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Biomedical subjects

L F Gram

Publications and source records attributed to L F Gram.

At least 145 records · Page 8Linked to original sources
PubMed1984

Suppression of plasma cortisol after oral administration of oxazepam in man.

In seven healthy male subjects plasma cortisol was measured at 20 min intervals from 07.00 to 13.00 h, during a drug free control test and after oral administration of 30 and 60 mg oxazepam. A significant suppression of the plasma cortisol levels for about 2 h after 30 mg oxazepam, and for about 3 h after 60 mg oxazepam was observed. The suppression wore off before the oxazepam plasma concentration started to decline significantly.

Administration, Oral↗
PubMed1984

Analgetic treatment in acute myocardial infarction. A controlled clinical comparison of morphine, nicomorphine and pethidine.

In a randomized double-blind study with flexible dosage, morphine, nicomorphine and pethidine were compared with regard to analgetic effect, dose requirements, dose intervals and adverse reactions. A total of 275 patients were included, and 28 patients were excluded due to adverse reactions (n = 16) and for practical reasons, etc. Acute myocardial infarction (AMI) was diagnosed in about 60% of the patients, and about 30% had ischemic heart disease without AMI. All three analgesics provided equally efficient pain relief in relative doses of morphine 10, nicomorphine 10 and pethidine 75 mg/ml. Severe adverse reactions were few (allergy 3 cases, respiratory insufficiency 4, severe bradycardia 4), whereas nausea was recorded in 20-30%, vomiting in 5-15% and dizziness in 10-30% of the patients, with no difference between the three drugs. Significant blood pressure drop (greater than 30 mmHg) was seen in 3-8% of the patients, with no significant differences between the drugs.

Aged↗
PubMed1984

Plasma level monitoring of antidepressants: theoretical basis and clinical application.

For TCAs there is a strong rationale for drug level monitoring in clinical therapy. Therapeutic drug concentration ranges have been established in controlled studies with NT, imipramine, and AT. It has been shown that by appropriate choice of antidepressant and close monitoring of drug levels, treatment with antidepressants in elderly and other risk patients can be carried out effectively and safely, reducing the use of electroconvulsive therapy. Finally, the practical clinical use of antidepressant concentration measurements is now feasible and not expensive, and the analytical procedures can be established in most hospital settings. On the basis of these premises the following can be concluded: Plasma level monitoring should be used as a routine for imipramine, NT, and AT. Further plasma level studies on other antidepressants and in overdose cases should be initiated. Plasma level monitoring is indispensable in clinical research on antidepressants (trials, new drugs, toxicology). Pharmacokinetic considerations may be useful to determine which receptor effects are clinically relevant in therapy and toxicology.

Amitriptyline↗
PubMed1983

Afternoon plasma cortisol in depressed patients: a measure of diagnosis or severity?

Plasma cortisol concentration was measured at 20 min intervals from 3 p.m. (1500 hrs) to 6 p.m. (1800 hrs) in 26 hospitalized patients classified according to the Newcastle Index as endogenously depressed (n = 16) or non-endogenously depressed (n = 10). When examined in depressed state, before treatment, maximum, mean and range of plasma cortisol concentration in this time interval was significantly higher in the endogenously depressed patients than in the non-endogenously depressed patients (p less than 0.01-0.02). The diagnostic identification of endogenous depression on the basis of these cortisol concentration measurements was at least as good as that reported by others using post-dexamethasone cortisol levels. The plasma cortisol levels (maximum, mean) and fluctuations (range) correlated significantly with the degree of depression (Hamilton Depression Scale), and differences in severity of depression could explain most of the differences in cortisol levels between the two diagnostic groups. Nine patients were reexamined after 3-12 months in a non-depressed state, and all unipolar endogenously depressed patients (n = 6) then had clearly reduced cortisol levels and fluctuations.

Adult↗
PubMed1983

Mianserin: cardiovascular effects in elderly patients.

Cardiovascular effects of the tetracyclic antidepressant drug mianserin were examined in a prospective study including ten elderly depressed patients (age 60-77 years). During 1 week on placebo and 5 weeks on mianserin, 60 mg per day, orthostatic blood pressure testing, recording of standard electrocardiogram, 24-h electrocardiographic recording and systolic time intervals were carried out along with frequent monitoring of plasma levels of mianserin (13-57 micrograms/l) and the primary metabolite desmethylmianserin (7-27 micrograms/l). Mianserin caused a significant increase in orthostatic systolic blood pressure drop, and this correlated well with the plasma mianserin levels (rs = 0.70). There were no significant changes in supine blood pressure or in orthostatic changes in heart rate. No cardiac conduction disturbances or arrhythmias were provoked, but mianserin caused changes in systolic time intervals indicating impairment of left ventricular contractility and performance. Like tricyclic antidepressants mianserin should thus be used with caution in patients with latent or overt cardiovascular disease.

Aged↗
PubMed1983

Imipramine metabolites in blood of patients during therapy and after overdose.

Plasma or serum concentrations of imipramine and five of its nonconjugated metabolites (desipramine, 2-OH-imipramine, 2-OH-desipramine, imipramine-N-oxide, and didesipramine) were followed in three cases of imipramine overdose and during steady state in 24 patients on continuous imipramine treatment. In the overdose cases the imipramine and desipramine concentrations declined monoexponentially with t 1/2s of 12 to 21 and 31 to 37 hr. The 2-OH-imipramine and 2-OH-desipramine levels were lower and declined in parallel with their corresponding parent compounds. In the patients on continuous imipramine treatment, the steady-state levels of 2-OH-imipramine and 2-OH-desipramine were very low or immeasurable (less than 15 nmol/l) in five patients. In most patients (n = 18) the hydroxymetabolite levels were much higher with 2-OH-imipramine/imipramine ratios of 0.09 to 0.45 and 2-OH-desipramine/desipramine ratios of 0.36 to 0.86. In one patient there were particularly high ratios (2-OH-imipramine/imipramine, 0.85; 2-OH-desipramine/desipramine, 1.30). The patients with very low hydroxymetabolite levels had considerably higher desipramine levels than the others, indicating that the low metabolite levels were due to poor hydroxylation. In one of these poor hydroxylators a desipramine t 1/2 of about 120 hr was estimated after imipramine discontinuation. With increased imipramine dose the 2-OH-imipramine levels tended to rise little or not at all. Imipramine-N-oxide could only be detected in the overdose cases during the first 6 to 12 hr and didesipramine was generally present only when the desipramine levels were above 200 nmol/l.

Adult↗
PubMed1982

Citalopram, a selective serotonin reuptake inhibitor: clinical antidepressive and long-term effect--a phase II study.

In a phase II study the antidepressive effect of citalopram, a selective and potent serotonin reuptake inhibitor, was examined in 20 endogenously and three non-endogenously depressed hospitalized patients. Four endogenously depressed patients dropped out due to deterioration early in the treatment period. The remaining 19 patients completed a 4-6 week treatment schedule. Of 16 endogenously depressed patients 11 responded, one was a partial responder and four did not respond. Of three patients with non-endogenous depressions, two responded and one did not respond. No correlation between plasma citalopram concentration and therapeutic outcome was found. Fourteen patients were given maintenance treatment for 8-113 weeks. One patient developed depression when the dose was reduced from 60 to 40 mg and one patient became manic. After discontinuation of treatment seven patients had a depressive relapse and six of these who again were treated with citalopram responded completely. Side effect rating scores of symptoms usually associated with depression or treatment with tricyclic antidepressants declined during treatment. Three patients complained of increased need of sleep for a period after several weeks of treatment. Apart from an unspecific, transient rise in liver enzymes in two patients, detailed biochemical laboratory tests were all normal. There were no effects on blood pressure, pulse rate, orthostatic reaction, or electrocardiogram. One patient took an overdose of citalopram resulting in plasma levels about six times higher than the average therapeutic level, but there were no signs of severe toxicity. In particular no change in consciousness, electrocardiogram or blood pressure occurred. Pharmacokinetic variables such as dose schedule, steady state kinetics, and metabolism are discussed.

Adult↗
PubMed1982

Overdosage of antidepressants: clinical and pharmacokinetic aspects.

Twenty-nine cases of self-poisoning with antidepressants (amitriptyline, imipramine, clomipramine, maprotiline, doxepine, nortriptyline, opipramol) were examined by frequent observation of CNS effects, heart rate, blood pressure and standard ECG, 24h-ECG-monitoring, measurement of systolic time intervals, EEG recordings and frequent measurement of serum levels of antidepressants and primary metabolites. None of the patients died. Maximum total serum antidepressant level (parent compound + desmethyl metabolite) ranged from 20 to 2200 micrograms/l, with concentrations above 500 micrograms/l in 11 cases. The serum amitriptyline concentration remained high for 3-4 days in some of the severely intoxicated patients and the decay curves were compatible with partly saturated elimination. A degree of unconsciousness and the occurrence of excitation and hallucinations were generally seen in cases with total serum antidepressant levels above 500 micrograms/l. Grand mal seizures occurred more frequently at high antidepressant levels, but could not be predicted from the EEG recordings. Increased heart rate and prolonged QRS- and QTc-intervals were significantly correlated with the total serum antidepressant level. 24 h-ECG-monitoring revealed no serious arrhythmias or instances of heart block. Hypotension was only seen initially in few patients. Systolic time interval measurements showed changes suggesting impaired myocardial performance (elevated PEP/LVET ratio) at intermediate (60-500 micrograms/l) but not high (greater than 500 micrograms/l) total serum antidepressant levels. Measurement of serum concentration in antidepressant intoxication is important for identification of patients with high serum levels and the corresponding risk of developing toxic reactions, and to exclude patients with a low concentration who do not require intensive observation.

Adult↗
PubMed1982

Equilibrium dialysis for determination of protein binding or imipramine--evaluation of a method.

A range of methodological problems associated with equilibrium dialysis for serum or plasma protein binding assay of a weakly basic drug imipramine, in man has been carried out in order to establish a reliable procedure for large scale studies. Freezing of serum samples did not change the binding significantly, but a slight tendency towards increased binding to samples stored for 30 days was found. Protein binding was significantly higher in serum than in heparinized or citrated plasma, whereas there was no significant difference between plasma obtained by use of heparin or citrate as anticoagulant. There was a linear correlation between temperature (25-42 degrees) and binding such that binding decreased 0.1% per centigrade increase in temperature. Increase in pH resulted in increase in binding (0.6% per 0.1 unit pH). Equilibrium between serum and buffer phase was obtained within 5-6 hrs. The changes following osmotic equilibrium necessitated volume corrections of about 4-5% after 5-6 hrs, and 20-25% after 16-20 hrs (overnight experiments). With this correction the free fraction estimate remained constant for 26 hrs. Application of small volumes in the dialysis chamber may make the volume correction difficult and inaccurate. The use of Tris-Ringer buffer gave free fraction values about 20% higher (absolute values of free fraction) than that with phosphate buffer. With different imipramine concentrations a constant degree of binding was found at "therapeutic" levels, whereas a significantly decreased binding was found at a concentration of 1000 ng/ml. Control of these methodological factors is a prerequisite for obtaining reproducible and valid results, and authors should give more details on methodology in this field.

Blood Proteins↗
PubMed1982

Imipramine kinetics in the single pass rat liver perfusion model.

Imipramine elimination and metabolism was studied in a single-pass rat liver perfusion model with flow and pressure kept constant for a perfusion-period of 120-200 min. Imipramine was eliminated from the liver mainly in three ways: unchanged in the outflow medium, by demethylation forming desipramine, and by 2-hydroxylation and subsequent glucuronide coupling. The formed desipramine was eliminated unchanged (outflow) or by 2-hydroxylation + glucuronide coupling. The conjugated metabolites were mainly eliminated via the bile. By perfusion with constant imipramine concentration in the inflow medium (10-15 microM), steady state could not be obtained within 120 min. perfusion time, neither in terms of a constant outflow concentration, nor in terms of balance between input and output. Perfusion with imipramine for 20 min. (single-dose) followed by perfusion with drug-free medium showed an extensive elimination of imipramine (extraction ratio 0.64-0.97) and rapid disappearance of imipramine from outflow medium (t 1/2 5-10 min). A second single dose imipramine perfusion given 70 to 90 min. after start showed a significant reduction in extraction ratio. At the same time the elimination via bile decreased about 50%, and only a fraction of this decrease was accounted for by a decrease in bile flow. The data thus indicate that a gradual decline in elimination rate may explain the difficulties in reaching a steady state during constant infusion with imipramine. Gradual changes in distribution kinetics could not be excluded though. Results of both types of experiments (continuous or single dose administration) indicated dose dependent elimination compatible with saturation kinetics.

Animals↗
PubMed1982

Paroxetine: pharmacokinetics and cardiovascular effects after oral and intravenous single doses in man.

Paroxetine kinetics and cardiovascular effects were studied in 4 healthy male subjects after single oral doses of 45 mg and after slow intravenous infusion of 23-28 mg. The plasma concentration/time curves could be described by a two-compartment open model, but the estimates of the model parameters were relatively inaccurate after the oral test. Plasma half-lives were longer after oral (19.8 hrs. S.D. 1.3 hrs) than after intravenous test (12.3 hrs. S.D. 3.8 hrs). Different methods of calculation of the systemic availability resulted in different values, most probably due to dose dependent kinetics. This is possibly related to saturated elimination kinetics during the first pass metabolism. Systolic time interval measurements showed that paroxetine causes a shortening of the electromechanical systole (QS2 corrected for heart rate) indicating a positive inotropic effect of the compound. Paroxetine also caused a reduction in heart rate and a moderate rise in systolic and diastolic blood pressure. After the intravenous dose some subjects experienced nausea and one subject a quite pronounced anxiety.

Administration, Oral↗
PubMed1982

The contribution of pharmacokinetics to the best use of benzodiazepines and antidepressants.

The practical utilization of clinical pharmacokinetics data are fundamentally different for benzodiazepines and antidepressants. This difference is a consequence of the difference in time-course of action of the two types of drugs. The anxiolytic, sedative or hypnotic effect of benzodiazepines is usually immediate, and the dose can be titrated on the basis of effect measurements. Pharmacokinetic data on benzodiazepines thus in particular are important for design of dose, dose intervals and prediction (warning) about possible accumulation after repeated doses. Different benzodiazepines differ in pharmacokinetic properties, and the clinician should be aware of these differences in order to select the proper drug for a given purpose. Antidepressants are characterized by exerting their effect gradually ovec weeks. It has been shown that the therapeutic effect is related to the steady state plasma concentration which may vary considerably among patients on a standard dose. A major significance of pharmacokinetics of antidepressants thus is, that therapy guided by monitoring of plasma levels of active compounds will improve both safety and efficacy of the treatment. For antidepressants and for benzodiazepines knowledge of the pharmacokinetics is the basis of designing rational dose schedules that take influencing factors such as age, disease, concurrent treatment, etc. into account.

Amitriptyline↗
PubMed1982

Drug level monitoring in psychopharmacology: usefulness and clinical problems, with special reference to tricyclic antidepressants.

The gradual onset of action and pronounced pharmacokinetic variability provide a solid rationale for drug plasma level monitoring in psychopharmacology. For tricyclic antidepressants a well-established drug level therapeutic effect relationship is available for a few compounds (imipramine, nortiptyline, amitriptyline); and for these, plasma level monitoring can ensure more efficient and safe treatment. The relationship has been demonstrated only in endogenously depressed patients. Various pharmacokinetic problems such as dose-dependent kinetics (imipramine in elderly patients), autoinduction (chlorpromazine), drug interaction (inhibitory effect of neuroleptics on metabolism of tricyclic antidepressants), and changes in protein binding may be better controlled by monitoring the drug levels. In amitriptyline intoxications, a possible change in the elimination kinetics results in a very slow decline in plasma levels for several days; and plasma level measurements might help to identify those patients at prolonged risk of adverse reactions. Some side effects--in particular, orthostatic hypotension--occur at subtherapeutic drug levels and therefore cannot be prevented by drug level monitoring, and monitoring of other (physiological) variables is more important. Drug level monitoring of tricyclic antidepressants thus can be considered a valuable addition to the treatment program, but it cannot replace proper clinical practice in terms of diagnostic evaluation and control of patients.

Antidepressive Agents, Tricyclic↗
PubMed1981

Cardiovascular effect of imipramine and nortriptyline in elderly patients.

Cardiovascular effects in elderly depressed patients (age 62-78 years) treated with imipramine (N = 11) or nortriptyline (N = 10) were recorded by monitoring of heart rate, blood pressure, systolic time intervals, standard ECG and 24-h ECG. The two drugs exhibited distinctly different cardiovascular reactions. The use of imipramine was severely limited by orthostatic hypotension occurring at subtherapeutic plasma levels, which resulted in falls with fracture in two patients. In contrast, nortriptyline at therapeutic drug levels did not significantly influence orthostatic blood pressure regulation. Nortriptyline caused moderate changes in systolic time intervals, indicating impairment in myocardial contractility. This effect was not seen with imipramine, but a majority of the patients did not reach therapeutic plasma levels because of blood pressure reactions. Neither imipramine nor nortriptyline induced changes in cardiac conduction time measurements or arrhythmias. In addition to the blood pressure reactions, the use of imipramine was complicated by dose dependent kinetics.

Aged↗