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Biomedical subjects

L F Gram

Publications and source records attributed to L F Gram.

At least 127 records · Page 7Linked to original sources

Extensive metabolizers of debrisoquine become poor metabolizers during quinidine treatment.

Seven male patients (age 55-75 years) were debrisoquine-tested immediately before and after one week of treatment with quinidine sulphate (200 mg X 3-4 day-1). Before quinidine all patients were classified as extensive metabolizers (metabolic ratio 0.1-3.6). During quinidine the formation of 4-OH-debrisoquine was practically abolished and the phenotype of the patients was altered to PM (metabolic ratio 15-51). This is probably due to an inhibition of debrisoquine hydroxylation by quinidine. Inhibition of 4-OH-debrisoquine formation was associated with a disproportionate increase in debrisoquine excretion.

Aged↗

Steady-state concentrations of imipramine and its metabolites in relation to the sparteine/debrisoquine polymorphism.

Thirty-five imipramine treated patients were phenotyped with regard to polymorphic drug oxidation using sparteine and/or debrisoquine. During treatment with 100 mg imipramine per day the mean steady-state concentrations and ratios in 28 extensive metabolizers were: imipramine 169 nmol/l; desipramine 212 nmol/l; 2-OH-imipramine/imipramine 0.25; 2-OH-desipramine/desipramine 0.57. The corresponding values in two poor metabolizers were: imipramine 455 and 302 nmol/l; desipramine 1148 and 1721 nmol/l; 2-OH-imipramine/imipramine 0.06 and 0.05; 2-OH-desipramine/desipramine: 0.09 and 0.04 respectively. The metabolic ratios (MR) sparteine/dehydrosparteine and debrisoquine/4-OH-debrisoquine (% of dose in 12-h urine samples) correlated poorly with the imipramine steady-state concentrations during administration of 100 mg per day, but quite well with the desipramine steady-state concentrations. Significant negative correlations were found between sparteine and debrisoquine MR and the 2-OH-imipramine/imipramine and 2-OH-desipramine/desipramine ratios. In most patients the initial dose was changed to obtain concentrations in the therapeutic range, and concentrations for imipramine + desipramine of (mean +/- SD) 713 +/- 132 nmol/l were achieved in 33 patients. The therapeutic dose was 50 mg per day in one poor metabolizer and ranged from 50-400 mg per day in 32 extensive metabolizers. There was a weak negative correlation between sparteine MR and daily dose. Treatment with imipramine inhibited metabolism of both sparteine and debrisoquine (MR values about doubled), but did not affect the interpatient correlations.

Adult↗

Steady-state levels of imipramine and its metabolites: significance of dose-dependent kinetics.

Seventeen hospitalized patients (age 39-66 years), received a loading dose of 100 mg imipramine HCl and then 50 mg b.i.d. The 12-h plasma concentration at steady-state varied between 40-637 nmol/l for imipramine, 49-1148 nmol/l for desipramine and 89-1603 nmol/l for imipramine + desipramine. Guided by plasma level monitoring, a final therapeutic plasma level between 548-910 nmol/l for imipramine + desipramine was achieved (therapeutic dose range: 50-400 mg/day). Mean time to reach the therapeutic level was 19 days. The mean 2-OH-imipramine/imipramine ratio was 0.24 and mean 2-OH-desipramine/desipramine ratio was 0.56. There was a significant intrapatient correlation between the two ratios, both during 100 mg imipramine/d and at the therapeutic dose level. A low ratio was associated with high imipramine and particularly with a high desipramine level. Well defined steady state levels were established at two different dose levels in 12 patients and at three dose levels in 5 patients. With increasing dose there was a marked and disproportionate rise in the desipramine level and to some extent in the imipramine level. Saturation of imipramine and desipramine hydroxylation appeared to be responsible for the dose-dependent kinetics. Concomitant treatment with levomepromazine and perphenazine in one patient resulted in a significant rise both in imipramine and desipramine concentration, apparently due to inhibition of the hydroxylation. Eleven out of twelve endogenously depressed patients responded completely to treatment, whereas the response was poor in the non-endogenously depressed patients despite optimal drug levels.

Adult↗

Imipramine demethylation and hydroxylation: impact of the sparteine oxidation phenotype.

Eighteen healthy volunteers, selected according to their ability to oxidize sparteine, took single oral doses of 100 mg imipramine and desipramine. For imipramine the following clearances (L X min-1) were found in six rapid extensive metabolizers (EM), six slow EM, and six poor metabolizers (PM), respectively (mean and range): apparent oral clearance: 2.55 (1.39 to 3.47), 2.28 (1.18 to 4.26), and 1.35 (0.96 to 1.64). Clearance via demethylation was: 1.42 (0.61 to 2.01), 1.60 (0.78 to 3.81), and 1.09 (0.76 to 1.64); clearance via other pathways was: 1.13 (0.74 to 1.75), 0.69 (0.40 to 1.59), and 0.26 (0 to 0.46). For desipramine the apparent oral clearance (L X min-1) was 0.19 (0.12 to 0.24) in PM compared with 1.64 (1.46 to 1.80) and 1.03 (0.77 to 1.13) in rapid EM and slow EM. Extremely long elimination t1/2s of desipramine were seen in PM: 81 to 131 hours compared with 13 to 23 hours in EM. 2-OH-imipramine and 2-OH-desipramine were detectable in plasma of only the 12 EM, where the ratio-to-parent compound was higher in rapid EM than in slow EM. This study confirms that 2-hydroxylation of imipramine and desipramine depends almost exclusively on the sparteine oxygenase, whereas the demethylation of imipramine depends mainly on a different isozyme.

Adult↗

Benzodiazepine suppression of cortisol secretion: a measure of anxiolytic activity?

Clinical studies on spontaneous afternoon cortisol levels in depressed patients revealed that oxazepam given a few hours before blood sampling, may suppress the cortisol levels. This was confirmed in a volunteer study, where oxazepam 30 and 60 mg caused a dose-dependent suppression of the cortisol level only lasting 2 or 3 hours in spite of persisting high oxazepam levels in plasma. Subsequently, a study in 28 depressed patients showed a substantial suppression of afternoon cortisol after oxazepam 45 mg given 2 hrs prior to sampling. It may be postulated that this effect is mediated through GABA-ergic receptors inhibiting the hypothalamic release of corticotropin releasing factor (CRF). This is interesting since CRF may have neurotropic effects related to the behavioral responses to stress, and the inhibitory effect thus may represent a mechanism of action for the anxiolytic effect of benzodiazepines.

Adrenocorticotropic Hormone↗

Sparteine oxidation polymorphism: a family study.

Polymorphic oxidation of the pharmacogenetic probe drug sparteine was investigated in 35 parents and 29 siblings of 20 unrelated poor metabolizer (PM) probands. Phenotyping was carried out on the basis of metabolic ratio (MR) = sparteine/dehydrosparteines in the 12 h urine. The distribution of MR was bimodal: 47 relatives (20 siblings and 27 parents) had MR ranging from 0.22-12 and were defined as extensive metabolizers (EM) whereas MR ranged from 20-340 in nine siblings and eight parents thus defined as PM. The 20 pedigrees confirmed that poor metabolism of sparteine is inherited as an autosomal recessive character. The mean recovery of dehydrosparteines (% of dose) was 27% in 23 positively identified drug free heterozygotes compared with 37% in unrelated EM (both genotypes) (P less than 0.05) previously phenotyped. Degrees of dominance of 73% and 77% were calculated on basis of log excretion of dehydrosparteines (% of dose in 12 h urine) and log MR, respectively.

Adolescent↗

Sparteine oxidation is practically abolished in quinidine-treated patients.

In eight patients a sparteine-test was carried out immediately before and after 1 week of treatment with quinidine 600-800 mg day-1. Before treatment one patient was classified as a poor metaboliser (metabolic ratio: greater than or equal to 20), and seven patients as extensive metabolisers. During quinidine treatment, the formation of sparteine metabolites (2- and 5-dehydrosparteine) was practically abolished. Patients initially classified as extensive metabolisers thus exhibited the phenotype of poor metabolisers during quinidine treatment.

Adult↗

Orthostatic side effects of clomipramine and citalopram during treatment for depression.

Orthostatic hypotension, the clinically most important side effect in treatment with tricyclic antidepressants, was investigated in a double-blind study with clomipramine and the selective serotonin reuptake inhibitor citalopram given for 5 weeks. All patients were initially given placebo for 1 week. In the clomipramine group (n = 17) a significant orthostatic drop in the systolic blood pressure was observed during treatment; this remained significant over the whole investigational period. A curvilinear correlation was demonstrated between the orthostatic drop in systolic blood pressure and the plasma levels of clomipramine and desmethylclomipramine. The most pronounced orthostatic reaction was thus seen in 1-2 weeks, at plasma levels of 25-75 micrograms/l (clomipramine). The correlation between the subjective symptoms and the measured orthostatic drop was poor, as was the correlation between the subjective symptoms and the plasma levels of the two active compounds. The change in orthostatic heart rate during clomipramine treatment was insignificant. In the citalopram group (n = 15) no significant changes in orthostatic blood pressure or heart rate were demonstrated during treatment and these patients had no orthostatic complaints.

Adult↗

Mianserin protein binding in serum and plasma from healthy subjects and patients with depression and rheumatoid arthritis.

Mianserin protein binding was measured in serum from 43 healthy subjects and plasma from 12 elderly depressed patients and 23 patients with rheumatoid arthritis. Free fraction (mean +/- SD) was 5.5 +/- 0.7% in the healthy subjects, 5.0 +/- 0.8% in the elderly subjects and 6.0 +/- 1.0 in the patients with rheumatoid arthritis. In the group of elderly patients treated with mianserin, a high correlation (r = 0.83, P less than 0.001) between total and free concentrations of mianserin was found. In both groups a high linear correlation (r = +0.90, P less than 0.001) between the free fraction of mianserin and that of imipramine was found, the latter being about twice as high as for mianserin. In both healthy subjects and arthritis patients the degree of protein binding was positively correlated to the concentration of alpha 1-acid-glycoprotein and complement C3c, and somewhat more weakly to haptoglobin. In the healthy subjects protein binding was also highly positively correlated to the concentration of apolipoprotein B, whereas no such correlation was found in the rheumatoid arthritis patients. In the rheumatoid arthritis patients protein binding was highly correlated to the concentration of hemopexin and somewhat more weakly to ceruloplasmin and fibrinogen; a weak negative correlation to the concentration of albumin was also found. Since significant intercorrelations between the concentrations of these proteins were found, the correlation to the degree of binding of mianserin may not necessarily represent binding of the drug to the protein.

Adult↗

Cardiovascular effects of amitriptyline in the treatment of elderly depressed patients.

Thirteen elderly depressed patients (age 60-82 years) were treated for 5 weeks with a fixed dose of amitriptyline 100 mg (sustained release preparation). In all patients the sum of concentrations of amitriptyline and nortriptyline exceeded 130 micrograms/l, which is the recommended plasma level. Cardiovascular side effects were recorded by monitoring heart rate, blood pressure, standard ECG and systolic time intervals. During treatment, a transient increase in the supine heart rate was observed without significant changes in the supine blood pressure. The orthostatic drop in blood pressure was markedly increased during treatment without a compensatory increase in heart rate, and these changes remained significant during the whole investigational period. PQ and QRS were significantly increased during treatment, and significant changes in the systolic time intervals were found indicating impairment of myocardial conduction and contractility. In three patients medication was discontinued due to cardiovascular side effects.

Aged↗

Zuclopenthixol decanoate in schizophrenia: serum levels and clinical state.

Serum concentrations of zuclopenthixol were determined in a group of 20 patients treated with a depot preparation, zuclopenthixol decanoate in Viscoleo. Clinical assessments according to a Clinical Global Impression (CGI) scale, Comprehensive Psychological Rating Scale (CPRS), 16-item subscale for schizophrenia, and the UKU side effect scale were performed on 3 consecutive days of injection. The serum concentrations showed a limited individual variation and a high and significant correlation between dose and serum concentration. One patient had a particularly high serum concentration of zuclopenthixol. This patient also had an elevated concentration of the N-dealkyl metabolite, but a low concentration of the sulphoxide. For serum concentrations versus clinical state and side effects some significant correlations were found. All correlations were positive, which means that the higher the serum concentration the poorer the clinical state of the patient. We think that this probably reflects a common clinical pattern of increasing the dose, when the antipsychotic response is unsatisfactory. The study also showed that for moderately ill patients, who were given the optimum dose of drug, the subgroup of patients not experiencing side effects had significantly lower serum concentrations than the subgroup with side effects.

Adult↗

Dextropropoxyphene kinetics after single and repeated oral doses in man.

The kinetics of dextropropoxyphene (DP) and its main metabolite norpropoxyphene (NP) were studied in 6 healthy male subjects after a single oral dose of 195 mg DP HCl, and during and after 12 daily single oral doses of 195 mg DP HCl. The kinetics varied up to five-fold between individuals after the single dose, the apparent mean elimination half-life (t1/2) was 16 h for DP and 29 h for NP. The mean apparent overall plasma clearance (CL) for DP was 2.61/min. There was no systematic difference in DP clearance between the single and multiple doses, but the accuracy of individual predictions from single to multiple doses was poor, probably because of imprecise determinations of the AUC and t1/2 in the single dose experiments. The individual correlation between single and multiple dose kinetics was good for NP, although the predicted plasma levels during steady state were significantly higher than the observed levels (mean AUCss/AUCsd: 0.81). There was no sign of saturation kinetics on repeated administration. In fact, autoinduction, resulting in significantly lower plasma concentrations after treatment for 1 week was found for NP and was indicated for DP. On discontinuing DP after 12 days of treatment, the apparent mean t1/2 of DP was 23 h and of NP 25 h.

Administration, Oral↗

Sparteine oxidation polymorphism in Denmark.

Sparteine oxidation was polymorphic among 301 healthy Danish volunteers. Hence 22 subjects or 7.3% were phenotyped as poor metabolizers (PM) whereas 279 subjects were classified as extensive metabolizers (EM). The metabolic ratio (MR) between sparteine and 2- and 5-dehydrosparteine (% of dose) in 12 hrs urine ranged from 0.11-12.6 in EM and from 30-394 in PM. Urinary excretion of 2- and 5-dehydrosparteine also discriminated between PM and EM. Age, sex, and smoking habits did not influence the MR. This study confirms that sparteine is a useful probe drug in pharmacogenetic investigations.

Denmark↗

Sympathetic hyperreactivity in offspring of essential hypertensive patients.

A multistage exercise test was carried out in normotensive subjects with normotensive parents (controls; n = 12), and 32 offspring of essential hypertensive patients that were normotensive (NTO; n = 20) or borderline hypertensive (BHO; n = 12) The groups were comparable as to age, weight and working capacity. Changes in sympathetic nervous activity were determined by measurements of plasma noradrenaline. The initial rise in noradrenaline levels during the exercise test was proportional to the increase in work load until the noradrenaline concentration rose sharply to levels more than 1000 pg/ml above baseline levels. The work load immediately prior to the steep rise in plasma noradrenaline (sympathetic threshold level: STL) is considered to represent the point from which anaerobic energy-yielding processes play an increasingly greater role as the work load increases. The initial increase in plasma noradrenaline until STL was significantly higher in both the NTO (p less than 0.02) and BHO (p less than 0.005) compared to the control group. The absolute noradrenaline level at STL and the increase in noradrenaline from baseline to STL were significantly higher in the BHO group (p less than 0.02, p less than 0.005). No significant differences between the groups were found when comparing noradrenaline levels at rest or at absolute or relative work loads. The systolic blood pressure response during the exercise test was significantly more pronounced in the BHO group (p less than 0.05) compared to the controls and the NTO group.

Adolescent↗

Imipramine treatment of painful diabetic neuropathy.

Twelve patients with severe, painful diabetic neuropathy in the lower extremities were treated with imipramine and placebo in a fixed-dose, double-blind, crossover study of five plus five weeks. Seven patients experienced notable improvement while receiving imipramine and none while receiving placebo. The rating of specific symptoms at the end of each treatment period showed a beneficial effect of imipramine on pain, paresthesia, dysesthesia, numbness, and nocturnal aggravation. The plasma levels of imipramine and its metabolite desipramine were significantly higher in patients who benefited from imipramine treatment.

Adult↗

Assessment of symptom change from improvement curves on the Hamilton depression scale in trials with antidepressants.

A total of 97 patients, who participated in two studies on the relationship between the clinical effect and plasma levels of imipramine and clomipramine, were examined for improvement curves by use of weekly ratings on the Hamilton Depression Scale (HDS). Although we confirmed that our six-item HDS subscale, in contrast to the total 17-item HDS, was a one-dimensional measure of depression, the Rasch analysis showed that the weekly improvement in subscale scores only applied to the individual patient, i.e. an average improvement curve for a group of depressed patients is an abstraction to which the individual curves cannot be transferred. Our results indicate, however, that when the subscale scores are transformed into three clinical categories of depression: no, mild (minor), moderate/-severe (major) they could be described by a common improvement curve for all patients. This is illustrated by the percentage of patients who, week to week, changed from major to minor or no depression, or from minor to no depression. We found no specific improvement pattern for imipramine or clomipramine which could be used diagnostically. There is reason to assume that patients completing a controlled trial necessarily will follow a monotonic improvement curve, and the improvement pattern of all patients fulfilling the entry criteria should, therefore, always be reported. The present study thus indicates that calculation of average improvement curves is neither clinically nor statistically meaningful, and should be replaced by measures of changes in number of patients in different main severity categories, or by the final rating score. No difference in outcome between imipramine and clomipramine was shown neither on the subscale nor on the 17-item HDS.

Adult↗

D-propoxyphene kinetics in man: significance of a deep third compartment.

Data from a previously published single dose study of d-propoxyphene 65 mg given i.v. to 8 healthy subjects have been subjected to non linear regression analysis by a curve-fitting program to test the applicability of a 2- and a 3-compartment open model. Analysis of residuals (difference between observed and computed concentrations) revealed similar systematic deviations in all 8 subjects when the 2-compartment model was used (5-10 h negative residuals, after 13 h positive residuals). In contrast, curve-fit by a 3-compartment model (with two parallel peripheral compartments) was good with no systematic deviations. The data show that a terminal monoexponential decline in d-propoxyphene concentrations cannot be expected until 15-30 h after single dose administration, and that the determination of the corresponding half-life is rather inaccurate. Accordingly, precise steady state level predictions may be difficult to obtain from conventional single dose studies with d-propoxyphene.

Adult↗