Biomedical subjects
Publications and source records attributed to P Bechtel.
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Human serum albumin is known to be the main carrier of 5-methoxypsoralen (5-MOP) in serum. As hypoalbuminaemia may occur in psoriasis with inflammatory syndrome, variability of the free 5-MOP fraction in serum can be expected. The free 5-MOP fraction was determined by equilibrium dialysis in serum samples obtained from 18 psoriatic patients and 18 control subjects. The median free 5-MOP fraction was not significantly different in the psoriatic group (fu = 4.75%) than in the control group (fu = 5%). However, there was a significantly larger variability of the free fraction in the psoriatic group (2.7 to 8.6%) than in the healthy group (3.2 to 6.8%) (p = 0.002). The binding index of 5-MOP (ratio of bound to free concentrations) was correlated with human serum albumin level (r = 0.784). This work confirms that the 5-MOP fraction in human serum is principally serum albumin dependent, as has been described with in vitro models. Free drug monitoring of 5-MOP is discussed.
The binding of 5-methoxypsoralen (5-MOP) to human serum and blood fractions was studied by equilibrium dialysis associated to high-performance liquid chromatography. 5-MOP serum binding was 95% and kept constant in the range of therapeutic concentrations. Albumin was the main binding protein with one class of binding sites (n = 2.05) and with a moderate affinity constant (Ka = 10,270 M-1). Free fatty acids (FFA) enhanced 5-MOP binding to albumin. Binding to other proteins, alpha 1-acid glycoprotein, gamma-globulins and lipoproteins (LDL, HDL, VLDL) also occurred, but was negligible. 5-MOP bound to red blood cells (RBCs) with a binding index (ratio of intra- to extra-globular 5-MOP concentrations) of 3.84 and 1.48 in buffer and plasma, respectively. 5-MOP distribution in blood was simulated. The free fraction of 5-MOP in blood could be increased in hypoalbuminemia, unchanged in acute inflammation, and decreased by FFA.
Paternity exclusions are known to be common in Western countries and are yet neglected in segregation analysis because it is almost impossible to check it systematically on a large family sample. We had the opportunity of observing the sensitivity of segregation analysis parameters to a paternity exclusion in analyzing 34 families for a simple Mendelian trait, the acetylator phenotype. We found that only one family, with proven paternity exclusion, was responsible for a strong rejection of Mendelian transmission probabilities (P much much less than 0.001).
The pharmacokinetic characteristics of a low molecular weight heparin (LMWH) (Cy 222; mean mw: 2500 daltons) are studied in 24 patients with 3 degrees of chronic renal failure (CRF) stage I (creatinine clearance between 50 and 30 ml/mn), stage 2 (creatine clearance between 30 and 10 ml/mn), stage 3 (creatinine clearance below 10 ml/mn). Patients with CRF have significantly higher values of anti Xa activity at 3 hours (p less than 0.05), 5 hours (p less than 0.05), and at 8 hours (p less than 0.03) after injection than controls, CMAX values, VDSS and AUC do not differ, whereas patients with the highest stage of CRF are characterised by the most important t1/2 a (p less than 0.001) and the smallest total body clearance (p less than 0.01). Consequences of these disturbances of pharmacokinetic characteristics have to be evaluated before adequate posology of heparin fragments could be determined in patients with CRF.
1. Determination of debrisoquine oxidation phenotype was carried out in 119 healthy subjects, 135 patients with chronic bronchitis and 153 patients with lung cancer, all of Caucasian origin. 2. A non-Gaussian distribution of the log D/HD ratio was observed in the three groups. 3. Assuming an antimode of 1.12, the proportion of PMs was found to be 6.7% in healthy subjects, 8.9% in chronic bronchitics and 6.5% in patients with lung cancer. These differences were not significant. 4. The presence of a lung tumour itself had no influence on phenotype in a group of 14 patients who were phenotyped before and after surgery. 5. We conclude that a link between debrisoquine phenotype and lung cancer is unlikely.
European data on the polymorphic metabolism of debrisoquine, sparteine, dextromethorphan and mephenytoin have been collected. No significant difference in phenotype frequencies was found between the separate series for debrisoquine, sparteine and dextromethorphan, which supports the claim that these probe drugs reflect the same enzyme polymorphism. The mean frequency of the phenotype slow debrisoquine metaboliser was 7.65% based on 5005 determinations. The overall mean reflecting all three drugs and 8764 determinations was 7.40%. This is consistent with a gene frequency of 0.27 (95% confidence interval 0.26-0.28). The overall mean of the phenotype slow metaboliser of mephenytoin was 3.52% corresponding to a gene frequency of 0.19 (confidence interval 0.17-0.20). The incidence of slow metabolism of debrisoquine and possibly also of S-mephenytoin was homogeneous in the samples from European populations. This is of considerable interest as interethnic differences are now being found both in the phenotypic characters as well as the genotypes of polymorphic drug oxidation.
The debrisoquine/sparteine phenotype was determined in 51 patients with depression, who were subdivided into 3 groups in terms of their drug treatment. Log (MR) for each group was compared. Patients treated with benzodiazepines had the same distribution of log (MR) as the healthy population, but the distribution was shifted towards higher values in patients treated with neuroleptics and antidepressants. It appears that the phenotypic expression of debrisoquine oxidation may be modified by drugs whose metabolism follows the same route as debrisoquine. The debrisoquine test must be carefully interpreted in patients receiving several drugs in the same time.
The authors present a prospective study of a rapid desipramine dose adjustment on the basis of a 24-hour plasma concentration after a single 150 mg dose. For this, they use a prediction table constructed from data in the literature showing strong correlation between steady-state plasma levels and 24-hour single-dose levels. Despite the fact that desipramine action is not always linear, the method appears to be feasible and valid. In an attempt to reach a 150 ng/ml level, the authors obtained steady-state levels ranging from 85 to 317 ng/ml, with 14 of the 19 patients in the range between 125 and 250 ng/ml. Moreover, 11 of the 19 patients received a daily dose of 250 mg or more desipramine from the third day of treatment onward; in ten of these cases, this dose had been adapted.
1. The kinetics of dextromethorphan O-demethylation were measured in microsomes prepared from five human livers, both in the absence and in the presence of quinidine. 2. For each liver and over the concentration range of dextromethorphan examined (4.2-3400 microM), this reaction involved an enzymatic component of high affinity, with an apparent Michaelis-Menten constant (Km) of 4.6 +/- 1.8 microM (mean +/- s.d.) and a maximum velocity (Vmax) of 4.2 +/- 3.5 nmol mg-1 h-1 (mean +/- s.d.). 3. Quinidine was a potent and competitive inhibitor of the activity of this component (mean Ki +/- s.d. of 0.025 +/- 0.008 microM) as it is for other oxidation reactions which have already been found to co-segregate with the debrisoquine-type polymorphism. 4. With microsomes from four of the five livers studied, there was evidence of a second enzymatic component of activity characterized by a similar Vmax and about 20-fold higher Km compared with the high affinity component. The activity of this low affinity component was unaffected by quinidine in the concentrations studied.
During the last decade, the Drug Monitoring allowed the clinician to control the efficiency and/or the toxicity of the used drugs. This control is of a posteriori type. The discovery of the various genetic polymorphisms (acetylation, oxidation), the use of probe drugs (caffeine, sulfadimidine, dapsone, debrisoquine, sparteine) and the fact that other drugs exhibit the same polymorphisms as the probe drugs gave the opportunity to develop non invasive methods, to study in population the distribution of the various genetic tracts, to check the subjects who might be at risk toward a drug. Can, the obtained results in simple situation be extrapolated to complex pathological or therapeutic situations? Among patients with side and/or toxic effects of the drugs, there is a significant increase of the poor metaboliser (PM) status of debrisoquine. But it is necessary to carefully check the state of the patients before phenotyping them (drug, hepatic, metabolic, renal diseases). If the patients are taking drugs which share the same genetic polymorphism as debrisoquine during the time where the phenotype is established, some misfits can happen. The patients taking propafenone present a false PM status of debrisoquine. This is less obvious with mexiletine. In a population of 200 epileptics neither the disease nor the therapeutics seem to modify the distribution of the two phenotypes PM and EM. All things considered we do not know exactly the limits of use of these tests in the patients. We need more data to validate the advices dealing with the use of pharmacogenetic concepts as a provisional tool for patient cares?
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The antipyrine metabolic clearance rate (MCR) was studied in two groups of patients with similar degrees of cholestasis and hepatic damage, but differing mechanisms of cholestasis. The plasma disappearance rate of antipyrine in 18 patients with extrahepatic cholestasis and 11 patients with intrahepatic cholestasis was compared with that of two groups of control subjects without liver disease who were matched for age. Whereas no significant difference was observed for the antipyrine MCR between patients with extrahepatic cholestasis and their controls [30.7 +/- 11.2 (SD) as against 31.6 +/- 10.0 ml/min], the antipyrine MCR was significantly lower (P less than 0.001) in the patients with intrahepatic cholestasis than in their controls (16.2 +/- 4.5 vs 37.4 +/- 17.3 ml/min). These results suggest that cholestasis per se does not change the rate of metabolism of drugs by the liver. The decrease of antipyrine MCR in patients with intrahepatic cholestasis could be due to a reduced functional parenchymal mass related to some degree of hepatic necrosis.
The aim of this study was to look for correlations between the metabolic clearance rate of antipyrine and (a) the concentration of cytochrome P-450, and (b) the NADPH cytochrome c reductase, aminopyrine demethylase, and aniline hydroxylase activities in the liver microsomes of 20 patients without liver diseases. The results confirmed interindividual differences in the values of in vivo and in vitro assessments of hepatic drug metabolism. No significant correlation appeared in this group of patients between the metabolic clearance rate of antipyrine and the microsomal amount of cytochrome P-450, whereas the metabolic clearance rate of antipyrine exhibited a significant relationship to the NADPH cytochrome c reductase (p < 0.05), aminopyrine demethylase (p < 0.05), and aniline hydroxylase (p < 0.02) activities. These results suggest that the metabolic clearance rate of antipyrine: (a) is not strictly related to the amount of cytochrome P-450 in hepatic microsomes; and (b) although significantly related to the activity of hepatic drug-metabolizing enzymes, does not have a predictive value to assess the enzyme equipment of liver microsomes in a given normal subject.
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Plasma levels of amitriptyline and nortriptyline were measured twice weekly in 62 patients treated for three weeks with i.m. amitriptyline 120 mg/day. In half the patients the ratio of amitriptyline to nortriptyline was under 1 and in the other half it was greater than 1. 30 of these 62 patients were clinically monitored with the Hamilton Rating Scale and the side effects of the drug were recorded. There was no correlation between plasma level of the drug and its side effects, but there was a statistically significant curvilinear correlation between the plasma levels of amitriptyline plus nortriptyline and nortriptyline alone, and the clinical effect. The practical value of this type of investigation was demonstrated by showing that patients whose drug plasma level was not in the therapeutic range, were clinically improved after adjustment of the dose. The plasma level of amitriptyline plus nortriptyline must lie between 60 to 220 ng/ml, and that of nortriptyline between 60 to 140 ng/ml, to obtain the best clinical effect. Associated treatments, age, weight and sex of patients, and the type of depression did not appear significantly to affect the plasma level of the drug.
Filamin is a high molecular weight protein that binds to actin filaments in cells. It is found in large amounts in several different cells and tissues, including smooth muscle, fibroblasts, platelets, and macrophages. It is immunologically related to the previously described macrophage high molecular weight actin-binding protein but clearly different from erythrocyte spectrin. Filamin is a phosphoprotein; it is phosphorylated in vivo in intact tissues and cells. It can be phosphorylated in vitro with endogenous kinases; cyclic AMP stimulates this phosohorylation. Furthermore, the purified protein can be phosphorylated by purified cyclic AMP-dependent protein kinase. In smooth muscle homogenates, the stimulation of filamin phosphorylation by cyclic AMP is specific. Cyclic GMP and Ca2+ do not increase its phosphorylation, although they do stimulate phosphorylation of other proteins.