose and with outcome but not with side effects. Patients with plasma clomipramine levels in the range 100-250 ng/ml and N-desmethylclomipramine levels between 230-550 ng/ml were found to improve significantly more than patients outside these ranges, thus suggesting a therapeutic window for clomipramine and its primary metabolite.

Clomipramine↗
PubMed1980

Some pharmacological aspects of desmethylclomipramine.

The N-desmethyl metabolites of imipramine and amitriptyline possess antidepressant activity in their own right. To test whether this is also true of desmethylclomipramine, studies have been carried out on appropriate models. Desmethylclomipramine was shown to be present in plasma in higher concentrations than the parent compound, to be strongly active in reversing or suppressing reserpine-induced hypothermia, to possess anticholinergic activity on gastrointestinal smooth muscle, inhibiting motility and antagonizing muscarinic receptors, though to a lesser extent than clomipramine. It is also a more potent inhibitor of noradrenaline and dopamine uptake than clomipramine is, though less potent in inhibiting 5-hydroxytryptamine uptake. The metabolite has antidepressant activity of its own, probably associated with its monoamine uptake inhibitory properties, and doubtless makes an important contribution to the efficacy of treatment of depression with clomipramine; for this reason plasma levels of the metabolite as well as those of the parent compound should be taken into account.

Clomipramine↗
PubMed1980

Clomipramine: plasma levels, side effects and outcome in obsessive-compulsive neurosis.

The relationship between plasma levels of clomipramine and desmethylclomipramine and clinical response was studied in a group of patients with obsessive-compulsive neurosis. In general the response was best in the middle range of plasma concentrations, showing the inverted U curve well recognized with nortriptyline. However, the results of this study suggest that the response of compulsive rituals correlates with levels of plasma clomipramine, while depression appears to correlate with plasma levels of desmethylclomipramine. The former relationship may be the stronger. There may also be some relationship between side effects and relative plasma levels of clomipramine and desmethylclomipramine.

Adolescent↗
PubMed1980

Plasma concentrations of clomipramine and desmethylclomipramine in obsessive-compulsive neurosis.

Patients suffering from chronic obsessive-compulsive states were treated with clomipramine up to 200 mg/day according to tolerance for periods up to 8 months and their plasma clomipramine and desmethylclomipramine concentrations determined weekly by a double radioisotope derivative technique. Plasma concentrations of both the parent compound and its metabolite rose with dose and within 7-14 days of constant dosage reached steady states. A strong positive correlation was found between clomipramine, and to a lesser extent desmethylclomipramine, and the daily dose of clomipramine. In almost all patients plasma desmethylclomipramine concentrations exceeded those of unchanged drug by a factor of two or three.

Adolescent↗
PubMed1980

Influence of age, cigarette smoking and the oral contraceptive on plasma concentrations of clomipramine.

The influence of age, cigarette smoking and the oral contraceptive on the plasma profile and tolerability of clomipramine has been studied in depressed patients given the drug daily for four weeks. Older patients tend to have higher plasma concentrations of clomipramine than the younger and tolerate clomipramine less well; this latter is considered to be at least partly due to the increased plasma concentrations of the drug. Clearly elderly patients need a lower dose than the young if a high incidence of side effects is to be avoided. Patients smoking 15 or more cigarettes a day were found to tolerate daily doses of 75 mg clomipramine far better than non-smokers. Perhaps surprisingly, this was not reflected in lower plasma clomipramine concentrations in smokers, possibly owing to the high drop-out rate amongst non-smokers, which biased these data. Finally, no interaction was observed in females between clomipramine and oral contraceptives, the concomitant administration of which did not influence either plasma clomipramine concentrations or its tolerability.

Adolescent↗
PubMed1979

Quantitative structure--activity relationships and carminative activity II: steric considerations.

The unexplained variation in the relationships between carminative activities and octanol--water distribution coefficients of various classes of compounds was explained. The steric substituent constant (Es) value, van der Waals volume, and molecular connectivity were introduced into a previously derived correlation. Each parameter brought about an improvement, and molecular connectivity was the most successful. Correlations containing molecular connectivity was the most successful. Correlations containing molecular connectivity terms explained the excess variation. The results were in agreement with a mechanism in which carminative activity depended on the availability of the oxygen atom in the functional group of the molecule and was reduced when the substituent attached to the oxygen hindered the interaction between the oxygen atom and the receptor.

Animals↗
PubMed1979

Studies on the absorption, distribution and elimination of 6-o-chlorophenyl-2,4-dihydro-2(N-methyl-piperazin-1-yl)-methylene-8-nitro-1H-imidazo[1,2-a] [1,4]benzodiazepin-1-one methanesulphonate in the male rat and rabbit.

The fate of a novel imidazo-benzodiazepine (I) was studied in male rats and rabbits using 14C and 3H-labelled I. In both species the compound was rapidly and widely absorbed after an oral dose of 5 mg/kg to give peak tissue and plasma levels after 1 hour in the rat and 4 hours in the rabbit. The highest concentrations of radioactivity were present in the liver (rat) and liver, kidney and subcutaneous fat (rabbit). Plasma levels of radioactivity fell to 3% of the maximum value in 24 hours in the rat but 48 hours were required for a similar fall in the rabbit. The main route of elimination of radioactivity was via the bile followed by excretion in the faeces. For the rat the rate of biliary elimination was 16.6% of the administered dose/hour; for the rabbit this rate was 5.6%/hour. Recovery of administered radioactivity during 0-24 hours for urine and faeces respectively was 4.8% and 69% for the rat and 23.2% and 10.9% for the rabbit. Up to 97% of the radioactivity administered to rats could be recovered in the excreta in the 7 days following dosing. Up to 90% of the dose administered to rabbits appeared in the excreta during 10 days. No unchanged (I) could be detected in the urine or bile. The radioactive metabolites were polar products, some of which were in the form of glucuronide conjugates.

Animals↗
PubMed1979

Metabolism of beclamide, N-benzyl-3-chloropropionamide, in man.

1. Following oral administration of [14C]beclamide to human subjects there was almost complete elimination of radioactivity in the urine within 48 h. 2. Less than 1% of the administered dose was excreted unchanged. 3. The major metabolites were (a) N-(4-hydroxybenzyl)-3-chloropropionamide, (4-hydroxybeclamide; c. 56%), which was eliminated to a small extent in the free form and as a sulphate but mainly as a glucuronide, and (b) hippuric acid (c. 20%). 4. Six minor metabolites were also detected, of which the following were identified: benzoic acid (up to c. 7%), N-(4-hydroxybenzyl-3-chloro-2-hydroxypropionamide, (dihydroxy-beclamide; c. 2%, mostly as a glucuronide) and 4-hydroxybenzoic acid (c. 0.6%, partly as a glucuronide).

Adult↗
PubMed1978

Quantitative structure-activity relationships and carminative activity.

Carminative activities of 34 alcohols, esters, ethers, phenols, and carbonyl compounds were determined using the guinea pig isolated ileum preparation and are expressed as the ability to produce a 50% inhibition (ID50) of a standard response to carbachol. Aqueous solubilities were measured at 37 degrees using either UV absorption or GLC. The ratios of solubility to ID50 were reasonably constant, suggesting nonspecific biological activity, similar to that previously observed with general anesthetics. Hansch analysis indicated that carminative activities were largely controlled by solubility, as indicated by octanol-water distribution coefficients. The principal remaining factor appeared to be the steric availability of the oxygen atom in the functional group of the compound.

Animals↗
PubMed1977

Efficacy, side-effects, plasma and blood levels of maprotiline (Ludiomil).

Two trials of maprotiline (Ludiomil) were performed in general practice. In the first study depressed patients were given either 75 mg of maprotiline in a single dose or 25 mg three times daily. Assessments of the severity of depression and of side-effects were made initially and following 1, 2 and 4 weeks' treatment. At each assessment measurements of plasma levels of maprotiline were made. A second trial was performed in which some patients receiving 75 mg single dose of maprotiline had whole blood levels of maprotiline assayed. Steady-state levels of maprotiline were achieved after one week but these levels showed considerable individual variability. No clear correlation emerged between clinical response, side-effects and plasma or blood levels. Some of the factors which may be responsible are discussed.

Adult↗
PubMed1977

Pharmacokinetic studies in obsessional patients.

As part of a larger controlled study, 9 patients with chronic obsessive-compulsive rituals received oral clomipramine (Anafranil, Geigy Pharmaceuticals) and behavioural treatment. Dosage was 20 mg clomipramine during the first three days of treatment, increasing gradually over the next few weeks to a maximum daily dose of 200 mg clomipramine unless side-effects dictated a lower dose. Blood was sampled at weekly intervals and the plasma fraction analyzed simultaneously for clomipramine and its primary metabolic breakdown product, N-desmethylclomipramine, using a double radioisotope derivative technique. Plasma concentrations of clomipramine and desmethylclomipramine were observed to rise as the administered dose was increased during the first few weeks of treatment. However, within seven to fourteen days of constant daily dosing steady-state levels were reached in the plasma of clomipramine and its metabolite. Higher plasma levels were found with higher doses. Steady plasma clomipramine levels appeared to be related to dosage, the mean steady-state plasma concentrations between weeks 5 and 11 of treatment being 99 ng/ml, 145 ng/ml and 180 ng/ml, in patients receiving daily doses of 100, 150 and 200 mg clomipramine, respectively. In contrast, plasma metabolite levels did not show any apparent relationship to dosage. In most patients, the concentration of desmethylchlomipramine in the plasma was approximately twice that of the parent compound.

Adolescent↗