Harri Luurila

A potentially hazardous interaction between erythromycin and midazolam

Interaction between erythromycin and midazolam was investigated in two double‐blind, randomized, crossover studies. In the first study, 12 healthy volunteers were given 500 mg erythromycin three times a day or placebo for 1 week. On the sixth day, the subjects ingested 15 mg midazolam. In the second study, midazolam (0.05 mg/kg) was given intravenously to six of the same subjects, after similar pre‐treatments. Plasma samples were collected, and psychomotor performance was measured. Erythromycin increased the area under the midazolam concentration–time curve after oral intake more than four times (p <0.001) and reduced clearance of intravenously administered midazolam by 54% (p <0.05). In psychomotor tests (e.g., saccadic eye movements), the interaction between erythromycin and orally administered midazolam was statistically significant (p <0.05) from 15 minutes to 6 hours. Metabolism of both erythromycin and midazolam by the same cytochrome P450IIIA isozyme may explain the observed pharmacokinetic interaction. Prescription of midazolam for patients receiving erythromycin should be avoided or the dose of midazolam should be reduced by 50% to 75%.

Itraconazole increases but grapefruit juice greatly decreases plasma concentrations of celiprolol

Our objective was to evaluate the effects of itraconazole and grapefruit juice on the pharmacokinetics of the β‐adrenergic receptor‐blocking agent celiprolol in healthy volunteers.

Rifampin markedly decreases and gemfibrozil increases the plasma concentrations of atorvastatin and its metabolites

The pharmacokinetic interactions of the widely used statin atorvastatin with fibrates and enzyme inducers are not known. Therefore we studied the effects of rifampin (INN, rifampicin) and gemfibrozil on the pharmacokinetics of atorvastatin.

Rifampin reduces plasma concentrations and effects of zolpidem

Zolpidem is a short‐acting imidazopyridine hypnotic drug that is metabolized mainly by CYP3A4. Rifampin (INN, rifampicin) is a potent inducer of many cytochrome P450 enzymes, and it greatly reduces the plasma concentrations and effects of, for example, midazolam, triazolam, and zopiclone. In this study, the effects of rifampin on the pharmacokinetics and pharmacodynamics of zolpidem were studied.

Comparison of 27-gauge (0.41-mm) Whitacre and Quincke spinal needles with respect to post-dural puncture headache and non-dural puncture headache.

Background:  The incidence of headache after spinal anaesthesia has varied greatly between studies. We compared the incidence of postoperative headache in general and postdural puncture headache (PDPH) when using 27‐gauge (G) (outer diameter 0.41 mm) Quincke and Whitacre spinal needles in ambulatory surgery performed under spinal anaesthesia.

Serious overdoses involving buprenorphine in Helsinki.

Background:  Buprenorphine is used as maintenance therapy for opioid‐dependent patients. In comparison with other opioids it is thought to be safer because it is less likely to cause serious respiratory depression. However, concomitant use of psychotropics, especially benzodiazepines, and intravenous injection of dissolved buprenorphine tablets increase the risk of a serious overdose.

Diclofenac premedication but not intra-articular ropivacaine alleviates pain following day-case knee arthroscopy.

Purpose: To compare the postoperative analgesic effects of 50 mg diclofenacpo before surgery and intra-articular ropivacaine injected after diagnostic day-case knee arthroscopy performed under spinal anesthesia.Methods: In a randomized, double-blind investigation, 200 ASA physical status 1–2 outpatients, age 18–60 yr, received either 50 mg diclofenacpo or placebo one hour before operation (100 patients per group), and intra-articular injections of either 20 ml of ropivacaine 0.5% or 20 ml of saline 0.9% (50 patients in each premedication groups). Patients received 50 mg diclofenacpo prn and, if needed, 0.1 mg·kg−1 oxycodoneim for postoperative pain relief. Patients were discharged home with a supply of 50 mg diclofenac tablets and were given a sheet of paper with knee pain VAS scales and a questionnaire of analgesics taken. Patients rated their VAs scores eight hours after surgery and in the morning and at the end of the first and the second postoperative days, respectively.Results: The only statistically significant difference was found when the diclofenac groups were combined and compared with the combined placebo premedication groups. The VAS scores of knee pain at eight hours after the operation were 19±22 in the two diclofenac premedication groups and 32±28 in the two placebo groups (P=0.001).Conclusions: Diclofenac premedicationpo reduced the VAS scores at eight hours postoperatively while intra-articular ropivacaine did not.RésuméObjectif: Comparer les effets analgésiques postopératoires de 50 mg de diclofénacpo, administrés avant l’opération, à la ropivacaïne intra-articulaire, donnée parès l’arthroscopie diagnostique sous rachianesthésie.Méthode: Lors d’une étude randomisée et en double aveugle, 200 patients d’état physique ASA I–II, âgés de 18–60 ans, ont reçu 50 mg de diclofénacpo ou un placebo une heure avant l’opération (100 patients par groupe), et une injection intra-articulaire de 20 ml de ropivacaïne 0,5 % ou 20 ml de solution salée 0,9% (50 patients dans chaque groupe de prémédication). Les patients ont reçu 50 mg de diclofénacpo prn/it et, si nécessaire, 0,1 mg·kg−1 d’oxycodoneim pour soulager la douleur postopératorie. À leur départ, ils ont reçu des comprimés de 50 mg de diclofénac, un questionnaire concernant la prise d’analgésiques et une feuille de papier où inscrire le niveau de douleur au genou selon l’EVA. Les patients ont estimé leurs scores à l’EVA huit heures parès l’opération et au début et à la fin du premier et du deuxième jours postopératoires, respectivement.Résultats: La seule différence statistique significative a été trouvée en combinant les groupes de diclofénac et en les comparant aux groupes combinés de prémédication placebo. Les scores postopératoires de l’EVA ont été de 19±22 dans les deux groupes qui ont reçu une prémédication de diclofénac et de 32±28 dans les groupes qui ont reçu le placebo (P=0,001).Conclusion: La prémédication au diclofénacpo a réduit les scores postopératoires de l’EVA à huit heures, mais non pas la ropivacaïne intra-articulaire.

Effect of itraconazole on the pharmacokinetics and pharmacodynamics of zolpidem

Objective: Zolpidem is a short-acting␣imidazopyridine hypnotic which is biotransformed in humans mainly by CYP3A4. Itraconazole strongly interacts with many substrates of CYP3A4 such as midazolam and triazolam. In this study, the effect of itraconazole on the pharmacokinetics and pharmacodynamics of zolpidem was investigated to uncover a possible clinically significant interaction. Methods: In a randomized cross-over study with two phases, ten healthy volunteers took either 200 mg itraconazole or placebo once daily for 4 days. A single oral dose of 10 mg zolpidem was given on day 4. Plasma drug concentrations were measured up to 17 h and effects of zolpidem up to 9 h after the ingestion of zolpidem. Results: Itraconazole had no marked effects on the pharmacokinetics of zolpidem; the total area under the plasma zolpidem concentration–time curve (AUC0–∞) was 34% larger during the itraconazole phase (759 ng · h · ml−1) than during the placebo phase (567 ng · h · ml−1). Exophoria of the eyes by the Maddox wing test was significantly increased by itraconazole, but the results of the digit symbol substitution test, critical flicker fusion test, postural sway tests and the visual analogue scale tests for subjective drowsiness and overall drug effect did not differ between the phases. Conclusion: The pharmacokinetics and pharmacodynamics of zolpidem were not remarkably affected by itraconazole in healthy volunteers. Therefore, unlike triazolam, for example, zolpidem can be used in normal or nearly normal doses together with itraconazole and probably also with other CYP3A4 inhibitors.

Lack of interaction of erythromycin with temazepam

Erythromycin is a strong inhibitor of cytochrome P450 [CYP3A4] and has a potentially dangerous interaction with midazolam and triazolam. The possible interaction between erythromycin and a short-acting benzodiazepine, temazepam, was investigated in a double-blind, randomized crossover study. Ten healthy volunteers received 500 mg erythromycin or placebo orally three times a day for 6 days followed by a challenge dose of 20 mg temazepam. Plasma samples were collected for the determination of temazepam, oxazepam, and erythromycin, and psychomotor effects were measured during the 24 h after intake of temazepam. Erythromycin did not change the pharmacokinetics or pharmacodynamics of temazepam to a statistically significant degree. The metabolic fate of temazepam and its almost complete bioavailability explain the lack of interaction. Temazepam, unlike midazolam or triazolam, can thus be prescribed in the usual doses for patients receiving erythromycin.

Preoperative diclofenac is a useful adjunct to spinal anesthesia for day-case varicose vein repair

PurposeTo examine if preoperative diclofenac 50 mg or diazepam 10 mgpo are useful adjuncts to spinal anesthesia for daycase varicose vein repair.MethodsTwo hundred ASA physical status I–II outpatients, age 18–60 yr, were randomized to receive either diclofenac 50 mgpo or diazepam 10 mgpo one hour before operation in a double-blind fashion (100 patients in both groups). If the patient was distressed or feared the spinal puncture and requested sedation, a bolus dose of alfentanil 0.5 mg was giveniv as a rescue medication. On request, patients received diclofenac 50 mgpo and, when needed, oxycodone 0.1 mg·kg−1im for postoperative pain relief. They were discharged with a supply of diclofenac 50 mg tablets and were asked to record postoperative pain using a visual analogue scale (VAS) and quantity of tablets taken.ResultsThe VAS scores (± SD) eight hours after surgery, the next morning, and in the morning and at the end of the first and second postoperative days were 23 ±21, 12 ± 17, 11 ± 15, 8 ± 15 and 8 ± 15 in the diclofenac group, and 24 ± 23, 12 ± 20, 10 ± 17, 8 ± 16 and 7 ± 14 in the diazepam group, respectively (NS). In the diclofenac and diazepam groups, 31% and 67% of the patients required postoperative diclofenac during the first eight postoperative hours (P < 0.0S). Diazepam premedication did not alter the number of patients who required alfentanil before spinal puncture. Conclusion: Diclofenac premedication reduced the analgesic requirements during the first eight hours after varicose vein repair.RésuméObjectifVérifier si l’administration préopératoire de 50 mg de diclofénac ou de 10 mg de diazépam po sont un complément effectif à la rachianesthésie pour un tringlage variqueux.MéthodeOn a réparti de façon aléatoire en deux groupes égaux 200 patients ambulatoires d’état physique ASA I–II, de 18 à 60 ans, qui ont reçu, soit 50 mg po de diclofénac, soit 10 mg po de diazépam, une heure avant l’opération et en double insu. Si le patient était angoissé ou craignait la ponction rachidienne et demandait un analgésique, un bolus iv d’appoint de 0,5 mg d’alfentanil était administré. Sur demande, les patients ont reçu 50 mg po de diclofénac et, lorsque nécessaire, 0,1 mg·kg− 1 im d’oxycodone en analgésie postopératoire. Au départ du service, les patients ont reçu des comprimés de 50 mg de diclofénac. Ils devaient aussi noter les douleurs postopératoires, selon une échelle visuelle analogique (EVA), et la quantité de comprimés consommés.RésultatsLes scores à l’EVA (± l’écart type) ont été, huit heures après l’opération ainsi que le matin et le soir des premier et second jours postopératoires de: 23 ± 21, 12 ± 17, 11 ± 15, 8 ± 15 et 8 ± 15 dans le groupe diclofénac et 24 ± 23, 12 ± 20, 10 ± 17,8 ± 16 et 7 ± 14 dans le groupe diazépam, respectivement (NS). Dans les groupes diclofénac et diazépam, 31% et 67% des patients ont demandé du diclofénac pendant les huit premières heures postopératoires (P< 0,05). La prémédication avec le diazépam n’a pas modifié le nombre de patients qui ont demandé de l’alfentanil avant la ponction rachidienne.ConclusionLa prémédication avec le diclofénac a réduit les besoins analgésiques pendant les huit premières heures suivant un tringlage variqueux.