Bertold Renner

Dipyrone elicits substantial inhibition of peripheral cyclooxygenases in humans: new insights into the pharmacology of an old analgesic

Dipyrone (INN, metamizol) is a common analgesic used worldwide. Its widespread prescription or over‐the‐counter use in many countries (e.g., Brazil, Israel, Mexico, Russia, Spain) requires insight into its mode of action. This study therefore addressed the impact of its metabolites 4‐methyl‐amino‐antipyrine (MAA) and 4‐amino‐antipyrine (AA) on peripheral cyclooxygenases (COX). Pharmacokinetics of metabolites and ex vivo COX inhibition were assessed in five volunteers receiving dipyrone at single oral doses of 500 or 1000 mg. Coagulation‐induced thromboxane B2 formation and lipopolysaccha‐ride‐induced prostaglandin E2 synthesis were measured in vitro and ex vivo in human whole blood as indices of COX‐1 and COX‐2 activity. In vitro, metabolites elicited no substantial COX‐1/COX‐2 selectivity with MAA (IC50 = 2.55 μmol/L for COX‐1;IC50 =4.65 μmol/L for COX‐2), being ~8.2‐ or 9‐fold more potent than AA. After administration of dipyrone, MAA plasma concentrations remained above the IC50 values for each isoform for at least 8 h (500 mg) and 12 h (1000 mg) postdose. COX inhibition correlated with MAAplasma levels (exvivo IC50 values of 1.03 μmol/L [COX‐1] and 0.87 μmol/L [COX‐2]). By contrast, plasma peak concentrations of AA after the 1000 mg dose were 2.8‐ and 6.5‐fold below its IC50 values for COX‐1 and COX‐2, respectively. Maximal inhibitions of COX‐1 and COX‐2 were 94% and 87% (500 mg), 97% and 94% (1000 mg). Taken together, dipyrone elicits a substantial and virtually equipotent inhibition of COX isoforms via MAA. Given the profound COX‐2 suppression by dipyrone, which was considerably above COX‐2 inhibition by single analgesic doses of celecoxib and rofecoxib, a significant portion of its analgesic action may be ascribed to peripheral mechanisms. In view of the observed COX‐1 suppression, physicochemical factors (lack of acidity) rather than differential COX‐1 inhibition may be responsible for dipyrones favorable gastrointestinal tolerability compared with acidic COX inhibitors.—Hinz, B., Cheremina, O., Bachmakov, J., Renner, B., Zolk, O., Fromm, M. F., Brune, K. Dipyrone elicits substantial inhibition of peripheral cyclooxygenases in humans: new insights into the pharmacology of an old analgesic. FASEB J. 21, 2343–2351 (2007)

Role of P-Glycoprotein Inhibition for Drug Interactions : Evidence from In Vitro and Pharmacoepidemiological Studies

ObjectivesWe determined in vitro the potency of macrolides as P-glycoprotein inhibitors and tested in hospitalised patients whether coadministration of P-glycoprotein inhibitors leads to increased serum concentrations of the P-glycoprotein substrates digoxin and digitoxin.MethodsIn vitro, the effect of macrolides on polarised P-glycoprotein-mediated digoxin transport was investigated in Caco-2 cells. In a pharmacoepidemiological study, we analysed the serum digoxin and digitoxin concentrations with and without coadministration of P-glycoprotein inhibitors in hospitalised patients.ResultsAll macrolides inhibited P-glycoprotein-mediated digoxin transport, with concentrations producing 50% inhibition (IC50) values of 1.8, 4.1, 15.4, 21.8 and 22.7 μmol/L for telithromycin, clarithromycin, roxithromycin, azithromycin and erythromycin, respectively. Coadministration of P-glycoprotein inhibitors was associated with increased serum concentrations of digoxin (1.3 ± 0.6 vs 0.9 ± 0.5 ng/mL, p < 0.01). Moreover, patients receiving macrolides had higher serum concentrations of cardiac glycosides (p < 0.05).ConclusionMacrolides are potent inhibitors of P-glycoprotein. Drug interactions between P-glycoprotein inhibitors and substrates are likely to occur during hospitalisation.

Population Pharmacokinetics of Fast Release Oral Diclofenac in Healthy Volunteers: Relation to Pharmacodynamics in an Experimental Pain Model

AbstractPurpose. Population pharmacokinetics of a fast release diclofenac wereassessed with special focus on pharmacodynamic implications. Methods In a double blind four-way crossover study, 20 healthyvolunteers received orally 50 and 100 mg diclofenac-Na effervescent(“fast-release NSAID”), 50 mg diclofenac tablets (“control”), or placebo.Population pharmacokinetics of the fast release diclofenac wereassessed using a nonlinear mixed effects modeling approach(NON-MEM). Analgesic effects were investigated by means of anexperimental pain model based on both pain-ratings and cortical evoked potentialsafter specific stimulation of nasal nociceptors with short pulses ofgaseous CO2. Results. Pharmacokinetics of fast release diclofenac were bestdescribed by a two-compartment population model, with an estimatedterminal half-life of 1.2 hours. Pharmacokinetics of diclofenac tabletswere highly variable and a population pharmacokinetic model couldnot be obtained. As an indication of an early onset of analgesic effects,100 mg fast release diclofenac but not the tablets significantly reducedthe amplitudes of pain-related evoked potentials at 30 min afteradministration. Conclusions. Earlier drug absorption and lower pharmacokineticvariability of the fast-release formulation are likely to be preserved ina population.

Caffeine Accelerates Absorption and Enhances the Analgesic Effect of Acetaminophen

The aim of this study was to determine the analgesic effect of acetaminophen compared to a combination of both caffeine and acetaminophen or caffeine alone using tonic and phasic pain stimulation. Twenty‐four subjects were treated orally with 1000 mg acetaminophen, 130 mg caffeine, and a combination of both in a 4‐way crossover, double‐blind, placebo‐controlled study. Pharmacokinetics and analgesic effects were assessed by means of an experimental pain model based on pain‐related cortical potentials after phasic stimulation of the nasal mucosa with CO2 and based on pain ratings after tonic stimulation with dry air. Analgesic effects of acetaminophen and acetaminophen plus caffeine but not caffeine alone caused a significant reduction of pain‐related cortical potentials beginning 30 minutes after medication. The combination demonstrated an enhanced effect throughout the observation time up to 3 hours. Caffeine accelerated acetaminophen absorption, indicated by enhanced early AUCs. Significant analgesic effects of the combination on tonic pain ratings were found throughout the observation time as compared to acetaminophen and placebo. In this study, caffeine enhanced and prolonged the analgesic activity of acetaminophen.

Drug insight: cyclo-oxygenase-2 inhibitors--a critical appraisal.

Following the withdrawal of rofecoxib and valdecoxib, the discussion concerning selective cyclo-oxygenase (COX)-2 inhibitors was often characterized more by emotions than scientific evidence. In fact, the original rationale of these substances is still valid, in that selective COX2 inhibitors cause significantly fewer severe side effects in the gastrointestinal tract than traditional NSAIDs. Off-label long-term use of COX2 inhibitors in patients with a history of colorectal adenomas in well-designed, placebo-controlled trials showed that treatment with these agents is associated with an increased rate of cardiovascular adverse effects. Other studies have shown that both COX2 inhibitors and NSAIDs are associated with a similar cardiovascular risk, suggesting that there is presently no rationale for a further differentiation of these groups of drugs in terms of cardiovascular toxicity. Referring to the current debate, potential mechanisms underlying cardiovascular adverse effects associated with the long-term use of COX2 inhibitors and NSAIDs are discussed. Moreover, this Review summarizes the pharmacology of COX2 inhibitors with emphasis on their different pharmacokinetic characteristics.

Chemosensorisch evozierte Potentiale zur klinischen Diagnostik von Riechstörungen

Riechstörungen sind häufig. Zu ihrem Verständnis ist allerdings eine Intensivierung der Grundlagenforschung sowie der klinischen Forschung erforderlich. Dabei kommt den Verfahren zur objektivierenden Erfassung von Riechstörungen eine wesentliche Rolle zu. In der vorliegenden Arbeit werden Richtlinien für eine Olfaktometrie mit Hilfe evozierter Potentiale gegeben. Sie wurden von der Arbeitsgruppe “Standardisierung von Riech- und Schmeckprüfungen” der Arbeitsgemeinschaft Olfaktologie/Gustologie der Deutschen Gesellschaft für Hals-Nasen-Ohren-Heilkunde, Kopf- und Halschirurgie entwickelt. Wir hoffen, dass durch eine Standardisierung der Olfaktometrie mit Hilfe evozierter Potentiale ein Schubeffekt gerade hinsichtlich der vergleichenden Bewertung klinischer Studien zustande kommt. Letztlich soll durch diese Standardisierung eine effektivere Arbeit in Hinsicht auf eine rationell begründete Therapie von Riechstörungen ermöglicht werden.

A new procedure for the short screening of olfactory function using five items from the Sniffin' Sticks identification test kit

Background The aim of this study was to create a new protocol based on the “Sniffin’ Sticks” test kit, which would be suitable for short screening of olfactory function. Methods One hundred forty-one subjects were included in the investigation. In a first session, 106 subjects were presented five odorants together with a list of 20 descriptors. Additional choices were “no odor” and “undefinable.” The established 16-item identification test was then performed to assess olfactory function. In another session, the new procedure was repeated on 21 subjects to check the test-retest reliability. The Brief Smell Identification Test was used together with the five-item test in an additional 35 subjects for additional validation. Results The correlation coefficients between the results of the new test and the established procedures were r106 = 0.61 and r35 = 0.77 (p < 0.01). The new test procedure revealed two groups of subjects (score of 0 and scores 4 or 5). These groups had no overlapping results in the established odor identification tests. Repeated measurements of the short test showed a correlation coefficient of r21 = 0.77 (p < 0.01). Conclusion The present data indicate the usefulness of the short screening test. Given a maximum of one error, the test is able to confirm the presence of normosmia or mild hyposmia. The kit can be carried in a pocket and the test takes only 3 minutes to perform.

Acetaminophen/paracetamol: A history of errors, failures and false decisions

Acetaminophen/paracetamol is the most widely used drug of the world. At the same time, it is probably one of the most dangerous compounds in medical use, causing hundreds of deaths in all industrialized countries due to acute liver failure (ALF). Publications of the last 130 years found in the usual databases were analyzed. Personal contacts existed to renowned researchers having contributed to the medical use of paracetamol and its precursors as H.U. Zollinger, S. Moeschlin, U. Dubach, J. Axelrod and others. Further information is found in earlier reviews by Eichengrün, Rodnan and Benedek, Sneader, Brune; comp. references. The history of the discovery of paracetamol starts with an error (active against worms), continues with a false assumption (paracetamol is safer than phenacetin), describes the first side‐effect ‘epidemy’ (phenacetin nephropathy, drug‐induced interstitial nephritis) and ends with the discovery of second‐generation problems due to the unavoidable production of a highly toxic metabolite of paracetamol N‐acetyl‐p‐benzoquinone imine (NAPQI) that may cause not only ALF and kidney damage but also impaired development of the fetus and the newborn child. It appears timely to reassess the risk/benefit ratio of this compound.

Consumption of analgesics before a marathon and the incidence of cardiovascular, gastrointestinal and renal problems: a cohort study

Objectives To prevent pain inhibiting their performance, many athletes ingest over-the-counter (OTC) analgesics before competing. We aimed at defining the use of analgesics and the relation between OTC analgesic use/dose and adverse events (AEs) during and after the race, a relation that has not been investigated to date. Design Prospective (non-interventional) cohort study, using an online questionnaire. Setting The Bonn marathon 2010. Participants 3913 of 7048 participants in the Bonn marathon 2010 returned their questionnaires. Primary and secondary outcomes Intensity of analgesic consumption before sports; incidence of AEs in the cohort of analgesic users as compared to non-users. Results There was no significant difference between the premature race withdrawal rate in the analgesics cohort and the cohort who did not take analgesics (‘controls’). However, race withdrawal because of gastrointestinal AEs was significantly more frequent in the analgesics cohort than in the control. Conversely, withdrawal because of muscle cramps was rare, but it was significantly more frequent in controls. The analgesics cohort had an almost 5 times higher incidence of AEs (overall risk difference of 13%). This incidence increased significantly with increasing analgesic dose. Nine respondents reported temporary hospital admittance: three for temporary kidney failure (post-ibuprofen ingestion), four with bleeds (post-aspirin ingestion) and two cardiac infarctions (post-aspirin ingestion). None of the control reported hospital admittance. Conclusions The use of analgesics before participating in endurance sports may cause many potentially serious, unwanted AEs that increase with increasing analgesic dose. Analgesic use before endurance sports appears to pose an unrecognised medical problem as yet. If verifiable in other endurance sports, it requires the attention of physicians and regulatory authorities.

Using pharmacokinetic principles to optimize pain therapy

Cyclo-oxygenase (COX) inhibitors are widely used to relieve musculoskeletal pain. These agents block the production of prostaglandins (PGs) at sites of inflammation by inhibiting the activity of two COX enzymes necessary for PG production and normal organ homeostasis. Inhibition of PG production at sites unrelated to pain is associated with adverse drug reactions (ADRs). The degree of analgesic efficacy, as well as the incidence and the localization of ADRs, are critically influenced by the pharmacokinetics (absorption, distribution and elimination) of these drugs. Ideally, sufficient and permanent inhibition of COX enzymes should be achieved in target tissues, with minimal ADRs. To minimize underdosing or overdosing, which result in therapeutic failure or ADRs, the COX inhibitor with the most appropriate pharmacokinetic properties should be selected on the basis of a thorough pharmacokinetic–pharmacodynamic analysis. In this Review, the pharmacokinetics of the prevailing COX inhibitors will be discussed and enigmatic aspects of these intensively used drugs will be considered.