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Biomedical subjects

P Dayer

Publications and source records attributed to P Dayer.

At least 73 records · Page 4Linked to original sources
PubMed1994

[Clinical pharmacology in practice].

A university-hospital clinical pharmacology consult service was evaluated for: spontaneous use by clinicians (reflecting the competence conferred to clinical pharmacologists and the information clinicians seek), subject matters of postgraduate teaching to internal medicine trainees (needs perceived by the clinical pharmacologist), and finally, prescription profile of these trainees (clinical reality). Over 14 months, 663 requests were received (86% for a specific patient). Topics included adverse events (AE) (53%), pharmacokinetics (PK) (20%), treatment indications (T) (19%), and product identification (Id) (8%). In the service holding regular teaching sessions in clinical pharmacology, spontaneously requested consults pertained to: T 49% (mainly pain management, a domain of expertise of this particular clinical pharmacology service), AE 34%, PK 12% and Id 5%. In contrast, teaching covered PK 42%, T 39% (half on pain), and AE 16% of the time. The prescription profile included 201, mostly elderly patients, 40% with an estimated creatinine clearance < or = 50 ml/min. Of the renally compromised patients, only 14% were clearly identified as such by the doctor in charge, although 63% received at least one drug requiring dosage adjustment, which was done in 44% of cases. Interactions were present in 9% of treatments, which were appropriately adjusted in two thirds following routine in-hospital monitoring of low therapeutic index drugs, even though the possibility of an interaction was not explicitly charted. In conclusion, despite increasing complexity of therapeutics, reliance on clinical pharmacologists is variable.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1994

[Absence from work and illness behavior in patients with chronic pain].

Factors relating to working status, i.e. whether the subject is still at work or on workmen's compensation, have been studied in chronic pain patients. Sociodemographic and pain variables were not correlated with absence from work, nor was diagnosis. However, beliefs and attitudes concerning pain differed between patients still working and those on workmen's compensation. In chronic pain patients medical attention should focus not only on description of symptoms but also on the "illness behaviour" dimension.

Absenteeism↗
PubMed1994

[Predictive factors of resistance to treatment of neuropathic pain].

The aim of this retrospective study was to examine factors related to symptomatic pain treatment in 992 hospitalized patients referred to the pain clinic. These patients accounted for 1440 different pains (1.5 pains/patient), of nociceptive (59%), or neuropathic (24%) origin, a combination of both (16%) and of unidentified (1%) origin. Patients resistant to therapy did not differ from nonresistant patients (62%) in terms of age, sex, or number of pains. Although recommended pharmacological treatments were pursued, the neuropathic origin of pain was a factor in resistance to treatment. Among the neuropathic pains resistant to treatment (42%) a central nervous origin is more frequently found. Resistance to pain was more frequently encountered after strokes, primitive tumor of the central nervous system or traumatic plexopathy, whereas peripheral lesions of the nervous system were more easily controlled by symptomatic treatment. This study shows that central neuropathic pain is more frequently associated with resistance to recommended pharmacological symptomatic treatments. This observation underlines the limits of conventional medical therapy.

Analgesia↗
PubMed1994

[Evaluation of chronic pain in geriatric patients].

This retrospective study considers the influence of chronological age on the perception and consequential effects of chronic non-cancer pain in 203 patients referred to an ambulatory pain clinic. One patient in four (50) was 65 years or older. Pain had existed for more than a year in 66%. It was referred to an "unbearable" by 54% of elderly adults vs 44% (NS) of the younger adult population, and as "intense" by 61% vs 44% (p < 0.05). A higher proportion of neurogenic pain (54% vs 26%, p < 0.05) could explain this significant difference. Cognitive factors could also have amplified the painful syndrome since 59% (vs 54%) of the elderly considered they had received insufficient information on the potential consequences of their painful condition. However, despite a higher occurrence of other severe illnesses in the elderly (52% vs 35%, p < 0.05), they appear to worry less about their health problems (58% vs 78%, p < 0.01). Finally, in spite of increased severity of pain in the elderly, depression scores and consequential effects are similar in the two populations. In conclusion, the intensity of chronic pain appears to be more severe in the elderly, perhaps due to its more frequent neuropathic origin. Nonetheless, its repercussions on daily life activity seem no worse than for younger adults, and could reflect better coping strategies towards chronic pain.

Activities of Daily Living↗
PubMed1994

Influence of input rates on (+/-)-isradipine haemodynamics and concentration-effect relationship in healthy volunteers.

Since the magnitude of the response to a drug may depend upon the drug input rate, the concentration-effect relationship of the new dihydropyridine (+/-)-isradipine was investigated using different administration modalities. Ten normotensive healthy volunteers were given, double-blind and in a crossover fashion, isradipine as a 1 mg iv infusion, 5 mg oral solution, 5 mg standard tablet, 10 mg slow release formulation, and a placebo. Blood pressure, heart rate, and plasma isradipine concentrations were recorded for 24 h. The maximal fall in diastolic blood pressure was similar after the infusion (-11.40 mmHg), the oral solution (-15.20 mmHg), and the standard tablet (-12.50 mmHg). In healthy volunteers the slow release form had no significant effect on blood pressure. The concentration-effect plots showed an increasing slope in the order infusion, solution, and table, and anticlockwise hysteresis. This was partly due to marked heart rate counter-regulation, the corresponding mean maximal heart rate increases being 24, 19, and 17 beats.min-1. The pronounced counter-regulation of the heart rate implies that a slow isradipine input rate would be more effective in decreasing blood pressure.

Administration, Oral↗
PubMed1994

Selective inhibition of major drug metabolizing cytochrome P450 isozymes in human liver microsomes by carbon monoxide.

The selectivity of carbon monoxide binding to specific human cytochrome P450 isozymes was investigated by studying its inhibition of prototype reactions for 3 major drug metabolizing P450s in liver microsomes: dextromethorphan O-demethylation and (+)-bufuralol 1'-hydroxylation (P450DB1, CYP2D6), diclofenac 4'-hydroxylation (P450TB, CYP2C subfamily), and midazolam 1'-hydroxylation (P450NF, CYP3A subfamily). The affinity of carbon monoxide is different for each P450 isozyme. Warburg partition coefficients were 0.35, 1.1 and 3.9 microM for P450DB1, P450TB and P450NF, respectively. Differential inhibition by carbon monoxide may be a useful tool to identify specific human cytochrome P450 isozymes in the early screening of drug biotransformation catalysts. Further studies involving other P450 isozymes and substrates should extend our understanding of the phenomena and their implications.

Carbon Monoxide↗
PubMed1994

The pharmacology of tramadol.

(+/-)-Tramadol is a central analgesic with low affinity for opioid receptors. The rate of production of its M1 metabolite (O-demethyl tramadol) is influenced by debrisoquine-type polymorphism, and this metabolite shows a higher affinity for opioid receptors than the parent drug. Experimental and clinical data suggest that tramadol may also exert its analgesic effect through direct modulation of central monaminergic pathways. Indeed, after a single oral dose, the role of the mu-receptor agonist component of the antinociceptive effect of tramadol appears to be minor, with most of the analgesic effect being attributable to nonopioid properties of the parent compound. Approximately 2-fold accumulation of the parent compound and the M1 metabolite may be expected during multiple dose treatment. The duration of analgesic effect after a single oral dose of tramadol 100 mg is about 6 hours. Clinical experience has confirmed that tramadol is an effective and relatively safe analgesic that may be of value in several pain conditions not requiring treatment with strong opioids.

Drug Tolerance↗
PubMed1993

[Duality of the analgesic effect of tramadol in humans].

Tramadol is a central analgesic with low affinity for opioid receptors. A major active metabolite (O-desmethyl-tramadol) shows a higher affinity for opioid receptors than tramadol. The influence of naloxone and quinidine (a selective P450DB1 or CAP2D6 inhibitor) on tramadol effect was investigated crossover and double-blind vs placebo in healthy subjects. They received tramadol (100 mg p.o.), tramadol+naloxone (0.8 mg i.v.) and tramadol+quinidine (50 mg p.o.). Analgesia was assessed, after transcutaneous electrical stimulation, by a categorical numerical scale and by measurement of the antinociceptive effect at spinal level by R-III reflex. Analgesia peaked at 3 hours and lasted about 6 hours. The mean decrease in peak tramadol analgesia by naloxone was only 31%. Quinidine had no effect on the extent of tramadol analgesia, but inhibited tramadol induced myosis. We therefore conclude that tramadol analgesia is only partially mediated by a mu opioid agonist effect. Tramadol analgesia thus results from an action on opioid receptors other than the mu subtype and/or from nonopioid effects (monoaminergic system). Quinidine blockade of tramadol myosis suggests that the mu agonist component of tramadol effect results from its O-demethylation by the polymorphic P450DB1 enzyme.

Adult↗
PubMed1993

[Drug prices in Switzerland: European comparison of "comfort" drugs].

We compared the average Swiss prices of so-called "comfort medicines" with the prices operating in several other European countries. These drugs, which are numerous in Switzerland, were defined as having no demonstrable efficacy or as being prescribed for physiopathological entities of uncertain scientific basis. The comparison shows that the average price of comfort medicines in Switzerland is not different from the German price (-17%, ns), but is higher than in Sweden (+35%, p < 0.05), France (+61%, p < 0.01) and Italy (+65%, p < 0.01). Furthermore, the average price of innovative new chemical entities is strongly correlated with that of the comfort medicines in all the countries considered and despite the vastly different therapeutic value of these two categories of drugs.

Drug Costs↗
PubMed1993

Similar effect of oxidation deficiency (debrisoquine polymorphism) and quinidine on the apparent volume of distribution of (+/-)-metoprolol.

The influence of phenotype (debrisoquine type of oxidation polymorphism) and quinidine on (+/-)-metoprolol distribution parameters was investigated in 7 young male volunteers (4 extensive and 3 poor metabolisers). (+/-)-Metoprolol tartrate 20 mg was administered as a 20 min infusion i) alone, ii) 12 h after an oral 50 mg quinidine sulphate capsule, and iii) on the last day of 3 days of treatment with 250 mg quinidine sulphate b.d. as a slow-release tablet. No stereoselectivity was apparent in either poor or extensive metabolizers. When (+/-)-metoprolol was administered alone the apparent volume of distribution at steady-state (Vss) was higher in extensive than in poor metabolisers (4.84 vs 2.83 l.kg-1, respectively). Pre-treatment with low or multiple high doses of quinidine decreased Vss in extensive metabolisers to values comparable to those in poor metabolisers (3.50 and 3.18 l.kg-1, respectively), but had no significant effect in poor metabolisers (3.24 and 3.42 l.kg-1, respectively). Estimation of Vss by noncompartmental analysis or assuming elimination exclusively from the peripheral compartment yielded similar, although somewhat higher, estimates. Despite the small number of subjects, (+/-)-metoprolol distribution appeared to be different both in genetically and environmentally (quinidine)-determined poor metabolisers, and quinidine inhibition was a good, reversible in vivo model of the genetic deficiency in handling (+/-)-metoprolol. Differences both in first pass pulmonary elimination or in tissue binding are logically consistent with these observations, but the amplitude of the effect exceeds expectations from available biological evidence on selective pulmonary metabolic activity and on specific tissue binding sites.

Adult↗
PubMed1993

Cytochrome P450TB (CYP2C): a major monooxygenase catalyzing diclofenac 4'-hydroxylation in human liver.

The nature of the enzyme(s) catalyzing the major metabolic pathway of diclofenac, 4'-hydroxylation, was investigated in human liver microsomes. Inhibition studies were performed with tolbutamide and sulfaphenazole (respectively the prototype substrate and a selective inhibitor of cytochrome P450TB--CYP2C subfamily), and with phenytoin and (+/-)-warfarin, other proposed substrates of P450TB. Diclofenac 4'-hydroxylation displayed single enzyme Michaelis-Menten kinetics and was similar in microsomes from one poor and five extensive metabolizers of debrisoquin (CYP2D6), with a Km of 5.6 +/- 1.5 microM (mean +/- sd) and a Vmax of 60.6 +/- 23.5 nmol/mgP/h. Inhibition by tolbutamide, sulfaphenazole, phenytoin and (+/-)-warfarin was comparable in all livers, with values predicted from their Km or Ki for cytochrome P450TB determined in separate studies and a competitive inhibition model. Sulfaphenazole competitively inhibited diclofenac 4'-hydroxylation (Ki = 0.11 +/- 0.08 microM, n = 3). Diclofenac 4'-hydroxylation is predominantly catalyzed by a cytochrome P450 isozyme of the CYP2C subfamily, most likely CYP2C9. This particular isozyme therefore appears to be responsible for the oxidation of polar acidic substances such as non-steroidal anti-inflammatory drugs from different chemical classes. It also constitutes a common site for drug interactions involving these compounds, as well as tolbutamide, phenytoin and warfarin.

Aryl Hydrocarbon Hydroxylases↗
PubMed1993

Central analgesic effects of desipramine, fluvoxamine, and moclobemide after single oral dosing: a study in healthy volunteers.

The antinociceptive effect of three antidepressants with different postulated modes of action, 75 mg desipramine, 225 mg fluvoxamine, and 450 mg moclobemide, was evaluated after single oral dosing in a randomized, double-blind, placebo-controlled crossover study in 10 healthy volunteers. Experimental pain thresholds (polysynaptic R-III reflex and subjective pain rating) were monitored over 23 hours. Compared with placebo, all drugs induced significant subjective pain threshold increases (maximal increase: desipramine, +20%; fluvoxamine, +17%; moclobemide, +13%). However, only desipramine (maximal increase, +25%) and moclobemide (maximal increase, +14%) displayed a significative effect on R-III threshold. Antidepressants thus exert an antinociceptive effect after a single oral dose. The level of their action apparently relies on the postulated mode of action.

Administration, Oral↗
PubMed1993

Influence of rifampin on fleroxacin pharmacokinetics.

Staphylococcus aureus infections have been successfully treated in animal models with the combination of fleroxacin and rifampin. We studied the influence of rifampin, a potent cytochrome P-450 inducer, on the pharmacokinetics and biotransformation of fleroxacin in 14 healthy young male volunteers. Subjects were given 400 mg of fleroxacin orally once a day for 3 days to reach steady state. After a wash-out period of 2 days, the same subjects received 600 mg of rifampin orally once daily for 7 days. On days 5 to 7 of rifampin treatment, 400 mg of fleroxacin was again administered once daily. Concentrations of fleroxacin as well as its two major urinary metabolites, N-demethyl- and N-oxide-fleroxacin, in plasma and urine were determined by reverse-phase high-performance liquid chromatography. The extent of hepatic enzyme induction by rifampin was confirmed by a significant increase of 6-beta-hydroxycortisol urinary output from 160.8 +/- 41.4 to 544.8 +/- 120.7 micrograms/4 h. There were no significant changes in the peak fleroxacin concentration in plasma (6.3 +/- 1.2 versus 6.2 +/- 1.9 mg/liter), time to maximum concentration of fleroxacin in plasma (1.1 +/- 0.9 versus 1.3 +/- 1.1 h), or renal clearance (58.3 +/- 16.4 versus 61.9 +/- 19.2 ml/min). The area under the curve AUC (71.4 +/- 15.8 versus 62.2 +/- 13.7 mg.h/liter) and the terminal half-life of fleroxacin (11.4 +/- 2.2 versus 9.2 +/- 1.1 h) decreased (P < 0.05), while the total plasma clearance increased from 97.7 +/- 21.6 to 112.3 +/- 25.8 ml/min (P < 0.01). Despite being statistically significant, this 15% increase in total plasma clearance does not appear to be clinically relevant. Metabolic clearance by N demethylation was increased ( 6.9 +/- 2.4 versus 12.5 +/- 3.2 ml/min; P < 0.01), whereas clearance by N oxidation did not change (5.8 +/- 1.1 versus 5.8 +/- 1.5 ml/min). Fleroxacin elimination was slightly increased (about 15%) through induction of metabolic clearance to N-demethyl-fleroxacin. Since fleroxacin levels remained above the MIC for 90% of the tested isolates of methicillin-susceptible S. aureus for at least 24 h, dose adjustment does not appear necessary, at least for short-term treatments.

Adult↗
PubMed1993

A major role for cytochrome P450TB (CYP2C subfamily) in the actions of non-steroidal antiinflammatory drugs.

Most non-steroidal antiinflammatory drugs (NSAIDs) are extensively metabolized by liver oxidation with broad interindividual variability, but little is known about the nature of the enzyme(s) catalysing these reactions. The role of specific cytochrome P450 isozymes in the formation of the major oxidized metabolites of phenylacetic acid (diclofenac), propionic acid (ibuprofen), fenamate (mefenamic acid) and oxicam (piroxicam and tenoxicam) derivatives was studied in human liver microsomes using mostly selective inhibition by known substrates and inhibitors of specific cytochrome P450 monooxygenases. A common isozyme (P450TB, CYP2C subfamily) controls the major elimination pathways of these NSAIDs. The authors have also determined, in two in vitro models of P450TB activity, the affinity for this isozyme of other NSAIDs (acetylsalicylic acid, indomethacin, pirprofen). The NSAIDs tested displayed a high affinity (5-500 microM): diclofenac approximately mefenamic acid > ibuprofen approximately indomethacin approximately piroxicam approximately tenoxicam > acetylsalicylic acid approximately pirprofen. Cytochrome P450TB therefore plays a key role in the oxidation by human liver of major NSAIDs from various chemical classes. Inhibition data and chemical structure similarities suggest that many other NSAIDs may be substrates of this isozyme as well. P450TB appears to be a common site both for the control of interindividual differences in the capacity to oxidize major NSAIDs and for interactions involving NSAIDs as well as other known substrates (oral anticoagulants, hypoglycaemic sulfonylureas, phenytoin) or inhibitors (antifungals, antibacterial sulfonamides, calcium channel blockers) of P450TB. Consequently this P450 isozyme is likely to be a major determinant of NSAIDs action.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1992

[Use of conventional and complementary medical care in patients with chronic non-cancerous pain].

The use of medical care was surveyed among 157 chronic pain patients. Half of them had consulted more than 6 and up to 17 specialists in "conventional" medicine for their pain problem. Moreover, 46% had used "complementary" medicine. They had tried many different "alternative" therapies in 40% of the cases. The users of "complementary" medicine, mostly females, also sought care from a significantly higher number of "conventional" therapists, had more physiotherapy, took drugs more frequently and had tried a larger number of different medications, even though their pain characteristics were similar to those of the other patients studied. Interestingly, they remained significantly more active professionally than patients who had never used "complementary" medicine. These characteristics could be attributed to a more active manner of coping with chronic pain.

Adaptation, Psychological↗
PubMed1992

[Q-DIPS: current approach to prediction of drug interactions].

Interactions are an important cause of adverse drug effects. Because of the large number of substances and the complexity of the mechanisms involved, computers can be of great help in the detection, prediction and management of interactions. We propose a new complementary approach to the prediction of interactions through a key mechanism, hepatic drug biotransformation. The originality of the approach consists in integrating in vitro enzymatic data and pharmacokinetic data to make in vivo predictions. An Inhibition Index (II) is defined to characterize the interaction potential of an inhibitor for a specific isozyme independently of the isozyme's substrates. It is thus possible, even in the absence of prior clinical observations, to make individualized qualitative as well as quantitative predictions of potential in vivo interactions. Q-DIPS is a prototype computer system under development on a Macintosh to manage the large amount of multi-dimensional data and facilitate the investigation and validation of extrapolations. The kinetics of II for two antifungal drugs, fluconazole and ketoconazole, are simulated and compared in order to illustrate the potential of the approach.

Biotransformation↗
PubMed1992

[The biotransformation of NSAIDs: a common elimination site and drug interactions].

Many NSAIDs are eliminated predominantly through hepatic biotransformation in man. We have studied, in human hepatic microsomes, the role of specific cytochrome P450 isozymes in the formation of the major metabolites of oxicam (piroxicam and tenoxicam), phenylacetic (diclofenac) and propionic acid (ibuprofen) derivatives. A common isozyme (P450TB, CYP2C subfamily) controls the major elimination pathway of these NSAIDs. We have also determined, in two in vitro models of P450TB, the affinity for this isozyme of NSAIDs from other chemical classes (acetylsalicylic acid, mefenamic acid and indomethacin). All NSAIDs tested displayed a high affinity (3-300 microM) for cytochrome P450TB. Cytochrome P450TB plays a major role in the elimination of several NSAIDs with different chemical structures. NSAIDs are substrates as well as potential inhibitors of cytochrome P450TB. Their elimination can therefore be reduced by concomitant administration of known inhibitors of P450TB (antifungals, antibacterial sulfonamides, calcium channel blockers).

Anti-Inflammatory Agents, Non-Steroidal↗