Effect of age on pulmonary gas exchange during laparoscopy in the Trendelenburg lithotomy position.

BACKGROUND: Physiological changes in respiratory mechanics caused by aging may lead to a deterioration in pulmonary gas exchange, an increase in the alveolar-arterial oxygen gradient [(A-a)D(O2)] and a difference between the arterial carbon dioxide (CO(2)) tension (P(a)(CO(2))) and expired end-tidal CO(2) tension (P(ET)(CO(2))) [P((a-ET))(CO(2))] during laparoscopy in the Trendelenburg lithotomy position (TLP). METHODS: The subjects were 51 gynecologic patients. Pressure-controlled ventilation was used to maintain P(ET)(CO(2)), measured by the side stream method, within the range 4-4.67 kPa. During laparoscopy with CO(2) insufflation in TLP, the tidal volume was increased to keep P(ET)(CO(2)) within +/- 20% of the pre-insufflation value. The subjects were divided into three groups by age: young group (< 45 years); middle-aged group (45-64 years); and elderly group ( > or = 65 years). RESULTS: Before pneumoperitoneum (PPN), significant differences were found between the young and elderly groups in the arterial oxygen tension (P(a)(O(2))), (A-a)D(O(2)), P(a)(CO(2)) and P((a-ET))(CO(2)). In all groups, the peak inspiratory pressure and P(a)(CO(2)) increased progressively during PPN in TLP. P((a-ET))(CO(2)) increased gradually after starting CO(2) insufflation in TLP only in the elderly group. CONCLUSIONS: An increase in P((a-ET))(CO(2)) was seen during PPN in TLP in the elderly group. With CO(2) insufflation in TLP, the setting of mechanical ventilation based on the value of P(ET)(CO(2)) (measured by the side stream method) should be determined with caution in elderly patients.

Effect of CYP2C19 genetic polymorphism on pharmacokinetics of phenytoin and phenobarbital in Japanese epileptic patients using Non-linear Mixed Effects Model approach.

OBJECTIVE: To clarify the effect of genetic polymorphism of CYP2C19 on pharmacokinetics of phenytoin and phenobarbital using a Non-linear Mixed Effects Modelling analysis in Japanese epileptic patients. METHOD: A total of 326 serum phenytoin concentrations were collected from 132 patients, and a total of 144 serum phenobarbital concentrations were collected from 74 patients during their clinical routine care. RESULT: The maximal elimination rate of phenytoin decreased by 10.2% in patients with CYP2C19*1/*2 compared with patients with normal CYP2C19. The Michaelis-Menten constants in the patients with CYP2C19*1/*3 and the poor metabolizers of (CYP2C19*2/*2 or *2/*3 or *3/*3) were 27% and 54% higher than those for the patients with normal CYP2C19, respectively. The total body clearance of phenobarbital decreased by 19.3% in patients with CYP2C19*1/*3 or the poor metabolizers of CYP2C19 compared with patients with normal CYP2C19 or with CYP2C19*1/*2. CONCLUSION: These findings indicated that the genetic polymorphisms of CYP2C19 contribute to the pharmacokinetic variability of phenytoin and phenobarbital, the poor metabolizers of CYP2C19, which are relatively common in Asian groups.

Alpha-2 adrenergic regulation of pedunculopontine nucleus neurons during development.

Rapid eye movement sleep decreases between 10 and 30 days postnatally in the rat. The pedunculopontine nucleus is known to modulate waking and rapid eye movement sleep, and pedunculopontine nucleus neurons are thought to be hyperpolarized by noradrenergic input from the locus coeruleus. The goal of the study was to investigate the possibility that a change in alpha-2 adrenergic inhibition of pedunculopontine nucleus cells during this period could explain at least part of the developmental decrease in rapid eye movement sleep. We, therefore, recorded intracellularly in 12-21 day rat brainstem slices maintained in oxygenated artificial cerebrospinal fluid. Putative cholinergic vs. non-cholinergic pedunculopontine nucleus neurons were identified using nicotinamide adenine dinucleotide phosphate diaphorase histochemistry and intracellular injection of neurobiotin (Texas Red immunocytochemistry). Pedunculopontine nucleus neurons also were identified by intrinsic membrane properties, type I (low threshold spike), type II (A) and type III (A+low threshold spike), as previously described. Clonidine (20 microM) hyperpolarized most cholinergic and non-cholinergic pedunculopontine nucleus cells. This hyperpolarization decreased significantly in amplitude (mean+/-S.E.) from -6.8+/-1.0 mV at 12-13 days, to -3.0+/-0.7 mV at 20-21 days. However, much of these early effects (12-15 days) were indirect such that direct effects (tested following sodium channel blockade with tetrodotoxin (0.3 microM)) resulted in hyperpolarization averaging -3.4+/-0.5 mV, similar to that evident at 16-21 days. Non-cholinergic cells were less hyperpolarized than cholinergic cells at 12-13 days (-1.6+/-0.3 mV), but equally hyperpolarized at 20-21 days (-3.3+/-1.3 mV). In those cells tested, hyperpolarization was blocked by yohimbine, an alpha-2 adrenergic receptor antagonist (1.5 microM). These results suggest that the alpha-2 adrenergic receptor on cholinergic pedunculopontine nucleus neurons activated by clonidine may play only a modest role, if any, in the developmental decrease in rapid eye movement sleep. Clonidine blocked or reduced the hyperpolarization-activated inward cation conductance, so that its effects on the firing rate of a specific population of pedunculopontine nucleus neurons could be significant. In conclusion, the alpha-2 adrenergic input to pedunculopontine nucleus neurons appears to consistently modulate the firing rate of cholinergic and non-cholinergic pedunculopontine nucleus neurons, with important effects on the regulation of sleep-wake states.

Development of REM sleep drive and clinical implications.

Rapid eye movement (REM) sleep in the human declines from approximately 50% of total sleep time ( approximately 8 h) in the newborn to approximately 15% of total sleep time (approximately 1 h) in the adult, and this decrease takes place mainly between birth and the end of puberty. We hypothesize that without this developmental decrease in REM sleep drive, lifelong increases in REM sleep drive may ensue. In the rat, the developmental decrease in REM sleep occurs 10-30 days after birth, declining from >70% of total sleep time in the newborn to the adult level of approximately 15% of sleep time during this period. Rats at 12-21 days of age were anesthetized with ketamine and decapitated, and brain stem slices were cut for intracellular recordings. We found that excitatory responses of pedunculopontine nucleus (PPN) neurons to N-methyl-D-aspartic acid decrease, while responses to kainic acid increase, over this critical period. During this developmental period, inhibitory responses to serotonergic type 1 agonists increase but responses to serotonergic type 2 agonists do not change. The results suggest that as PPN neurons develop, they are increasingly activated by kainic acid and increasingly inhibited by serotonergic type 1 receptors. These processes may be related to the developmental decrease in REM sleep. Developmental disturbances in each of these systems could induce differential increases in REM sleep drive, accounting for the postpubertal onset of a number of different disorders manifesting increases in REM sleep drive. Examination of modulation by PPN projections to ascending and descending targets revealed the presence of common signals modulating ascending arousal-related functions and descending postural/locomotor-related functions.

A CYP2D6 phenotype-genotype mismatch in Japanese psychiatric patients.

The aim of the present study was to seek a CYP2D6 genotypic-phenotypic discordance possibility in Japanese patients under psychotropic drug treatment where the CYP2D6 status and pharmacodynamic responses differ from those in Caucasian psychiatric patients. Ninety drug-free, healthy volunteers and 14 patients undergoing psychotropic drug treatment were phenotyped for their individual CYP2D6 activity using dextromethorphan as a probe, and then the metabolic ratio (MR) was calculated. For the genotyping, eight mutant alleles of the CYP2D6 genes were identified. Serum concentrations of two frequently co-medicated psychotropic drugs, biperiden and levomepromazine, were determined by GC/MS. Genotyping revealed no poor metabolizers (PMs) enrolled in our study. Healthy volunteers exhibited an identical phenotype-genotype concordance, whereas 7 of the 14 patients had significantly high (p < 0.05) MRs compared with genotype-matched volunteers. Three of the patients who had the extensive metabolizer (EM) genotype had extremely high MRs and were classified as phenotypic PMs. Five patients plus all of the seven high MR patients were treated with levomepromazine and/or biperiden, respectively. Their mean serum steady-state concentrations were 27.4 and 7.6 ng/ml, respectively. A CYP2D6 phenotype-genotype mismatch (phenocopying) can occur in Japanese psychiatric patients receiving clinical doses of some psychotropic drugs where the prevalence of PMs is low and the pharmacodynamic responses to those drugs are enhanced compared to Caucasian patients.

[Effects of lumbar sympathetic ganglion block in a patient with acquired lymphangioma].

A 70-year-old woman developed lymphangioma following surgery for cervical cancer and subsequent radiotherapy. The operation was performed 12 years ago, and a swelling of lower extremities was recognized 8 years ago. Her lower extremities became greatly edematous, and leakage of lymph to the groin was observed. We performed bilateral lumbar sympathetic ganglion block. After the block, lymphedema was relieved dramatically, and the leakage of the lymph to the groin was gradually reduced. We conclude that lumbar sympathetic ganglion block may be very effective in some patients with acquired lymphangioma.

Genetic polymorphisms and functional characterization of the 5'-flanking region of the human CYP2C9 gene: in vitro and in vivo studies.

OBJECTIVE: Genetic polymorphisms were identified in the 5'-flanking region of the human CYP2C9 gene, and their effects on the phenotype were evaluated on the basis of the luciferase reporter gene assay and the in vivo pharmacokinetics of phenytoin. METHODS: Genetic polymorphisms were screened by polymerase chain reaction-single-strand conformational polymorphism analysis, following sequencing with DNA samples obtained from 50 healthy volunteers and 133 adult epileptic patients. HepG2 hepatoma cells were cotransfected with various sequence patterns of 5'-flanking region-luciferase reporter gene constructs. Pharmacokinetic parameters of phenytoin in relation to the corresponding sequence patterns were estimated by the Bayesian method, and the results were compared with in vitro activities. RESULTS: Genetic analysis revealed the existence of 7 single nucleotide polymorphisms (SNPs). Allele frequencies of T-->C transition at position -1912 (T-1912C), C-1886G, C-1566T, G-1538A, C-1189T, G-982A, and A-162G were 0.019, 0.019, 0.077, 0.019, 0.579, 0.019, and 0.003, respectively. Some mutations occurred simultaneously, and a total of 6 sequence patterns (patterns 1-6) were observed. The luciferase reporter gene assay indicated that the presence of mutation(s) resulted in a reduction in luciferase activity of 41.4% (pattern 2) to 86.8% (pattern 5) compared with the activity of the wild-type construct. The calculated intrinsic clearance of phenytoin was also lower (up to a 40% reduction for pattern 2) when a mutation(s) was present. CONCLUSION: In addition to the two major mutations in the coding region (CYP2C9*2 and CYP2C9*3 ), mutations in the 5'-flanking region of the human CYP2C9 gene appear to contribute to the large interindividual variability in drug metabolism activity.

[Perioperative management using propofol in a patient with uncontrolled preoperative hyperthyroidism].

There is a risk of thyrotoxic crisis during and after surgery in patients with uncontrolled hyperthyroidism. To avoid this, suppression of sympathetic activity during the perioperative period is important. For this purpose, we used propofol for the anesthetic and the postoperative management in a 19-year-old female with uncontrolled hyperthyroidism. Propofol 6 to 8 mg.kg-1.hr-1 plus 66% of nitrous oxide was not sufficient to obtain hemodynamic stability during the surgery, but propofol 3 mg.kg-1.hr-1 produced optimal sedation in the postoperative period. The results demonstrate that propofol is useful for the anesthetic management of patients with uncontrolled hyperthyroidism.

Patterns of population subdivision, gene flow and genetic variability in the African wild dog (Lycaon pictus).

African wild dogs are large, highly mobile carnivores that are known to disperse over considerable distances and are rare throughout much of their geographical range. Consequently, genetic variation within and differentiation between geographically separated populations is predicted to be minimal. We determined the genetic diversity of mitochondrial DNA (mtDNA) control region sequences and microsatellite loci in seven populations of African wild dogs. Analysis of mtDNA nucleotide diversity suggests that, historically, wild dog populations have been small relative to other large carnivores. However, population declines due to recent habitat loss have not caused a dramatic reduction in genetic diversity. We found one historical and eight recent mtDNA genotypes in 280 individuals that defined two highly divergent clades. In contrast to a previous, more limited, mtDNA analysis, sequences from these clades are not geographically restricted to eastern or southern African populations. Rather, we found a large admixture zone spanning populations from Botswana, Zimbabwe and south-eastern Tanzania. Mitochondrial and microsatellite differentiation between populations was significant and unique mtDNA genotypes and alleles characterized the populations. However, gene flow estimates (Nm) based on microsatellite data were generally greater than one migrant per generation. In contrast, gene flow estimates based on the mtDNA control region were lower than expected given differences in the mode of inheritance of mitochondrial and nuclear markers which suggests a male bias in long-distance dispersal.

Cesarean section in a patient with syringomyelia.

PURPOSE: To describe the anesthetic management of Cesarean section in a patient with syringomyelia. CLINICAL FEATURES: A 27-yr-old pregnant woman with syringomyelia was scheduled to undergo elective Cesarean section. At the age of 25 yr, she had begun to experience headaches, and at the age of 26 yr, a diagnosis of syringomyelia of the upper spinal cord was made on the basis of magnetic resonance imaging findings. No symptoms other than headache were noted preoperatively. General anesthesia was used for the Cesarean section. After the administration of 1 mg vecuronium as a priming dose, 5 mg vecuronium were injected. At the onset of clinical muscle weakness, 225 mg thiamylal were promptly administered as the induction agent and the patient was intubated (timing principle with priming method) and pressure on the cricoid cartilage applied to prevent regurgitation of stomach contents. Anesthesia was maintained with oxygen, nitrous oxide and isoflurane at a low concentration. Mild hyperventilation was used throughout the procedure. Anesthesia and surgery proceeded without any problem, response to vecuronium was clinically normal and recovery was uneventful. Neurological status remained normal. CONCLUSION: We report the safe use of general anesthesia for Cesarean section in a patient with syringomyelia. Precautions were taken to avoid increases in intracranial pressure and our patient experienced no untoward neurologic event.

P-hydroxylation of phenobarbital: relationship to (S)-mephenytoin hydroxylation (CYP2C19) polymorphism.

The aim of the current study was to compare the pharmacokinetics of phenobarbital (PB) in extensive metabolizers (EMs) and poor metabolizers (PMs) of S-mephenytoin. Ten healthy volunteers (5 EMs and 5 PMs) were given 30 mg PB daily for 14 days. PB and p-hydroxyphenobarbital (p-OHPB) in serum and urine were measured by high-performance liquid chromatography (HPLC). Urinary excretion (12.5% versus 7.7%) and formation clearance (29.8 versus 21.1 mL/h) of p-OHPB, one of the main metabolites of PB, were significantly lower (p < .05) in PMs than in EMs. However, area under the serum concentration-time curve (153.3 in the EMs versus 122.9 microg x h/mL in the PMs), total (210.8 versus 254.9 mL/h) and renal clearance (53.1 versus 66.1 mL/h) of PB were identical between the two groups. To compare the inducibility of CYP2C19, mephenytoin was also given prior to and on the last day of PB treatment. The urinary level of 4'-hydroxymephenytoin was analyzed by a validated gas chromatograpy/mass spectrometry (GC/MS) method. The mephenytoin hydroxylation index did not change in either EMs (1.42 versus 1.42) or PMs (341.4 versus 403.5), showing that CYP2C19 was not induced by treatment with PB. These results indicated that the p-hydroxylation pathway of PB co-segregates with the CYP2C19 metabolic polymorphism. However, the overall disposition kinetics of PB were not different between EMs and PMs, and therefore polymorphic CYP2C19 seems have no major clinical implications.

[A survey of 3,303 6th-year medical students from 36 universities concerning knowledge of resuscitation--more than 80% of medical students can not perform standard cardiopulmonary resuscitation?].

Questionnaires on knowledge of resuscitation were distributed to 3,303 6th-year medical school students from 36 universities. The questionnaire included 13 questions based on the 1992 guidelines for cardiopulmonary resuscitation. From the 13 questions, each student was instructed to select 6 questions concerning assessment of consciousness level, method for confirming respiration, method for securing the airway, method for confirming circulation, pressure points for cardiac massage, and the ratio of respiration and cardiac massage. If all of these six questions could not be answered correctly, it was considered that the student was not able to perform resuscitation according to the guidelines. At least one incorrect answer was given to the six questions by 84% of students, indicating that most medical students are not able to actually perform standard resuscitation. Possible reasons for these results may be the lack of desire on the part of students to master resuscitation, confusion over new findings concerning resuscitation and guideline, insufficient understanding of the difference between the guidelines and new findings by educators, and restricted teaching time for resuscitation. Possible ways to improve the situation include efforts to make students more responsible to master resuscitation, efforts to enhance students' desire to learn, adoption of more practical education, inclusion of such questions in graduation examinations and the national examination for a medical license, adherence by educators to the guidelines, and efforts by educators to make a clear distinction between the guidelines and new findings. With new guidelines for cardiopulmonary resuscitation due out in the year 2000, methods for teaching resuscitation should be reconsidered in order to ensure that all medical students can competently perform resuscitation.

Phenytoin intoxication induced by fluvoxamine.

A patient had phenytoin intoxication after administration of fluvoxamine, a selective serotonin reuptake inhibitor. The serum concentration of phenytoin increased dramatically from 16.6 to 49.1 microg/mL when fluvoxamine was coadministered, although the daily dosage of phenytoin and other drugs had not changed. During phenytoin and fluvoxamine treatment, ataxia, a typical side effect of phenytoin, was observed. The genotypes of CYP2C9 and 2C19, the enzymes responsible for phenytoin metabolism, were homozygous for the wild-type alleles (CYP2C9*1/*1 and 2C19*1/ *1). The interaction may be a result of inhibition of both CYP2C9 and 2C19 by fluvoxamine.

Catalytic activity of three variants (Ile, Leu, and Thr) at amino acid residue 359 in human CYP2C9 gene and simultaneous detection using single-strand conformation polymorphism analysis.

This study evaluated the catalytic activity of three variants (Ile, Leu, and Thr) at codon 359 of CYP2C9 enzymes expressed in a yeast cDNA expression system, and then established single-strand conformation polymorphism (PCR-SSCP) analysis for simultaneous detection as a screening method. Diclofenac was used for the in vitro experiment, and its hydroxy metabolite (4'-hydroxydiclofenac) was measured by HPLC. To discuss the in vivo effect of the Thr359 variant on the pharmacokinetics of phenytoin, a case report is presented. The efficiency of the SSCP method was evaluated by analyzing DNA samples from a homozygote for Ile359 and a heterozygote for Leu359 or Thr359. To evaluate the interaction between the P450 level and reductase activity, two batches of the Thr359 variant with a different P450:reductase activity ratio (1:4.0 and 1:1.4) were used. The in vitro study revealed that recombinant Ile359, Leu359, and Thr359 (2 batches) possessed a mean Km of 2.0, 16.5 and (3.8 and 2.9) micromol and Vmax of 12.4, 17.9 and (4.4 and 5.1) nmol/min/nmol P450, respectively. Although the magnitude of the change in catalytic efficiency for the Thr359 variant was close to that of the Leu359 variant, the effect of the two variants on diclofenac 4'-hydroxylation appears to be different because Leu359 variant was associated with a high Km, and Thr359 with a low Vmax. No significant differences in the kinetic data were observed between the two Thr359 enzymes, suggesting that low reductase activity in the Thr359 enzyme was not a major determinant in the present in vitro experiment. Estimated pharmacokinetic parameters of phenytoin obtained by the Bayesian method in an epileptic patient who was a heterozygote carrier for Thr359 variant were: Km = 6.45 microg/mL, Vmax = 5.77 mg/kg/d, and Vmax/Km = 0.89 L/kg/day. The Vmax/Km value in this patient was similar to the population mean value (0.90 L/kg/day) in Japanese heterozygotes for the Leu359 variant. Results for PCR-SSCP were in complete agreement with those obtained using established methods. Thus, the PCR-SSCP approach is useful for identifying these three variants of the CYP2C9 gene.

CYP2C19 polymorphism effect on phenobarbitone. Pharmacokinetics in Japanese patients with epilepsy: analysis by population pharmacokinetics.

OBJECTIVE: The aim of this study was to clarify the effect of genetic polymorphisms of CYP2C19 on the pharmacokinetics of phenobarbitone (PB) using a nonlinear mixed-effects model (NONMEM) analysis in Japanese adults with epilepsy. METHODS: A total of 144 serum PB concentrations were obtained from 74 subjects treated with both PB and phenytoin but without valproic acid. All patients were classified into three groups by CYP2C19 genotyping: G1, G2 and G3 were homozygous for the wild type of CYP2C19 (*1/*1), heterozygous extensive metabolizers (EMs), (*1/*2 or *1/*3), and poor metabolizers (PMs), (*2/*2, *2/*3), respectively. All data were analyzed using NONMEM to estimate pharmacokinetic parameters of PB with respect to the CYP2C19 genotype. RESULTS: Thirty-three patients belonged to G1 (44.6%), 35 to G2 (47.3%), and 6 to G3 (8.1%). The total clearance (CL) of PB significantly decreased by 18.8% in PMs (G3) relative to EMs (G1 and G2). The CL tended to be lower in G2 than in G1. CONCLUSION: In this study, we first demonstrated the effect of the CYP2C19 polymorphism on pharmacokinetics of PB by genotyping. The contribution of other metabolic enzymes in the metabolism of PB in humans remains to be elucidated; however, it appears that the disposition of PB is mediated in part by this enzyme. The estimated population clearance values in the three genotype groups can be used to predict the PB dose required to achieve an appropriate serum concentration in an individual patient.

Genetic polymorphism of the CYP2C subfamily and excessive serum phenytoin concentration with central nervous system intoxication.

The authors report on a Japanese adult male patient with a long history of partial seizures that were poorly controlled by conventional doses of phenytoin and other drugs. His treatment was complicated by toxic symptoms and an excessive serum phenytoin concentration, 32.6 microg/mL at a dose of 187.5 mg/day. Polymerase chain reaction-restriction fragment length polymorphism analysis disclosed heterozygosity involving cytochrome P450 subfamilies 2C9 (*1/*3) and 2C19 (*1/*3). Currently, it is generally accepted that the former mutation is responsible for the CYP2C9 poor metabolizer phenotype. Pharmacokinetic parameters were estimated by a kinetic analysis, MULTI, using 17 observed dose-concentration data sets: a lower Vmax (5.6 mg/kg/day) and a higher Km (11.5 microg/mL) were observed. Although phenytoin is metabolized predominantly by CYP2C9 with a minor contribution of CYP2C19, patients with the Leu359 variant should be monitored closely when treated with a moderate to high daily dose of phenytoin.

Preoperative anxiety is associated with a high incidence of problematic behavior on emergence after halothane anesthesia in boys.

BACKGROUND: In our clinical experience, children who are crying before anesthesia are more likely to show agitated behavior on emergence. METHODS: One hundred and ten boys aged 3-6 years old (ASA 1) who underwent circumcision were studied. The children were assigned to one of two groups, depending on their attitude during induction: the anxious group and the calm group. Anesthesia was induced by inhalation of halothane in oxygen, and was maintained at 1% throughout surgery. For intra- and postoperative analgesia, caudal block with 0.5 ml/kg of 0.25% plain bupivacaine and topical infiltration with 1 to 2 ml of 1% lidocaine were provided for all patients. The incidence of delirium on emergence was compared between the groups. RESULTS: We excluded 4 boys showing signs of incomplete pain relief. Twenty of 27 boys in the anxious group showed a significantly greater incidence of problematic behavior on emergence, compared to 5 of 79 in the calm group. CONCLUSION: The boys who were anxious before anesthesia showed a significantly greater incidence of problematic behavior on emergence from halothane anesthesia, compared with the boys who were calm before anesthesia.

Complete atrioventricular block during anesthesia.

PURPOSE: To describe a case of asymptomatic first degree atrioventricular block with a bifascicular block that progressed to complete atrioventricular block during anesthesia. This potentially fatal block was successfully treated with transesophageal ventricular pacing. CLINICAL FEATURES: A 67-yr-old man was scheduled for microvascular decompression of the right trigeminal nerve under general anesthesia. His preoperative ECG showed first degree atrioventricular block with complete right bundle branch block and left anterior hemiblock, but he had experienced no cardiovascular symptoms. Anesthesia was induced with sevoflurane 5%, and maintained with isoflurane 1.5-2% in oxygen. Fifteen minutes later in the left lateral decubitus position, the systolic arterial blood pressure suddenly decreased from 80 mmHg to 0 mmHg. Then, the ECG abruptly changed from sinus rhythm to complete atrioventricular block. The heart was unresponsive to drug therapy such as atropine 1.3 mg and isoproterenol 0.5 mg, or transcutaneous pacing but transesophageal pacing was successful. CONCLUSION: Asymptomatic first degree atrioventricular block with bifascicular block advanced to complete atrioventricular block during anesthesia. The block was successfully managed with transesophageal pacing.

Reliability of the omeprazole hydroxylation index for CYP2C19 phenotyping: possible effect of age, liver disease and length of therapy.

AIMS: To evaluate the reliability of the omeprazole hydroxylation index as a marker for polymorphic CYP2C19 activity in a Japanese population of healthy young subjects (n = 78) and patients with peptic ulcer (n = 72). METHODS: Healthy subjects were administered a single dose of omeprazole (20 mg), whereas patients received 20 mg daily for at least 1 week. The ratio of the serum concentration of omeprazole to hydroxyomeprazole at 3 h postdose was determined and used as a measure of CYP2C19 activity. The CYP2C19 wild type (wt) gene and four mutant alleles associated with the poor metaboliser phenotype of (S)-mephenytoin, CYP2C19*2 in exon 5, CYP2C19*3 in exon 4, CYP2C19m4 in exon 9, and CYP2C19m3 in the initial codon were analysed. RESULTS: In the healthy volunteer study there was complete concordance between genotype and phenotype. However, eight of the patients who had the EM genotype had a high value for their hydroxylation index, and were classified as phenotypic PMs. No CYP2C19m4 and CYP2C19m3 mutations were detected in the eight mismatched patients. They were all genotypic heterozygous EMs, elderly (> or = 65 years) and/or had hepatic disease. Therefore, impaired CYP2C19 activity combined with partial saturation of omeprazole metabolism during multiple dosing may have contributed to the discrepancy between CYP2C19 genotyping and phenotyping. CONCLUSION: Although omeprazole has been used instead of mephenytoin as a probe for polymorphic CYP2C19, it does not appear to be reliable enough for clinical application in Japanese patients.