Venlafaxine serum levels and CYP2D6 genotype.

Thirty-three patients with depression treated with 225 mg venlafaxine were genotyped for the polymorphic enzyme, debrisoquine 4-hydroxylase (CYP2D6). The relationship between drug and metabolite levels and between genotype and clinical response were investigated. Although the number of responders in this study is insufficient for definite conclusions to be drawn, a target therapeutic concentration ranging from 195-400 microg/L for the sum of venlafaxine and O-desmethylvenlafaxine is suggested. The ratio of O-desmethylvenlafaxine to venlafaxine in the serum concentrations is a measure of metabolic turnover, and can be used to distinguish between ultrarapid and poor metabolizers. All but one of the nonresponders in this study had lower ratios than the responders. Three patients (9%) had homozygous defective CYP2D6 alleles and did not readily metabolize venlafaxine to O-desmethylvenlafaxine, pointing to poor metabolism. In these patients, N-desmethylation was increased. Two out of four patients detected by the ratio as potentially ultrarapid metabolizers were shown to have multiple copies of a functional CYP2D6 gene.

Evaluation of the cloned enzyme donor immunoassay for measurement of phenytoin and phenobarbital in serum.

We report the evaluation of the cloned enzyme donor immunoassay (CEDIA) for the estimation of phenytoin and phenobarbital in serum. The assays were performed with a Hitachi 911 analyzer. Intra-assay coefficients of variation were from 1.5 to 4.4% for phenytoin and 1.6 to 5.5% for phenobarbital. Interassay coefficients of variation ranged from 1.8 to 5.3% for phenytoin and 2.9 to 4.8% for phenobarbital. Linearity was satisfactory, with a recovery of 103% at 11 mg/L and 110% at 22 mg/L phenytoin and 93% at 14 mg/L and 101% at 40 mg/L for phenobarbital. The detection limit was 1.2 mg/L for phenytoin and 0.6 mg/L for phenobarbital. Results of this assay correlated well with those of a conventional high-performance liquid chromatography (HPLC) method; r = 0.99 for phenytoin (n = 47) and r = 0.98 for phenobarbital (n = 48). The CEDIA was easy to handle and especially suitable for short turn-around time application.

Cardiac damage caused by direct application of defibrillator shocks to isolated Langendorff-perfused rabbit heart.

The purpose of this study was to establish the damaging dose of defibrillator pulses. The damage caused to isolated perfused rabbit hearts by synchronized defibrillator shocks with a stored energy from 15 up to 70 joules is reported. The damage was characterized by the duration and severity of post-shock arrhythmias, changes in the elastic properties of the left ventricle, the first derivative of left ventricular pressure, morphological changes of the heart muscle, elevation of creating kinase, potassium washout, and a change in mean coronary flow rate. Varying the electrode area showed that densities of applied current and energy are major factors in damaging the heart. At current and energy densities of 0.5 amp./cm.2 and 0.6 J./cm.2, respectively, potassium washout and mild arrhythmias are seen, as is complete arrest of the ventricles at 1.2 amp./cm.2 and 1.5 J./cm.2 pulses. After 1.8 amp./cm.2, irreversible cell damage occurs, as demonstrated by CK release, and also cardiac function is reduced, measured by increased diastolic stiffness and decreased contractility. Current and energy densities exceeding 2.5 amp./cm.2 and 4.2 J./cm.2, respectively, cause changes in cardiac function incompatible with life. Accumulation of damage was observed with a series of 1.2 amp./cm.2 shocks.

Evaluation of ampouled tonometered buffer solutions as a quality-control system for pH, pCO2, and pO2 measurement.

In response to the need for an adequate quality-control system for blood-pH and blood-gas analyzers, we investigated the practical application of ampouled phosphate-bicarbonate-chloride solutions tonometered with mixtures of carbon dioxide, oxygen, and nitrogen. This system offers three discrete sets of pH, pCO2, AND PO2 values, which are consistent with normal and pathophysiologically high and low values. The stated values were based on the U.S. National Bureau of Standards scale for pH and on gas analysis for pCO2 and pO2. Influence of temperature, air contact, calibration gas, and storage was established. Internal and external quality control by means of these ampoules is presented. The system is stable, accurate, precise, and suitable for simultaneous quality control of pH, pCO2, and pO2 measurements.

Use of carbon dioxide- and oxygen-tonometered phosphate-bicarbonate-chloride-glycerol-water mixtures for calibration and control of pH, pCO2, and pO2 electrode systems.

Calibration of pH, PCO2, and PO2 electrode systems of modern blood-gas analyzers, designed with one sample cuvet for measurement, is mostly performed separately with buffer solutions of known pH, PCO2, and PO2 for doing such calibrations simultaneously, containing phosphate, bicarbonate, and chloride in glycerol-water mixtures as solvent. A method is suggested for computing the relation between pH and log PCO2 of these solutions in equilibrium with carbon dioxide gas. It is demonstrated that a solution of phosphate (Na2HPO4, KH2PO4, each 25 mmol/liter), bicarbonate (NaHCO3, 30 mmol/liter), and chloride (Nacl, 30 mmol/liter) in glycerol-water mixture (3/7 by vol) and equilibrated with CO2 in air (4 vol/100 vol) and CO2 in nitrogen (8 vol/100 vol), respectively, makes possible acurate and simultaneous calibration of the pH, PCO2, PO2 electrodes of a Corning Model 165 blood-gas analyzer. Similar solutions may also be used for quality-control of blood-gas measurement.