The possible influence of pulmonary arterio-venous shunt and hypoxic pulmonary vasoconstriction on arterial sevoflurane concentration during one-lung ventilation.

Sevoflurane is widely used for its rapid onset and offset due to a lower blood/gas coefficient. However, involuntary movements, tachycardia, and hypertension have been observed in some patients despite a continuing constantly delivered concentration of sevoflurane during 1-lung ventilation (OLV), indicating the possibility of insufficient depth of anesthesia. We observed a temporary but obvious decrease in arterial sevoflurane concentration and pulse oximeter readings in a patient during OLV. This may have resulted in the depth of inhaled anesthesia being insufficient during OLV because the arterial sevoflurane concentration was lower than expected in spite of constantly delivered and inspiratory/expiratory sevoflurane concentrations.

Nitrogenous subcutaneous emphysema caused by spray application of fibrin glue during retroperitoneal laparoscopic surgery.

We report a case of a patient treated by retroperitoneoscopic partial nephrectomy who developed nitrogenous subcutaneous emphysema (SCE) as a complication. The use of a nitrogen gas-pressured fibrin tissue adhesive applied as a spray caused excessively increased pressure in the closed retroperitoneal space and resulted in widespread SCE with protracted clinical course. To the best of our knowledge, this is the first report of nitrogenous SCE associated with pneumoperitoneum. The clinical significance of nitrogenous SCE is emphasized, and the risks associated with the use of fibrin glue as a spray during laparoscopic surgery are discussed.

Successful treatment of bepridil-induced intraoperative torsades de pointes by isoproterenol infusion.

BACKGROUND: Several types of antiarrhythmic drugs are known to induce QT prolongation and torsades de pointes. CASE PRESENTATION: An 84-year-old man was scheduled for open gastrectomy for residual cancer. He had been prescribed bepridil for atrial fibrillation that converted to sinus rhythm with prolonged QT interval in the operating room. After the surgery was initiated under general and epidural anesthesia, the patient's heart rate decreased to 50/min and multifocal premature ventricular contractions appeared, followed by several episodes of torsades de pointes, each lasting for 5 to 15 s. Infusion of isoproterenol was started (0.01 µg/kg/min), and the heart rate was maintained at around 80/min. Premature ventricular contractions disappeared, and torsades de pointes did not recur during the surgery. The operation was completed uneventfully. The serum bepridil concentration was found to be extremely high postoperatively. CONCLUSIONS: Bepridil-induced intraoperative episodes of torsades de pointes were successfully treated by increasing the heart rate with isoproterenol.

A case of malignant hyperthermia that was difficult to be differentiated from oral antipsychotic polypharmacy-associated neuroleptic malignant syndrome.

Malignant hyperthermia (MH) occurred during anesthesia with volatile inhalation anesthetics in a patient under treatment with multiple oral antipsychotic drugs and with a history of multi-acting receptor-targeted antipsychotic drug (MARTA)-induced elevation of serum creatine kinase (CK). Since the patient was considered to be at high risk for neuroleptic malignant syndrome (NMS) based on this history, differential diagnosis between MH and NMS was difficult at the time of onset. Later, the patient was found to be predisposed to MH based on abnormal high rate of the Ca2+-induced Ca2+ release (CICR). We concluded that MH was induced by the volatile inhalation anesthetics.

Genetic polymorphisms of CYP2A6 affect the in-vivo pharmacokinetics of pilocarpine.

OBJECTIVE: Pilocarpine is metabolized to pilocarpic acid by plasma esterase and to 3-hydroxypilocarpine by CYP2A6. The objective of this study was to identify the determinants of interindividual differences in pilocarpine pharmacokinetics after oral administration and to investigate the possible involvement of genetic polymorphisms of CYP2A6. METHODS: The pharmacokinetic parameters of pilocarpine, pilocarpic acid, and 3-hydroxypilocarpine after oral administration of pilocarpine hydrochloride in 28 Japanese participants were calculated based on the data obtained from two phase-1 clinical studies. Probit analysis was carried out for the pharmacokinetic parameters, and participants were accordingly classified into two groups: poor metabolizers and nonpoor metabolizers of pilocarpine. The poor metabolizers were genotyped for CYP2A6, and the pharmacokinetic parameters in this group were compared with those in the nonpoor metabolizers. RESULTS: Relatively large interindividual differences were observed in the pharmacokinetic parameters of pilocarpine, pilocarpic acid, and 3-hydroxypilocarpine. Probit analysis of the pharmacokinetic parameters revealed that seven of the 28 participants exhibited significantly low plasma concentrations and urinary recovery of 3-hydroxypilocarpine and were classified as poor metabolizers. Genotyping analysis revealed that these poor metabolizers had two inactive CYP2A6 alleles, CYP2A6*4A, CYP2A6*7, CYP2A6*9, or CYP2A6*10. The apparent pilocarpine clearance was significantly lower in the poor metabolizers than in the nonpoor metabolizers (P<0.05). CONCLUSION: We demonstrated that CYP2A6 genotype is a contributor to pilocarpine pharmacokinetics, although the impact of the CYP2A6 polymorphism may be pharmacologically and toxicologically tolerable.

Involvement of CYP2A6 in the formation of a novel metabolite, 3-hydroxypilocarpine, from pilocarpine in human liver microsomes.

Pilocarpine is a cholinergic agonist that is metabolized to pilocarpic acid by serum esterase. In this study, we discovered a novel metabolite in human urine after the oral administration of pilocarpine hydrochloride, and we investigated the metabolic enzyme responsible for the metabolite formation. The structure of the metabolite was identified as 3-hydroxypilocarpine by liquid chromatography-tandem mass spectrometry and NMR analyses and by comparing to the authentic metabolite. To clarify the human cytochrome P450 (P450) responsible for the metabolite formation, in vitro experiments using P450 isoform-selective inhibitors, cDNA-expressed human P450s (Supersomes; CYP1A2, -2A6, -2B6, -2C9, -2C19, -2D6, -2E1, and -3A4), and liver microsomes from different donors were conducted. The formation of 3-hydroxypilocarpine in human liver microsomes was strongly inhibited (>90%) by 200 microM coumarin. Other selective inhibitors of CYP1A2 (furafylline and alpha-naphthoflavone), CYP2C9 (sulfaphenazole), CYP2C19 [(S)-mephenytoin], CYP2E1 (4-methylpyrazole), CYP2D6 (quinidine), and CYP3A4 (troleandomycin) had a weak inhibitory effect (<20%) on the formation. The highest formation activity was expressed by recombinant CYP2A6. The K(m) value for recombinant CYP2A6 was 3.1 microM, and this value is comparable with that of human liver microsomes (1.5 microM). The pilocarpine 3-hydroxylation activity was correlated with coumarin 7-hydroxylation activity in 16 human liver microsomes (r = 0.98). These data indicated that CYP2A6 is the main enzyme responsible for the 3-hydroxylation of pilocarpine. In conclusion, we identified a novel metabolite of pilocarpine, 3-hydroxypilocarpine, and we clarified the involvement of CYP2A6 in the formation of this molecule in human liver microsomes.

Absorption, distribution and excretion of 14C-pilocarpine following oral administration to rats.

The absorption, distribution and excretion of pilocarpine (CAS 92-13-7) were studied after single oral doses of 14C-pilocarpine hydrochloride (CAS 54-71-7) to the Sprague-Dawley rat, administered in aqueous solution mainly at a dose level of 0.3 mg/kg. Rats also received single intravenous doses at 0.3 mg/kg so as to compare 14C pharmacokinetics and excretion. The oral 14C-dose was rapidly and almost completely absorbed from the duodenum and small intestine within 30 min in the male rat and 14C concentrations in plasma declined biexponentially with a terminal half-life of about 9 h. Over the oral dosage range studied, i.e. 0.1-1.0 mg/kg, there was no evidence of significant non-proportionality for Cmax of 14C, whereas there was some such evidence for AUG24. Tissue 14C concentrations in male and pregnant female (Day 18) rats peaked at 0.5 h and mostly declined in parallel with those in the plasma. Excluding tissues concerned with drug absorption and elimination, 14C concentrations in most tissues were similar to, or lower than, those in the plasma. The extent of placental transfer of 14C was small and less than 0.09% of a maternal dose reached a foetus. 14C diffused into maternal milk at concentrations similar to those in the plasma. The 14C-dose was rapidly excreted in male rats, mostly in the urine (about 80%) during 6 h post dose. Recoveries of 14C in mass balance (excretion) studies were in the range 96-100%. There were no apparent gender differences in the disposition of 14C-pilocarpine in the rat.