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Biomedical subjects

P Dayer

Publications and source records attributed to P Dayer.

At least 91 records · Page 5Linked to original sources
PubMed1992

[Therapy compliance. A matter of concern in clinical medicine].

Approximately one half of the patients takes prescribed medications irregularly or omits these altogether. On the basis of our own observations and published reports we analyze the factors influencing compliance. The motivation of the patients plays a decisive role, it is rooted in the meaning the patient gives to his existence, to where the strength of his family bonds and the confidence in the care-taking persons lays as well as the possibility to express himself which is most important. The better guidance and training of the doctors in the difficult task of strengthening such motivation may contribute to substantially improve this situation.

Adult↗
PubMed1992

Pharmacokinetic-pharmacodynamic modeling of the effects of clonidine on pain threshold, blood pressure, and salivary flow.

Although clonidine analgesia appears to be mediated by the same central alpha 2-adrenoceptors that mediate its hypotensive effect, it is short-lasting when compared to the fall in blood pressure. This has been investigated by combined pharmacokinetic-pharmacodynamic analysis in 10 healthy volunteers who received (double-blind and crossover) clonidine 200 micrograms orally + placebo i.v. and clonidine orally + naloxone i.v. (2.8 mg/5 h). Analgesia was assessed by measuring the subjective (VAS) and objective (RIII) pain thresholds after transcutaneous electrical stimulations of the sural nerve; the mean arterial blood pressure (MAP), salivary flow (SF), and plasma clonidine concentrations were also monitored. A combined pharmacokinetic (first order absorption - 1 compartment) - pharmacodynamic (linear) model, including a hypothetical effect compartment with and without tolerance, were fitted to the data. Clonidine and clonidine + naloxone increased subjective and objective pain thresholds for 4 h. The concentration-effect plot for MAP showed distinct hysteresis. The t1/2s for effect compartment equilibration were 29 and 42 min for clonidine + naloxone and clonidine. The concentration-effect curves for RIII had the same shape as MAP but the starting hysteresis suddenly collapsed, suggesting acute tolerance. The best fit was obtained with a model where the linear relationship between concentration in the effect compartment and analgesia changed acutely after the third hour. The short-lived analgesia was probably related to an acute change in pain sensitivity induced by food, suggesting that it is not mediated solely by the alpha 2-adrenoceptors responsible for hypotension.

Adult↗
PubMed1992

Serum concentration-effect relationship of (+/-)-nicardipine and nifedipine in elderly hypertensive patients.

The concentration-effect relationships of (+/-)-nicardipine and nifedipine have been investigated in hypertensive geriatric patients. Following a parallel group, randomised, double blind trial design, they received either slow release nifedipine 20 mg b.d. (n = 9) or slow release (+/-)-nicardipine 50 mg b.d. (n = 10) for 7 days. On Days 1 and 7 serum (+/-)-nicardipine and nifedipine, blood pressure and heart rate were measured 6 and 12 h after drug administration. (+/-)-Nicardipine showed significant cumulation (ca 2 x) without a corresponding decrease in blood pressure or increase in heart rate. Concentration-effect plots indicated that (+/-)-nicardipine was more potent than nifedipine but that it showed apparently comparable efficacy in reducing the blood pressure. Compared to young healthy volunteers, both drugs had a more pronounced effect in elderly patients.

Aged↗
PubMed1992

In vitro oxidation of oxicam NSAIDS by a human liver cytochrome P450.

The nature of the enzyme(s) catalyzing the major metabolic pathway (5'-hydroxylation) of oxicam NSAIDs was investigated in subcellular preparations of human liver tissue. Microsomal, but not cytosolic, fractions catalyzed the 5'-hydroxylation of tenoxicam. This reaction required NADPH and was inhibited by various nonselective P450 inhibitors (CO, SKF-525A, ketoconazole), but not by the peroxidase inhibitor NaN3. Tenoxicam 5'-hydroxylation exhibited simple Michaelis-menten kinetics compatible with catalysis by a single enzyme, but it strongly inhibited its own oxidation at concentrations higher than 100-150 microM. Piroxicam competitively inhibited tenoxicam 5'-hydroxylation and, conversely, tenoxicam competitively inhibited piroxicam 5'-hydroxylation. Tenoxicam 5'-hydroxylation kinetics were similar in microsomes from one poor and five extensive metabolizers of debrisoquin (CYP2D6). Dextromethorphan (CYP2D6 prototype substrate) and midazolam (CYP3A prototype substrate) had no influence on tenoxicam 5'-hydroxylation, whereas mephenytoin, tolbutamide and sulfaphenazole (Ki = 0.1 microM) inhibited it. This indicates that the 5'-hydroxylation of both piroxicam and tenoxicam is predominantly catalyzed by at least one cytochrome P450 isozyme of the CYP2C subfamily.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1992

Once-a-week azithromycin in AIDS patients: tolerability, kinetics, and effects on zidovudine disposition.

Toxoplasmic encephalitis is one of the leading causes of morbidity in patients with AIDS. Lifelong treatment is needed to prevent relapses, and primary prevention is desirable in high-risk patients, but the available drugs are often poorly tolerated. Azithromycin (AZM) has been considered a drug candidate because of its efficacy in the animal model and its kinetic properties, which would allow intermittent administration. The tolerability and kinetics of AZM and its effect on the disposition of zidovudine (ZVD) were therefore evaluated in a preliminary open study in nine human immunodeficiency virus-infected patients. AZM was administered once weekly for 5 weeks 2 h before the usual morning ZVD dose. The day before and on the first and fifth AZM dosings, blood samples were drawn every 30 min during 5 h for determination of the concentrations of ZVD and its glucuronide metabolite. Blood samples were drawn for AZM measurement over 72 and 360 h on the first and fifth AZM administrations, respectively, as well as before and 3 h after dosing on the second, third, and fourth AZM dosings. After the first and fifth administrations, maximum AZM concentrations in serum were 0.6 +/- 0.1 and 0.8 +/- 0.2 microM (mean +/- standard error of the mean), respectively; times to peak concentration in serum were 3.7 +/- 0.2 and 2.9 +/- 0.4 h, respectively; areas under the plasma concentration-time curves were 9.2 +/- 1.6 and 9.3 +/- 2.0 micrograms.h/ml, respectively; and half-lives were 61.0 +/- 5.4 and 63.8 +/- 6.7 h, respectively. On days -1, 1, and 29, ZVD kinetic parameters were as follows: maximum concentrations in serum, 3.1+/- 0.6, 4.3 +/- 0.6, and 4.2 +/- 0.9 microM, respectively; times to maximum concentrations in serum, 1.1 +/- 0.4, 0.8 +/- 0.2, and 1.2 +/- 0.3 h, respectively: areas under the plasma concentration-time curves, 5.3 +/- 0.9, 5.9 +/- 0.6, and 5.7 +/- 0.8 microgram . h/ml, respectively; and half-lives, 1.3 +/- 0.08, 1.4 +/- 0.04, and 1.3 +/- 0.04 h, respectively. Except for transient mild abdominal cramps that occurred at 2 to 3 h postdose (6 of 45 exposures) and nausea (4 of 45 exposures), neither subjective nor objective side effects were observed. The kinetics of AZM were similar after the first and repeated administrations, and the disposition of ZVD was not altered by this treatment. The efficacy of AZM in preventing cerebral toxoplasmosis can therefore be safely tested in human immunodeficiency virus-infected patients concomitantly treated with zidovudine.

Acquired Immunodeficiency Syndrome↗
PubMed1991

[Central analgesic effects of antidepressant drugs with various mechanisms of action: desipramine, fluvoxamine and moclobemide].

Analgesic properties of antidepressants are not yet well established. The aim of this study was to investigate the analgesic effect of three antidepressants after single oral dose administration to healthy volunteers. The late spinal R-III reflex threshold (objective pain threshold) and the subjective pain threshold (numerical categorical scale) were markers of analgesic effect. Desipramine induced significant increases in both thresholds. Fluvoxamine and moclobemide also exerted a significant analgesic effect, although displaying distinct patterns depending on the analgesic marker considered. Antidepressants exert a central analgesic effect independent of their antidepressive effect and, depending on their mode of action, already detectable at spinal level.

Analgesics↗
PubMed1991

Impact of environmental and genetic factors on codeine analgesia.

The polymorphic cytochrome P-450 DB1 (P-450 IID6) is responsible for the O-demethylation of codeine to morphine by human liver microsomes. The influence of P-450 DB1 variable activity on the bioactivation of codeine in vivo to morphine and on its analgesic effect was investigated in phenotyped healthy volunteers--7 extensive [EM] and 1 poor [PM] metabolizer of debrisoquine. After pretreatment with oral placebo or quinidine sulphate 50 mg, codeine phosphate 100 mg or placebo were administered orally according to a double-blind randomized crossover design. In EM subjects the plasma morphine Cmax was 17.9 nmol/l, whereas virtually no morphine was detectable after quinidine pretreatment (1.5 nmol/l), and in the PM subject (0.60 nmol/l). In EM codeine significantly increased subjective (VAS) and objective (R-III reflex) pain thresholds in response to selective transcutaneous nerve stimulation, whereas no significant analgesia was detected after placebo, or after codeine with quinidine pretreatment, or in the PM. In PM of genetic origin, or due to environmental alteration of the phenotypic expression (i.e. drug interaction), codeine is not activated into morphine and is an inefficient analgesic.

Administration, Oral↗
PubMed1991

In vitro forecasting of drugs which may interfere with the biotransformation of midazolam.

The biotransformation of midazolam is mediated by a cytochrome P-450 isozyme (P-450 IIIA) whose activity is highly variable. The kinetics of the 1'- and 4-hydroxylation of midazolam, the major routes of midazolam oxidation, by human liver microsomes have been examined to characterize further the cytochrome isozyme(s) catalysing these reactions, and to screen for drugs that might interfere with them. In hepatic microsomal preparation from two kidney donors (extensive and poor metabolisers of debrisoquine) KM values for 1'-hydroxylation were 4.2 and 6.1 microM (extensive and poor metabolisers, respectively), and for the 4-hydroxylation they were 14.7 and 18.1 microM, respectively. The corresponding Vmax values were 25.8 and 29.8 and 17.0 and 18.1 nmol.mg P-1.h-1. Both reactions appeared to be catalysed by the same or by coregulated isozymes. Midazolam hydroxylations in vitro are inhibited by many drugs, including nifedipine and other dihydropyridine-type calcium channel blockers, ergot alkaloids, cyclosporine, erythromycin and phenothiazine-type neuroleptics. A clinical case report illustrates the consequence of such a drug-drug interference with hepatic biotransformation; midazolam-induced sleep in a patient lasted for 6 days (t1/2 = 25 h).

Biotransformation↗
PubMed1991

The role of lipophilicity in the inhibition of polymorphic cytochrome P450IID6 oxidation by beta-blocking agents in vitro.

The importance of lipophilicity as a determinant of the affinity of beta-adrenoceptor blocking agents for a specific human hepatic monooxygenase--cytochrome P450IID6 (responsible for the debrisoquine-type of oxidation polymorphism)--was investigated in vitro by estimating the inhibition constants of a series of compounds in a microsomal system with monitoring of the kinetics of dextromethorphan O-demethylation. Lipophilicity is a key predictor of the affinity of beta-blocking drugs for cytochrome P450IID6 and of their potential to cause specific competitive drug interactions, but more complex structural factors appear to be important as well. A high lipophilicity is also a necessary, but not a sufficient condition for these compounds to be metabolized by cytochrome P450IID6.

Adrenergic beta-Antagonists↗
PubMed1991

Central analgesic effect of acetaminophen but not of aspirin.

The central nervous system effect of acetaminophen (paracetamol) and acetylsalicylic acid was investigated in healthy volunteers according to a crossover, double-blind, and placebo-controlled design. Ten subjects received, by intravenous route, a placebo, 1 gm acetaminophen, and 1 gm acetylsalicylic acid. Analgesia was assessed by measurement of the subjective pain threshold and the objective nociceptive flexion reflex threshold in response to selective transcutaneous electrical stimulations. A close correlation was observed between subjective and objective pain thresholds. Acetaminophen increased both thresholds for more than 4 hours (24% and 23% of baseline value at 120 minutes, respectively; p less than 0.001, ANOVA). In contrast, acetylsalicylic acid had no noticeable effect on either threshold. These findings show that acetaminophen-induced analgesia is centrally mediated, in contrast to aspirin. The time delay between plasma concentration kinetics and acetaminophen analgesic effect is another argument in favor of its direct action on the central nervous system.

Acetaminophen↗
PubMed1991

Fetal drug metabolism and its possible clinical implications.

The ability of the human conceptus to metabolise xenobiotics during early gestation is now well established. Specific activities of liver enzymes have been demonstrated to exist in the late embryonic phase for numerous cytochrome P450 monooxygenases and many phase II enzymes such as glutathione-, N-acetyl-, sulpho- and uridine diphosphate-glucuronosyltransferase. As in the adult, fetal drug metabolism may function in a dual manner, either as a protective mechanism against chemical aggression when transforming active molecules into inactive ones, or as a toxifying system when transforming innocuous compounds into reactive metabolites. Recent advances in the understanding of enzyme variabilities at molecular and functional levels illustrate the necessity of studying these variations in the human fetus as well as in adults, since the combination of genetic, developmental and environmental factors seem to control fetal enzyme activities and ultimately determine the variability in individual susceptibility to chemicals in utero. Despite the scarcity of well documented cases of adverse fetal reactions resulting directly from metabolic toxicity, the clinical relevance of the potential role of biotransformation in generating fetal toxicity is a strong appeal to promote further studies dealing with the ontogeny of drug-metabolising capacity and its regulation.

Abnormalities, Drug-Induced↗
PubMed1990

[Central analgesic effect of paracetamol].

Although biochemical data suggest a direct effect of paracetamol on the CNS, its mode of action is still poorly understood. We investigated the central impact of paracetamol compared to acetylsalicylate in response to transcutaneous electrical nerve stimulation in man. Healthy volunteers received i.v. paracetamol, acetylsalicylic acid, and placebo. Analgesia was assessed by measurement of objective (R-III reflex) and subjective (VAS) pain thresholds. A close correlation was observed between both objective and subjective thresholds. Paracetamol raised the objective and subjective thresholds. In contrast, acetylsalicylic acid had no noticeable effect on either threshold. These data demonstrate a central analgesic effect of paracetamol.

Acetaminophen↗
PubMed1990

[The effect of rate of administration of isradipine on the hemodynamic response].

As the magnitude of drug response may depend on its input rate, we investigated the rate of administration-effect relationship of the new dihydropyridine isradipine. Ten healthy volunteers received (double-blind and cross-over) isradipine 1 mg i.v. (5 min), 5 mg solution, 5 mg tablet, 10 mg sustained release, and placebo. Blood pressure and heart rate were recorded for 24 h. A single dose of slow-release formulation isradipine does not induce significant hemodynamic effects in healthy subjects. The maximal BP fall was comparable with either i.v., solution, and conventional tablet administration. This is due to a stronger heart rate counter-regulation, linked to rapid isradipine administration. These results imply that slow input rates of isradipine are more effective in lowering blood pressure.

Administration, Oral↗
PubMed1990

Indirect assessment of the enterohepatic recirculation of piroxicam and tenoxicam.

To assess the extent of enterohepatic recycling of piroxicam and tenoxicam, their pharmacokinetics have been compared in the absence and presence of concomitant treatment with cholestyramine. In a randomized crossover study 6 healthy volunteers received piroxicam and tenoxicam 20 mg p.o., alone or with cholestyramine 24 g/day for 4 days. Cholestyramine increased piroxicam & tenoxicam elimination approximately 2-fold (t 1/2 50.3 vs 28.1 h and 73.6 vs 35.8 h, respectively). It also increased the apparent clearance (Cl/f) of piroxicam and tenoxicam by 58% and 112%. When cholestyramine was administered, the t 1/2 of piroxicam & tenoxicam were correlated (r = 0.89), which suggests that their hepatic biotransformation is under a common control. It is concluded that: piroxicam and tenoxicam are eliminated to a large and comparable extent through the biliary route, and the administration of cholestyramine may help to accelerate their elimination in cases of overdosage.

Adult↗
PubMed1990

Objective assessment of clonidine analgesia in man and influence of naloxone.

Experimental data indicate that clonidine can induce marked analgesia. We characterized this effect in healthy volunteers and investigated possible links with the opioid peptide system by means of naloxone antagonism. According to a cross-over, double-blind, placebo-controlled design, 10 subjects received oral and i.v. placebo or clonidine (0.2 mg p.o.) or clonidine and naloxone (2.8 mg i.v. in 5 h). Analgesia was assessed by measurement of the subjective pain threshold (visual analog scale) and the objective nociceptive flexion reflex (R III) threshold after transcutaneous electrical stimulations. A correlation was observed between subjective and objective thresholds (r: 0.78). Oral clonidine alone or with naloxone increased subjective and objective pain thresholds for at least 4 hours (p less than 0.01, ANOVA). Naloxone tended to reinforce clonidine analgesia. Only moderate and well tolerated side-effects were observed.

Adult↗
PubMed1990

Effects of beta-blockade on energy metabolism following burns.

The purpose of this study was to compare the effects of propranolol administered either by i.v. infusion or by prolonged oral administration (4 days) during the first 3 weeks following burns. The resting metabolic rate (RMR) of 10 non-infected fasting burned patients (TBSA: 28 per cent, range 18-37 per cent) was determined four times consecutively by indirect calorimetry (open circuit hood system) following: (1) i.v. physiological saline; (2) i.v. propranolol infusion (2 micrograms/kg/min following a bolus of 80 micrograms/kg); (3) oral propranolol (40 mg q.i.d. during 4 +/- 1 days); and (4) in control patients. All patients showed large increases in both RMR (144 +/- 2 per cent of reference values) and in urinary catecholamine excretion (three to four times as compared to control values). The infusion of propranolol induced a significant decrease in RMR to 135 +/- 2 per cent and oral propranolol to 129 +/- 3 per cent of reference values. A decrease in lipid oxidation but no change in carbohydrate and protein oxidation were observed during propranolol administration. It is concluded that the decrease in RMR induced by propranolol was not influenced by the route of administration. The magnitude of the decrease in energy expenditure suggests that beta-adrenergic hyperactivity represents only one of the mediators of the hypermetabolic response to burn injury.

Administration, Oral↗
PubMed1990

Serum concentrations and effects of (+/-)-nicardipine compared with nifedipine in a population of healthy subjects.

The dihydropyridine calcium antagonist (+/-)-nicardipine shares some of the pharmacologic properties of the dihydropyridine prototype nifedipine. To compare them, serum concentrations and cardiovascular effects of 10 mg nifedipine and 20 mg (+/-)-nicardipine were evaluated at 1, 2, and 3 hours after oral intake in a randomized, crossover, single-blind study involving 79 healthy volunteers. (+/-)-Nicardipine serum concentrations were much lower than those of nifedipine, indicating a greater hepatic first-pass metabolism of (+/-)-nicardipine. There was a significant correlation between serum concentrations of both drugs. The frequency distributions of nifedipine and (+/-)-nicardipine AUC (0-3), heart rate increase, and mean arterial pressure decrease showed no bimodality. This does not confirm the proposed polymorphism of nifedipine oxidation. Concentration-effect plots indicate that (+/-)-nicardipine is more potent than nifedipine but shows comparable efficacy in blood pressure reduction.

Adult↗