Search PubMed⌕ Search

Biomedical subjects

P Dayer

Publications and source records attributed to P Dayer.

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

[Drug interactions of midazolam].

Midazolam is a short-acting benzodiazepine with a short half life (1.5-2.5 h) due to intense biotransformation by liver monooxygenases. Anecdotal clinical reports have mentioned a wide interpatient variability in its duration of action. We investigated by in vitro screening factors that could interfere with the rate of midazolam biotransformation (drug-drug interactions). Metabolite production (1'-and 4-OH-midazolam) was monitored in human liver microsomes. Midazolam hydroxylations are inhibited by several drugs (i.e. erythromycin, phenothiazine-type neuroleptics, cyclosporine). The clinical relevance of these drug interactions is illustrated by the example of a patient treated with amiodarone, erythromycin and midazolam during anesthesia. Midazolam-induced sleep lasted about 6 days due to inhibition of its biotransformation by concomitant drug treatment.

Biotransformation↗
PubMed1989

[Analgesic effects of an oral dose of clonidine].

Experimental data and anecdotal clinical observations have shown that clonidine, an alpha 2-agonist, has a marked analgesic effect. We investigated clonidine-induced analgesia in response to nociceptive stimuli. On 2 different days 7 normal volunteers received either placebo or clonidine (200 micrograms) orally according to a cross-over, double-blind, randomized, placebo-controlled design. Analgesia was assessed by measurement of the subjective (VAS) and objective (R III reflex) pain thresholds. A close correlation was observed between subjective and objective pain thresholds (r = 0.88, y = 0.2 + 1.2 x). Clonidine increased the objective threshold by 21% (+6.2 mA, SEM 2.4) and the subjective threshold by 10% (+2.4 mA, SEM 1.3). Drug effect was rapid (peak between 90 and 120 min) and overall analgesia lasted up to 4 hours. Side effects were a moderate fall in blood pressure, sedation and dryness of the mouth. A single oral dose of clonidine induces significant analgesia. These results suggest that clonidine is potentially a worthwhile drug for pain treatment which deserves further clinical investigation.

Administration, Oral↗
PubMed1989

Dextromethorphan O-demethylation in liver microsomes as a prototype reaction to monitor cytochrome P-450 db1 activity.

Liver dextromethorphan O-demethylation to dextrorphan is associated with the debrisoquin type of oxidation phenotype in humans. We studied dextromethorphan oxidation in vitro using human liver microsomes to investigate the kinetics of the polymorphic monooxygenase (cytochrome P-450 db1) and factors that may influence its activity. In microsomal preparations from six extensive metabolizers the reaction parameters were: Michaelis-Menten constant = 3.4 +/- SD 1.0 mumol/L and maximum rate of metabolism = 10.2 +/- 5.3 nmol x mg P-1 x hr-1, vs 48 mumol/L and 2.2 nmol x mg P-1 x hr-1, respectively in microsomes prepared from the liver of one poor metabolizer. The reaction was inhibited by nonspecific monooxygenase inhibitors such as SKF 525-A (Ki = 100 nmol/L) and cimetidine (Ki = 40 mumol/L), by known substrates of the polymorphic isozyme such as [+]-bufuralol (Ki = 7.5 mumol/L), debrisoquin (Ki = 25 mumol/L), and sparteine (Ki = 45 mumol/L), and by the selective cytochrome P-450 db1 inhibitor quinidine (Ki = 15 nmol/L). This assay permits in vitro screening for candidate substrates or inhibitors of the polymorphic isozyme.

Cytochrome P-450 CYP2D6↗
PubMed1988

[Absence of polymorphism in individual response to the dihydropyridines nifedipine and (+/-)-nicardipine].

Nifedipine, the dihydropyridine calcium channel antagonist prototype, is characterized by wide variability of its hepatic first-pass metabolism and individual response. This could be due to a new genetic polymorphism of drug metabolism, and this hypothesis was investigated in a randomized and cross-over population study in normal volunteers (n = 80). The kinetics and effects of an oral dose of nifedipine (10 mg) and (+/-)-nicardipine (20 mg), a second generation derivative with presumed different biotransformation routes, were evaluated at 0, 1, 2 and 3 h. The two drugs displayed a similar pharmacodynamic profile in terms of heart rate and blood pressure. The observed frequency distributions showed no asymmetry or bimodality suggesting polymorphism. The frequency of headaches and flushes were 21/80 and 19/80 respectively for nifedipine and (+/-)-nicardipine. At the doses administered nifedipine and (+/-)-nicardipine show the same efficacy. This study does not confirm the presence of polymorphism in the response to these dihydropyridines.

Adult↗
PubMed1988

Bioactivation of the narcotic drug codeine in human liver is mediated by the polymorphic monooxygenase catalyzing debrisoquine 4-hydroxylation (cytochrome P-450 dbl/bufI).

Codeine O-demethylation to its active moiety morphine was investigated in human liver microsomes from 1 poor and 5 extensive metabolizer subjects (debrisoquine-type of oxidation polymorphism). Apparent Km of the reaction in one extensive metabolizer's microsomes was 149 microM and Vmax 17.6 nmol X mg P-1 X hour-1 versus greater than 1 mM and 1.6 nmol X mg P-1 X hour-1 respectively in one poor metabolizer. In vitro morphine production was competitively inhibited by quinidine (Ki 15 nM), the selective inhibitor of cytochrome P-450 dbl/bufI. There was also an excellent correlation between dextromethorphan O-demethylation, a prototype reaction for cytochrome P-450 dbl/bufI activity, and codeine O-demethylation. These data allow to conclude that codeine bioactivation to morphine is dependent on the polymorphic monooxygenase known as cytochrome db1/bufI.

Biotransformation↗
PubMed1988

Propranolol treatment in children with tetralogy of Fallot alters the response to isoprenaline after surgical repair.

When propranolol is given to prevent hypoxaemic episodes in children with tetralogy of Fallot who are awaiting operation it is advisable to continue the treatment until shortly before the induction of anaesthesia. Because catecholamines are often required to maintain adequate cardiac output after surgical correction the effect of preoperative treatment with beta blockers on the response to isoprenaline after the operation was investigated in nine children given propranolol before operation and nine who were not. They were studied three and 24 hours after cardiopulmonary bypass. The haemodynamic response to increasing doses of infused isoprenaline was monitored. Immediately after cardiopulmonary bypass the response to isoprenaline was significantly blunted in the patients who had been given propranolol before operation. Their dose-response curve lay to the right of that for patients not given propranolol, and this indicates competitive inhibition. Propranolol concentrations in the blood and myocardium correlated significantly with the heart rate response to isoprenaline. Twenty four hours after operation the isoprenaline response was similar in both groups and concentrations of propranolol in the blood were minimal or undetectable. beta Blockers given up to the time of operation significantly altered the postoperative response to catecholamines.

Blood Pressure↗
PubMed1987

[In vitro tests of hepatic oxidation in man, predictive of drug interactions].

Liver monooxygenases are of primary importance in the metabolism of numerous drugs. Their activity, which is genetically controlled, is modulated by environmental factors such as drug treatment. We have developed an in vitro model of human oxidative metabolism in order to evaluate the activity of a specific monooxygenase (debrisoquine type of cytochrome P-450). Substances capable of inhibiting monooxygenase function can be identified and the in vivo occurrence of drug interactions can thus be predicted. - Dextromethorphan O-demethylation in human microsomes prepared from small human liver tissue samples is monitored as the prototype reaction. The kinetic parameters of this reaction are stable and reproducible (Km 1-5 microM, Vmax 9.1 +/- SD 4.6 nmol x mg P-1 x h-1). The reaction is inhibited by numerous drugs (quinidine, phenothiazine type neuroleptics, some dihydropyridines). Preliminary clinical results demonstrate the predictive value of this assay.

Chromatography, High Pressure Liquid↗
PubMed1987

[Evaluation of a caffeine test for determining the phenotype of N-acetyltransferase].

Xenobiotic acetylation by N-acetyltransferase is genetically controlled. This polymorphism governs the intestinal and liver metabolism of numerous amines. The use of caffeine, a ubiquitous and nontoxic amine, has been proposed as a probe for phenotyping. The aim of the present study is to evaluate this test and to identify the metabolite of caffeine used as substrate by the polymorphic enzyme. - A cup of coffee, tea or Coca-Cola is administered to fasting subjects. The molar ratio of two metabolites of caffeine (AFMU and 1X) is determined on a spot urine sample 4-6 hours later by means of a UV liquid chromatographic assay. In a reference population (n = 63), the distribution of molar ratios is trimodal with frequencies of 0.14, 0.35 and 0.51. These results correlate with those obtained by the classic isoniazid test. However, in vitro experiments in human liver subcellular fractions did not lead to the identification of a xanthine as the precursor of the acetylated metabolite.

Acetyltransferases↗
PubMed1987

Enzymatic basis of the debrisoquine/sparteine-type genetic polymorphism of drug oxidation. Characterization of bufuralol 1'-hydroxylation in liver microsomes of in vivo phenotyped carriers of the genetic deficiency.

The genetically controlled polymorphic oxidation of debrisoquine and sparteine is caused by the absence or functional deficiency of a cytochrome P-450 isozyme. In order to elucidate the mechanisms underlying the differences in cytochrome P-450 function we have studied the 1'-hydroxylation of the prototype drug bufuralol in human liver microsomes of individuals phenotyped in vivo as extensive metabolizers (EM, N = 10), poor metabolizers (PM, N = 5) and in subjects with an intermediate rate of metabolism (IM, N = 4). PM- as compared to EM-microsomes were characterized by a decreased Vmax for (+)-bufuralol 1'-hydroxylation (7.51 +/- 2.03 nmol X mg-1 X hr-1 vs 11.95 +/- 4.80 nmol X mg-1 X hr-1) but not for (-)-bufuralol 1'-hydroxylation (4.72 +/- 0.87 nmol X mg-1 X hr-1 vs 5.55 +/- 1.49 nmol X mg-1 X hr-1). The apparent Km for (+)-bufuralol 1'-hydroxylation was increased in PM microsomes (118 +/- 84.9 microM vs 17.9 +/- 6.30 microM). Inhibition of bufuralol 1'-hydroxylation by quinidine was biphasic in EM microsomes, providing further support for the involvement of at least two cytochrome P-450 isozymes. Quinidine acted as a competitive inhibitor of only the high affinity/stereoselectivity component of the reaction. Our data suggest that the debrisoquine/sparteine type of oxidation polymorphism is caused by an almost complete loss of a minor cytochrome P-450 isozyme which has a high affinity and stereoselectivity for (+)-bufuralol and a high sensitivity to inhibition by quinidine.

Adult↗
PubMed1987

Evidence for altered catalytic properties of the cytochrome P-450 involved in sparteine oxidation in poor metabolizers.

Sparteine metabolism was studied in human liver microsomes from nine extensive ([EM] urinary metabolic ratio [MR] less than 20) and four poor metabolizers ([PM] MR greater than 20). The formation of 2- and 5-dehydrospartein displayed monophasic Michaelis-Menten kinetics. In livers from PMs the formation of the major sparteine metabolite 2-dehydrosparteine was characterized by more than a thirtyfold increase in Michaelis-Menten constant (Km)(1880 +/- 1044 mumol/L) as compared with EM subjects with an MR less than 1 (58.3 +/- 38.8 mumol/L). EM subjects with an MR greater than 3 who may constitute heterozygous metabolizers showed Km values in between (658 +/- 301 mumol/L). There was no difference in maximum rate of metabolism (Vmax) of 2-dehydrosparteine formation between EM and PM subjects (101 +/- 39 vs. 86 +/- 52 pmol/min/mg). The formation of 5-dehydrosparteine exhibited a Km of 100 +/- 123 mumol/L similar to the Km of 2-dehydrosparteine formation. The urinary MR correlated positively with the Km for 2-dehydrosparteine formation. The intrinsic clearance for 2-dehydrosparteine showed a highly significant negative correlation with the MR. The pronounced differences in Km together with the significant correlation between Km and MR with no marked differences in Vmax between phenotypes suggest that the impaired oxidation capacity in PM subjects is more likely the result of a P-450 isozyme with altered catalytic properties rather than a decreased amount of enzyme.

Adult↗
PubMed1986

Debrisoquine/sparteine-type polymorphism of drug oxidation. Purification and characterization of two functionally different human liver cytochrome P-450 isozymes involved in impaired hydroxylation of the prototype substrate bufuralol.

The debrisoquine/sparteine-type polymorphism of drug oxidation presumably is caused by the absence or deficiency of cytochrome P-450 (P-450) isozyme(s). Using bufuralol 1'-hydroxylation as a prototype reaction of this polymorphism, two functionally distinct forms, P-450 buf I and P-450 buf II, with identical apparent Mr of 50,000 were purified from liver microsomes of three different human livers. P-450 buf I exhibited a marked selectivity for the (+)-enantiomer of bufuralol ((-)/(+) ratio = 0.15), P-450 buf II was nonstereoselective((-)/(+) ratio = 1.03). The Km values for (-)- and (+)-bufuralol were 31 and 54 microM with P-450 buf I and 314 and 245 microM with P-450 buf II. P-450 buf II generated two other metabolites in addition to 1'-OH-bufuralol which were not observed with P-450 buf I. Using the inhibitor quinidine, a Ki of 0.06 microM was observed with P-450 buf I as opposed to 80 microM with P-450 buf II for bufuralol 1'-hydroxylation. A strong immunochemical relatedness of P-450 buf I and P-450 buf II was found since polyclonal antibodies against either form recognized the heterologous antigen to the same extent as the homologous antigen on Western blots and in immunoinhibition and in immunoprecipitation experiments. Cross-reactivity of these antibodies with a microsomal nonheme protein of unknown function (apparent Mr 50,000) also was noted. Western blots of microsomes of in vivo and in vitro phenotyped extensive and poor metabolizer individuals revealed no correlation of in vivo-determined metabolic ratio, microsomal activity, and amount of immunoreactive material. Antibodies against P-450 buf I and P-450 buf II inhibited bufuralol 1'-hydroxylation in microsomes of in vivo and in vitro phenotyped poor metabolizer individuals demonstrating that the residual activities are immunochemically related to the activities in extensive metabolizers.

Cytochrome P-450 Enzyme System↗
PubMed1986

[Ordering laboratory tests: their quantity and causes of variations among physicians].

To establish whether some physicians contribute more than others to the alarming increase in laboratory related expenditure, 317 consecutive medical files established by 10 residents of an outpatient clinic were analyzed. The expense incurred in establishing a diagnosis varied, according to the physicians involved, by a factor of 4.9 for back pain and 2.6 for acute respiratory illness. The difference is even more striking when the various types of investigation are analyzed (blood count, ESR, X-rays). It is therefore possible to group physicians according to their individual tendency to order tests. This classification is not related to age, sex, former professional experience or sub-specialty in internal medicine. There is a significant correlation (Spearman's test) between this classification and the approach to medicine, as evidenced by analysis of the content of an interview on medical practice. These interviews were conducted double blind, recorded and transcribed to determine psychological traits. Physicians who order a large number of tests are characterized by a high index of uncertainty, as evidenced by the large number of hesitant expressions and a tendency to cut the interview short, showing off to compensate for lack of self-assurance, depersonalized reference to patients, few references to the interviewer, difficulty in establishing a true dialogue. These characteristics can be considered to form a coherent entity which shows that even the material aspects of medical practice are strongly influenced by the physician-patient relationship.

Attitude of Health Personnel↗
PubMed1986

Importance of oxidative polymorphism and levomepromazine treatment on the steady-state blood concentrations of clomipramine and its major metabolites.

The relationship between the debrisoquine oxidation status and the metabolism of clomipramine was studied in nine healthy volunteers (five rapid hydroxylators, three slow hydroxylators and one of intermediate status). The hydroxylation of clomipramine and demethylclomipramine were found to covary with that of debrisoquine, whereas demethylation of clomipramine seemed to be independent of the debrisoquine hydroxylation phenotype. The steady-state blood concentrations of clomipramine and its three main metabolites were measured in 122 depressed patients. Thirteen patients who concomitantly received a neuroleptic tended to have higher levels of demethylclomipramine and clomipramine, whereas the levels of the hydroxylated metabolites were hardly affected. Benzodiazepine co-administration did not modify the pharmacokinetics of clomipramine. The results suggest that benzodiazepines rather than levomepromazine should be used in depressed patients with anxiety and/or agitation in combination with the antidepressant treatment.

Adult↗
PubMed1986

Stereo- and regioselectivity of hepatic oxidation in man--effect of the debrisoquine/sparteine phenotype on bufuralol hydroxylation.

The influence of the debrisoquine/sparteine-type of oxidation polymorphism on plasma bufuralol concentration and the pattern of urine metabolites was studied in extensive and poor metabolizer subjects. (+)- and (-)-bufuralol, and (+)- and (-)-OH-bufuralol in plasma were determined by enantioselective HPLC, and urinary bufuralol and its metabolites were assayed by gas chromatography-mass spectrometry. Three hours after administration of racemic bufuralol the plasma (-)/(+) isomeric ratio for unchanged bufuralol was 1.84 in extensive metabolizers, indicating preferential clearance of the (+)-isomer through aliphatic 1'-hydroxylation and glucuroconjugation, while the (-)-isomer was mainly eliminated by aromatic 4-hydroxylation. Poor metabolizers were characterized by impaired 1'- and 4-hydroxylation, with almost total abolition of the stereoselectivity of these reactions. The data strongly suggest that both 1'- and 4-hydroxylation are catalyzed by the same enzyme. These in vivo observations are in agreement with recent in vitro data obtained in human liver microsomes from phenotyped patients and support the concept of deficiency of a highly stereoselective cytochrome P-450 isozyme as the cause of this polymorphism.

Adrenergic beta-Antagonists↗
PubMed1986

Interindividual pharmacokinetic and pharmacodynamic variability of different beta blockers.

Hepatic drug metabolism influenced by genetic and environmental factors is a major source of variation in the response to a number of beta-adrenoceptor antagonists. The first study described here was carried out to define the role of a genetic determinant (debrisoquine-type oxidation polymorphism) on plasma concentration of bopindolol and its pharmacological effect. Atenolol was used as a negative and metoprolol as a positive control. In a second study, the relative potency and duration of action of bopindolol were assessed in comparison to atenolol and slow-release oxprenolol. The first study was carried out using 10 healthy volunteers (6 extensive and 4 poor metabolizers), and the second study was carried out using 12 volunteers, all of whom were extensive metabolizers. Genetic polymorphism did not influence the kinetic behavior or pharmacological effects of atenolol. The elimination of bopindolol was slightly but significantly prolonged in poor metabolizers, but this did not significantly alter the cardiac effects of the drug. In the case of metoprolol poor metabolizers showed a significant prolongation of drug elimination, and this was associated with a significant prolongation of the cardiac effects of the drug. The second study revealed that, in terms of cardiac beta-adrenoceptor blockade, 1 mg bopindolol was equipotent to 100 mg atenolol or 160 mg slow-release oxprenolol and that both bopindolol and atenolol had a longer duration of action than slow-release oxprenolol. It is concluded that bopindolol is a potent beta-adrenoceptor antagonist with a very long duration of action which shows little interindividual variability.

Adrenergic beta-Antagonists↗