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Biomedical subjects

L F Gram

Publications and source records attributed to L F Gram.

At least 109 records · Page 6Linked to original sources
PubMed1989

Cortisol and treatment of depression: predictive value of spontaneous and suppressed cortisol levels and course of spontaneous plasma cortisol.

In 72 consecutive depressed hospitalized patients afternoon plasma cortisol was measured in three ways before treatment with antidepressants: 1) Spontaneous (n = 72), 2) 2h after oxazepam suppression (45 mg, n = 28; 60 mg, n = 37) and 3) 16 h after dexamethasone suppression (2 mg, n = 71). In addition, spontaneous cortisol was measured after 3 weeks' treatment (n = 55) and 5 weeks' treatment (n = 36). Both spontaneous and suppressed cortisol levels seemed to have a predictive value in the endogenously depressed patients: complete responders had significantly lower pretreatment cortisol levels compared to poor responders. However, other covarying factors such as distress and age may as well account for the differences in treatment effect. During treatment a significant decrease of spontaneous cortisol was found from about 400 nM in poor responders and 325 nM in complete responders to about 300 nM in all groups. There was a positive correlation between pre- and post-treatment cortisol levels and between pretreatment levels and per cent fall in spontaneous cortisol levels.

Adult↗
PubMed1989

Imipramine treatment in diabetic neuropathy: relief of subjective symptoms without changes in peripheral and autonomic nerve function.

The effect of imipramine on symptomatic peripheral diabetic neuropathy in 9 patients was examined in a double-blind cross-over study against placebo. The dose of imipramine was adjusted to yield optimal plasma levels of imipramine plus desipramine of 300-750 nM. Imipramine had a clear beneificial effect on the symptoms of the neuropathy, whereas no changes in a range of neurophysiological measurement was detected. Despite some adverse effects, especially of an anticholinergic nature, the patients generally preferred imipramine to placebo.

Adult↗
PubMed1989

Quinidine inhibits the 2-hydroxylation of imipramine and desipramine but not the demethylation of imipramine.

On separate occasions 6 extensive metabolizers of sparteine took a single oral dose of 100 mg imipramine and desipramine before and during the intake of quinidine sulphate 200 mg/day. During quinidine the total oral clearance of imipramine on average was reduced by 35%, and that of desipramine by 85%. The clearance of imipramine via demethylation was not significantly reduced during quinidine administration, whereas its clearance by other pathways, largely 2-hydroxylation, was reduced by more than 50%. 2-OH-Imipramine and 2-OH-desipramine were detected in plasma before (maximum concentrations 30-100 nmol.l-1) but not during quinidine. It appears that quinidine is a potent inhibitor of the sparteine/debrisoquine oxygenase, P450dbl, which is responsible for the 2-hydroxylation of imipramine and desipramine, but not of the P450 isozyme responsible for the demethylation of imipramine.

Adult↗
PubMed1989

Clinical significance of the sparteine/debrisoquine oxidation polymorphism.

The sparteine/debrisoquine oxidation polymorphism results from differences in the activity of one isozyme of cytochrome P450, the P450db1 (P450 IID1). The oxidation of more than 20 clinically useful drugs has now been shown to be under similar genetic control to that of sparteine/debrisoquine. The clinical significance of this polymorphism may be defined by the value of phenotyping patients before treatment. The clinical significance of such polymorphic elimination of a particular drug can be analyzed in three steps: first, does the kinetics of active principle of a drug depend significantly on P450db1?; second, is the resulting pharmacokinetic variability of any clinical importance?; and third, can the variation in response be assessed by direct clinical or paraclinical measurements? It is concluded from such an analysis that, in general, the sparteine/debrisoquine oxidation polymorphism is of significance in patient management only for those drugs for which plasma concentration measurements are considered useful and for which the elimination of the drug and/or its active metabolite is mainly determined by P450db1. At present, this applies to tricyclic antidepressants and to certain neuroleptics (e.g. perphenazine and thioridazine) and antiarrhythmics (e.g. propafenone and flecainide). Phenotyping should be introduced in to clinical routine under strictly controlled conditions to afford a better understanding of its potentials and limitations. The increasing knowledge of specific substrates and inhibitors of P450db1 allows precise predictions of drug-drug interactions. At present, the strong inhibitory effect of neuroleptics on the metabolism of tricyclic antidepressants represents the best clinically documented and most relevant example of such an interaction.

Antidepressive Agents, Tricyclic↗
PubMed1989

Plasma noradrenaline response to a multistage exercise test in young men at increased risk of developing essential hypertension.

Venous plasma noradrenaline (PNA) was recorded during a multistage exercise test in order to assess the possible role of excess sympathetic nervous system activity in young men at increased risk of developing essential hypertension, and to analyse whether any such involvement was associated with heredity and/or borderline hypertension. Four groups were evaluated: 28 normotensive (NTO) and 20 borderline hypertensive (BHO) offspring of hypertensives, 12 borderline hypertensives with normotensive parents (BH) and 28 normotensives with normotensive parents (NT). Analysis of variance showed that heredity per se was associated with an increased PNA response to light exercise. In NT, PNA correlated with age at rest and light exercise (r = 0.39-0.58, P less than 0.05-0.005). When the influence of age was controlled for by dividing the subjects into two age groups a more pronounced increase in PNA response to light exercise was found in the youngest age group of offspring hypertensives (17-26 years), whereas no differences between the groups were observed in the upper age group (27-40 years). Our results indicate the presence of a hyperreactivity of the sympathetic nervous system during light exercise in young offspring of hypertensives.

Adolescent↗
PubMed1989

Steady-state plasma levels of E- and Z-10-OH-nortriptyline in nortriptyline-treated patients: significance of concurrent medication and the sparteine oxidation phenotype.

Steady-state plasma levels of nortriptyline and E- and Z-10-OH-nortriptyline were determined in 55 depressed patients during long-term treatment. Dose-corrected steady-state levels varied by a factor of 20 for nortriptyline, a factor of 7 for E-10-OH-nortriptyline (sum of enantiomers), and a factor of 12 for Z-10-OH-nortriptyline (sum of enantiomers). The E-10-OH-nortriptyline levels were higher than the corresponding nortriptyline levels in about 50% of the patients and the nortriptyline/E-10-OH-nortriptyline ratio ranged from 0.27 to 4.8. In contrast to E-10-OH-nortriptyline, the steady-state levels of Z-10-OH-nortriptyline correlated significantly with the nortriptyline levels (rs = 0.68, n = 55, p less than 0.001) and the nortriptyline/Z-10-OH-nortriptyline ranged from 1.7 to 10. Patients on concurrent treatment with perphenazine or benzodiazepines had higher nortriptyline and nortriptyline/E-10-OH-nortriptyline ratios than patients taking lithium or no other psychotropic drugs. A sparteine test was carried out in 22 patients and the sparteine metabolic ratio correlated significantly with the dose-corrected steady-state levels of nortriptyline (rs = 0.62, p less than 0.01) and E-10-OH-nortriptyline (rs = -0.52, p less than 0.02) and particularly well with the ratio nortriptyline/E-10-OH-nortriptyline (rs = 0.83). The genetic variability in the sparteine/debrisoquine P-450 isozyme appeared to be clearly more important for the interindividual variation in 10-hydroxylation of nortriptyline than the possible interactions with concurrent medication.

Adult↗
PubMed1989

Mephenytoin and sparteine oxidation: genetic polymorphisms in Denmark.

The oxidation of mephenytoin was polymorphic in 358 healthy Danish volunteers. The ratio between the chromatographic peak areas of (S)- and (R)-mephenytoin (S/R) in 12 h urine was less than or equal to 0.48 in 349 extensive metabolizers (EM) and greater than or equal to 1 in 9 (2.5%) poor metabolizers (PM). Concomitant intake of mephenytoin and sparteine and subsequent assay by gas chromatography had no influence on the test results (mephenytoin S/R ratio or sparteine metabolic ratio). Among ten parents and seven siblings to six unrelated PM of mephenytoin only one (1/17 = 5.9%) was a PM. The pedigrees were compatible with an autosomal recessive mode of inheritance.

Adolescent↗
PubMed1989

Substantial rise in sparteine metabolic ratio during haloperidol treatment.

A sparteine test was carried out in 14 patients suffering from acute schizophrenic psychoses before and 1-2 times during oral haloperidol treatment in doses of 10-40 mg day-1. In patients classified as extensive metabolisers (sparteine MR less than 20 before treatment), haloperidol treatment resulted in a rise in sparteine MR that correlated with the serum-haloperidol concentration both within and between patients. At the highest serum haloperidol concentrations (60-80 nM) an increase in sparteine MR by a factor 15-50 was seen, but no patients were transformed into phenotypically poor metabolisers. The steady state concentration of haloperidol on the initial standard dose of 10 mg day-1 was the same in one patient classified as a sparteine poor metaboliser (MR = 112) as in eleven patients classified as extensive metabolisers (MR:0.22-1.47).

Adult↗
PubMed1989

Quinidine disposition in relation to antipyrine elimination and debrisoquine phenotype in alcoholic patients with and without cirrhosis.

Single dose disposition of oral quinidine (400 mg sulfate) was studied in a control group of subjects (No. = 6) and in hospitalized alcoholic patients involving one group with (No. = 6) and one group without (No. = 11) hepatic cirrhosis. All subjects also underwent an antipyrine and a debrisoquine test. Patients with cirrhosis had a prolonged elimination half-life (29.5 +/- 5.9 h) and low clearance (24 +/- 7 ml.kg-1.h-1) of antipyrine and also a considerably higher debrisoquine metabolic ratio (18.8 +/- 3.3) than the controls, whereas the alcoholics without cirrhosis had metabolic patterns for these two test compounds comparable to those seen in the controls (antipyrine half-life: 8.8 +/- 1.1 h and 9.8 +/- 2.0 h; debrisoquine metabolic ratio: 3.6 +/- 0.7 and 3.8 +/- 1.2 for alcoholics and controls respectively). In patients with cirrhosis the apparent elimination half-life of quinidine was longer (12.8 +/- 1.8 h) whereas after oral administration clearance of quinidine (15.6 +/- 3.5 l.h-1) and quinidine/3-hydroxyquinidine ratio (9.9 +/- 2.1) were not different from controls (quinidine clearance: 13.45 +/- 1.9 l.h-1; quinidine/3-hydroxyquinidine: 10.3 +/- 2.7). A possible change in distribution patterns of quinidine in cirrhotics may explain these findings.

Adult↗
PubMed1988

Adverse drug reactions and drug non-compliance as primary causes of admission to a cardiology department.

426 consecutive patients admitted to a Danish University Department of Cardiology have been studied. Drug intake prior to admission by each patient was ascertained from medical records and personal interviews. Adverse drug reactions (ADR) were the primary cause of admission in 49 patients (11.5%), and 16 patients (3.8%) were admitted due to drug non-compliance (DNC). Thiazide diuretics, beta-adrenoceptor blocking agents and calcium antagonists accounted for almost 60% of all the ADR-related admissions. Patients admitted for ADR took significantly more drugs than patients admitted for other reasons. DNC was not correlated with the number of prescribed drugs. It is concluded that drug-related hospital admissions are an important medical and economic problem. Most of the ADRs were well-known and predictable actions of the drugs, and could have been avoided by more careful clinical and laboratory monitoring of the patients. Most of the DNC, too, could have been avoided by giving better information to the patients.

Age Factors↗
PubMed1988

First-pass metabolism of imipramine and desipramine: impact of the sparteine oxidation phenotype.

Four rapid extensive metabolizers (EM), four slow EM, and three poor metabolizers (PM) of sparteine were given single intravenous doses of 50 mg imipramine and desipramine. All subjects had previously taken single oral doses (100 mg) of imipramine and desipramine. The first-pass metabolism of imipramine and desipramine ranged from 23% to 73% and 0% to 48%, respectively, and was more pronounced for both drugs in EM than in poor metabolizers. The study suggested saturable 2-hydroxylation of imipramine and desipramine during the first-pass through the liver, especially in EM.

Adult↗
PubMed1988

Afternoon plasma cortisol in relation to depression. A replication study.

In 37 consecutive depressed inpatients afternoon plasma cortisol (1500-1520 h) was measured in 3 ways: 1) spontaneously; 2) 2 h after oral administration of 60 mg oxazepam; and 3) 16 h after oral administration of 2 mg dexamethasone. Both oxazepam and dexamethasone caused a significant suppression of cortisol secretion. Spontaneous and suppressed cortisol levels correlated significantly to stress/distress items on the Hamilton Rating Scale for Depression (sum of items 8, 9, 10 and 12), whereas no correlations to age, or type of depression were found. In an earlier similar study of 35 patients both spontaneous and suppressed cortisol levels correlated significantly with age, type and severity of depression as well as with the stress/distress items. Those patients were older, more depressed (HRSD-17) and had higher stress/distress scores compared with the present sample of 37 patients. The consistent finding of a correlation with the stress/distress items suggest that this factor is important in relation to the hypersecretion of cortisol during depression and this may explain the limited diagnostic power of spontaneous and suppressed cortisol levels.

Adult↗
PubMed1988

Imipramine: a model substance in pharmacokinetic research.

The pharmacokinetics of imipramine have been studied over a period of 20 years. Imipramine is rapidly and almost completely metabolized with the formation of desipramine (desmethylation), 2-hydroxy metabolites and subsequent glucoronide coupling. Imipramine has a high clearance (0.8-1.5 l/min) and a corresponding high first pass elimination (30-70%). Volume of distribution is high (650-1100 1) and half-lives accordingly of medium length (6-12 h). The 2-hydroxylation which is the most important step of elimination is mediated via microsomal cytochrome P450 isozyme that exhibit monogenetic polymorphism such that 5-10% of the population have a severely reduced clearance. Co-administration of neuroleptics may also considerably impair the 2-hydroxylation. Steady-state levels of imipramine and desipramine varies considerably among individuals mainly due to variations in metabolism, but also to a smaller extent due to variations in binding to plasma proteins. The variations in steady-state concentrations appear to have clear implication for the clinical effects of imipramine.

Depressive Disorder↗