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A sensitive method is described for the measurement of remoxipride in human plasma and urine. Remoxipride and its internal standard are extracted from plasma or urine at pH 12 with a mixture of hexane and methyl tert.-butyl ether. After washing the organic phase with base, the compounds are extracted into acid and analyzed on a C18 column with ultraviolet detection at 214 nm. The mobile phase is composed of acetonitrile and aqueous buffer (sodium perchlorate and phosphoric acid, pH 1.7). The limits of reliable quantitation for remoxipride are 12.5 and 50 ng/ml for plasma and urine, respectively. The run times are 6 min for plasma and 3 min for urine. The method has been successfully used to assay remoxipride clinical study samples. This mobile phase has also been successfully applied to the analysis of other basic drugs such as cimetidine, codeine, diltiazem and quinidine with minor modifications.

The pharmacokinetics of intravenous and oral nalbuphine were studied in 24 healthy male volunteers ranging in age from 21 to 30 years. On separate test days over a five-week period, subjects received single doses of each of four different formulations of nalbuphine, with a one-week washout period between treatments: 10 mg intravenously administered over two minutes, 45 mg orally given as a solution, and 45 mg orally administered in two tablet formulations (formulation A and formulation B). Blood samples were collected over 48 hours postadministration, and plasma nalbuphine concentrations were determined by reversed-phase high-performance liquid chromatography (HPLC) with electrochemical detection. The mean nalbuphine plasma concentration five minutes after 10 mg intravenously was 53 ng/mL, and the half-life of nalbuphine with this route of administration was 2.3 hours. In contrast, mean maximum nalbuphine concentrations (Cmax) after the three orally administered preparations ranged from 14.4 to 15.5 ng/mL, and occurred 0.9 to 1.2 hours after dose administration. Mean elimination half-lives after administration of the three nalbuphine oral formulations were essentially identical, ranging from 6.9 to 7.7 hours. Nalbuphine plasma concentration curves decayed biexponentially regardless of route of administration or type of formulation. Absolute bioavailability of the orally administered forms of nalbuphine ranged from 16.4 to 17.4% and Cmax and AUC data further established the bioequivalence of the three oral formulations. The low absolute bioavailability and prolonged elimination half-life of nalbuphine associated with oral administration are likely due to extensive first-pass metabolism and enterohepatic circulation, respectively.

Fast, reliable, specific and sensitive methods are reported to accurately quantitate unchanged propranolol in plasma, and its major metabolites in plasma and urine after enzymatic hydrolysis without the need for solvent extraction. These methods enable the analyst to process a large number of propranolol samples in one working day and should prove valuable to clinical laboratories demanding both speed and specificity in an assay.

The formation of four major metabolites of propranolol by the liver was examined at steady state in three dogs that had undergone surgical portacaval transposition, following which injection of drug into the hindlimb delivers the total dose to the liver. Propranolol was infused directly into the liver via a hindlimb vein at dose rates ranging from 1.01 to 6.3 mg/min. In all dogs the formation of 4-hydroxypropranolol, alpha-naphthoxylactic acid, and propranolol glycol was saturable. Vmax and Km values were determined at steady state by relating the rate of excretion of each metabolite into bile and urine to the blood concentration of propranolol. The formation of propranolol glucuronide was a first order process. The use of a dog with a portacaval transposition has permitted development of a method to estimate, in vivo, the kinetic properties of enzymes responsible for hepatic first-pass metabolism of drugs.

BackgroundElderly patients are the fastest growing age group in end-stage renal failure. Data from overseas show that transplantation is a safe and reliable mode of treatment for this group of patients. However, local data about the outcome in these patients are lacking. The aim of this study was to determine and compare the outcomes of renal transplantation among elderly recipients and younger recipients.MethodsUsing the Organ Registry and Transplant System in Kwong Wah Hospital and Princess Margaret Hospital, adult patients who had undergone renal transplantation and who had been followed-up by the two medical units were recruited. They were divided into the control group (age < 60) and the elderly group (age ≥ 60) according to age at transplantation. The following data were collected for cross-sectional analysis: comorbid illnesses, transplantation details, immunosuppressive therapy, incidence and severity of acute rejections, incidence of infection and malignancy, graft and patient survival, and causes of graft loss and death.ResultsA total of 324 episodes of transplantation were recorded (266 controls and 58 elderly). The incidence of acute rejection was higher in the control group (18% vs. 8.6%, p = 0.08). There was a trend towards higher incidence of infection and malignancy in the elderly group, though the difference did not reach statistical significance. The graft survival rate was similar in the two groups, while the 5-year patient survival rate was worse in the elderly group (92.1% vs. 79.3%, p = 0.0058).ConclusionThe transplantation outcomes in elderly recipients are satisfactory, and age per se should not be considered a contraindication to transplantation.

Naloxone hydrochloride is extremely valuable for diagnosing and managing the opioid overdose. Due to naloxone's short half life and a long duration of action of most opioids, repeated naloxone dosing often is required to prevent the recurrence of respiratory depression. An alternative to repeated bolus administration is a continuous IV infusion. We conducted a two-phase study to determine the pharmacokinetics of naloxone and to develop a continuous dosing nomogram. In the first phase seven patients were given an IV bolus dose alone and serial plasma naloxone levels were determined. Naloxone elimination was found to be biexponential with the mean beta half life equal to 0.023 +/- 0.002 reciprocal minutes in two patients and 0.015 +/- 0.02 reciprocal minutes in five patients. In the second phase ten volunteers were given either a 2-mg or a 4-mg bolus dose followed by a 1.5-mg/hr or a 3-mg/hr continuous infusion. The mean volume of distribution of the central compartment was found to be 0.806 +/- 0.408 L/kg. The mean beta rate constant of elimination was found to be 0.036 +/- 0.027 reciprocal minutes. A computer simulation of the pharmacokinetic parameters determined in our study found that a continuous infusion of two-thirds of the bolus dose that resulted in reversal each hour will maintain the plasma naloxone levels equal to or greater than the naloxone levels that would have existed 30 minutes following the bolus dose.

An automated HPLC method is described for the simultaneous determination of propranolol, 4-hydroxypropranolol, and N-desisopropylpropranolol in plasma and urine before and after beta-glucuronidase/aryl sulfatase treatment. It involves extraction with ether at pH 10 in the presence of ascorbic acid, added to prevent oxidation of 4-hydroxypropranolol. The compounds are then back extracted into dilute acid and assayed on an HPLC using a fluorescence detector. Three HPLC columns have been used (a phenyl, an octyl, and an octadecyl column). The last column was found to be most reproducible with minimal intercolumn variation. The solvent system includes a combination of acetonitrile, methanol, and phosphoric acid. Concentrations as low as 0.2, 1.0, and 0.2 ng/ml of propranolol, 4-hydroxypropranolol, and N-desisopropylpropranolol, respectively, can be measured using 1 ml of plasma.

The efficacy of naloxone in reducing the incidence of side effects after intrathecal injection of morphine and the effects of maternal naloxone administration on the condition of the newborn were evaluated in 40 patients. Patients in labor were given a 1-mg intrathecal injection of morphine and, 1 hr later, either a 0.4-mg bolus of naloxone, followed by a 0.4-0.6 mg/hr intravenous infusion of naloxone, or an intravenous bolus of saline, followed by an intravenous infusion of saline. Intrathecal morphine provided at least 50% pain relief in 78% of patients given naloxone, and in 82% given saline. Intravenous naloxone significantly decreased the incidence of pruritus during labor and delivery. There was no significant decrease in the incidence of nausea, vomiting, somnolence, dizziness, or urinary retention in patients given naloxone. Despite placental transfer of naloxone, neonatal outcome was not adversely affected. For both groups, maternal beta-endorphin levels decreased significantly with the onset of analgesia and returned to control levels at delivery. We conclude that intravenous infusion of naloxone reduced pruritus after intrathecal injection of 1 mg of morphine for labor pain without lessening analgesia or adversely affecting maternal or neonatal status.