Effect of rifampin and tobacco smoking on the pharmacokinetics of ropivacaine.

OBJECTIVE: Our objective was to assess the effect of rifampin (INN, rifampicin) and tobacco smoking on the pharmacokinetics of ropivacaine. METHODS: A randomized, 2-phase, crossover study was performed in both a group of 10 healthy nonsmokers and a group of 8 healthy smokers. In both groups each subject ingested daily for 5 days either placebo or 600 mg rifampin. On day 6 each subject received intravenously over 30 minutes a single dose of 0.6 mg/kg ropivacaine. Ropivacaine, 3-hydroxyropivacaine (3-OH-ropivacaine), and (S) -2',6'-pipecoloxylidide (PPX) in venous plasma and urine were measured for up to 12 hours and 24 hours, respectively. Pharmacokinetic parameters were calculated with noncompartmental methods, and t tests were used for comparisons between the phases and between the smokers and nonsmokers. The electrocardiogram was monitored for 3 hours. RESULTS: There were no statistically significant differences in the area under the plasma concentration-time curve (AUC), plasma clearance (CL), or half-life (t(1/2)) of ropivacaine between the smokers and nonsmokers. However, smokers excreted in urine 31% more 3-OH-ropivacaine and 62% less PPX than nonsmokers did. Rifampin decreased the AUC of ropivacaine in nonsmokers by 52% and in smokers by 38%. In nonsmokers rifampin increased the CL of ropivacaine by 93% and shortened its t(1/2) by 25%. In smokers rifampin increased the CL of ropivacaine by 47% and shortened its t(1/2) by 20%. Rifampin decreased the urinary excretion of 3-OH-ropivacaine in nonsmokers by 74% and in smokers by 68%, and it increased the excretion of PPX by 97% and 158%, respectively. No clinically significant differences in the QTc times were found between the groups or treatments. CONCLUSIONS: Tobacco smoking increases the excretion of 3-OH-ropivacaine in urine, probably because of the increased cytochrome P450 (CYP) 1A2-mediated metabolism of ropivacaine, and decreases the excretion of CYP3A4-formed PPX in urine. Rifampin considerably increases the metabolism of ropivacaine to PPX and decreases the metabolism to 3-OH-ropivacaine in both nonsmokers and smokers.

Effect of clarithromycin and itraconazole on the pharmacokinetics of ropivacaine.

In a double-blind, randomised, three-way cross-over study, eight healthy volunteers ingested daily for 4 days either 250 mg clarithromycin twice daily, 200 mg itraconazole once daily, or placebo. On day 4, each subject received a single dose of 0.6 mg kg-1 ropivacaine intravenously over 30 min. Ropivacaine and (S)-2',6'-pipecoloxylidide in venous plasma and urine samples were measured for up to 12 hours and 24 hours, respectively. There were no significant changes in the pharmacokinetic parameters of the parent ropivacaine after ingestion of clarithromycin or itraconazole. However, the peak plasma concentration and AUC of (S)-2',6'-pipecoloxylidide metabolite were significantly decreased in both the clarithromycin and itraconazole phases, compared with the placebo phase. The fraction of ropivacaine metabolised to (S)-2',6'-pipecoloxylidide excreted in urine was decreased in the itraconazole phase. Both clarithromycin and itraconazole inhibit the CYP3A4 mediated formation of (S)-2',6'-pipecoloxylidide from ropivacaine. With the doses used, itraconazole is a stronger inhibitor than clarithromycin. The interaction of clarithromycin with ropivacaine seems to be dose (concentration)-dependent.

The effect of erythromycin, fluvoxamine, and their combination on the pharmacokinetics of ropivacaine.

UNLABELLED: We studied the effect of fluvoxamine and erythromycin on the pharmacokinetics of ropivacaine in a double-blinded, randomized, four-way cross-over study. Eight healthy volunteers ingested daily 1500 mg erythromycin for 6 days, 100 mg fluvoxamine for 5 days (Days 2-6), both erythromycin and fluvoxamine, or placebo. On Day 6, each subject received a single dose of 0.6 mg/kg ropivacaine IV over 30 min. Ropivacaine, 3-hydroxyropivacaine, and 2',6'-pipecoloxylidide in venous plasma and urine samples were measured for up to 12 h and 24 h, respectively. Fluvoxamine increased the area under the drug plasma concentration-time curve (AUC) of ropivacaine 3.7-fold (P: < 0.001), prolonged the elimination half-life (t(1/2)) from 2.3 to 7.4 h (P: < 0.01), and decreased the clearance by 77% (P: < 0.001). Erythromycin alone had only a minor effect on the pharmacokinetics of ropivacaine. However, when compared with fluvoxamine alone, the combination of fluvoxamine and erythromycin further increased the area under the drug plasma concentration-time curve and t(1/2) of ropivacaine by 50% (P: < 0.01). We conclude that inhibition of CYP1A2 by fluvoxamine considerably reduces elimination of ropivacaine. Concomitant use of fluvoxamine and CYP3A4 inhibitor erythromycin further increases plasma ropivacaine concentration by decreasing its clearance. IMPLICATIONS: Clinicians should be aware of the possibility of increased toxicity of ropivacaine when used together with inhibitors of CYP1A2. Concomitant use of CYP1A2 and CYP3A4 inhibitors further increases ropivacaine concentration.

Deformed spinal needle tips and associated dural perforations examined by scanning electron microscopy.

BACKGROUND: The tips of modern thin Quincke-type spinal needles may be easily damaged by bone contact during the puncture. The purpose of this study was to find out the frequency of tip deformation in routine clinical work and the appearance of the dural perforations made by such damaged needles. METHODS: Two hundred and ninety-five Quincke-type needles (22G-29G) used in routine spinal anaesthesia were inspected by light microscopy. Scanning electron micrographs were taken of some of the damaged tips and of experimental dural perforations made by these. RESULTS: Four per cent of the needle tips were clearly bent or hooked and 11% were slightly bent. When an introducer needle was used (19 cases), one needle was clearly bent and one slightly bent. A puncture with a bone contact was associated with clear tip damage in 7%; a puncture without bone contact resulted in an undamaged or slightly bent needle tip in 99% of the cases. The numbers of bent tips among the various sizes were: 22G-2/21, 25G-13/40, 27G-28/231, 29G-1/3. In scanning electron microscopy (SEM) images of four clearly bent needle tips the deviation of the tip was between 10 microns and 20 microns. In SEM of eleven dural perforations, the holes made by needles with clearly bent tips were almost closed and three of them exhibited an "open tin can" appearance. None of the dural perforations was badly torn. CONCLUSIONS: We verified that the tips of modern thin spinal needles are vulnerable to damage due to contact with bone. However, the holes made in dura by needles with bent tips do not appear to be excessively torn.

Association between dental health and acute myocardial infarction.

Known risk factors for coronary heart disease do not explain all of the clinical and epidemiological features of the disease. To examine the role of chronic bacterial infections as risk factors for the disease the association between poor dental health and acute myocardial infarction was investigated in two separate case-control studies of a total of 100 patients with acute myocardial infarction and 102 controls selected from the community at random. Dental health was graded by using two indexes, one of which was assessed blind. Based on these indexes dental health was significantly worse in patients with acute myocardial infarction than in controls. The association remained valid after adjustment for age, social class, smoking, serum lipid concentrations, and the presence of diabetes. Further prospective studies are required in different populations to confirm the association and to elucidate its nature.