Investigations into the potential effects of multiple dose ketorolac on the pharmacokinetics and pharmacodynamics of racemic warfarin.

1. The potential interaction between racemic warfarin given as a 25 mg single oral dose and chronically administered ketorolac was studied in 12 young healthy male volunteers. 2. Ketorolac produced no major change in the pharmacokinetics of (R)- or (S)-warfarin. 3. Ketorolac did not alter the pharmacodynamic profile of racemic warfarin. 4. Ketorolac increased template bleeding time by a factor of 1.35 as compared with placebo. 5. The results suggest that the ketorolac-warfarin interaction is unlikely to be of major clinical significance; however, combined use of ketorolac and warfarin in patients should be undertaken with due caution and appropriate monitoring.     

After bioethics and towards virtue?

The place of philosophical medical ethics in medical education and clinical practice has recently been questioned. Although partially valid, the criticisms do not warrant abandoning the enterprise. Instead a reappraised model, based on Aristotelean concepts of intellectual and moral virtue is suggested.     

The pharmacokinetics of the enantiomers of flurbiprofen in patients with rheumatoid arthritis.

Plasma and synovial fluid concentrations of the enantiomers of flurbiprofen were measured in 15 rheumatoid patients receiving 100 mg racemic flurbiprofen twice daily. Pharmacokinetic parameters showed considerable variability within the group of patients, although differences in S(+)/R(-) plasma concentration ratios were small. The average values (+/- s.d.) of oral plasma clearance, volume of distribution and elimination half-life for R(-)-flurbiprofen were 0.075 (+/- 0.066) l min-1, 12.47 (+/- 5.79) l and 138 (+/- 61) min, respectively. The average values (+/- s.d.) of oral plasma clearance, volume of distribution and elimination half-life for S(+)-flurbiprofen were 0.057 (+/- 0.035) l min-1, 12.81 (+/- 4.43) l and 155 (+/- 49) min, respectively. S(+)/R(-) ratios (+/- s.d.) rose from 1.06 (+/- 0.12) to 1.75 (+/- 0.61) at the end of the 12 h interval in plasma and from 1.18 (+/- 0.13) to 1.47 (+/- 0.24) over the measured time course in synovial fluid. Increases in S(+)/R(-) ratios may be clinically important as they demonstrate accumulation of the pharmacologically active species.     

Clinical evaluation of the Bentley Univox membrane oxygenator

This paper reports a clinical evaluation of Bentley's new Univox membrane oxygenator (Bentley Laboratories, Irvine, California). In this new device, the blood flow path is outside the fibre, the incorporated heat exchanger consists of a 22-channel stainless-steel bellows, and the polypropylene fibres are woven into fibre ribbons and wound into each of the bellows channels. In this way, heat and gas transfers take place simultaneously. The priming volume has been reduced to 220ml and the membrane has an effective surface area of 1.6m 2. A BMR 1900 collapsible reservoir (Bentley Laboratories, Irvine, California) was used as a venous reservoir. Ten consenting patients undergoing elective coronary artery bypass surgery were perfused with this new oxygenator. BSA was between 1.7 and 2.11m 2; mean BSA was 1.81. Minimum priming was 1200 ml. The blood-gas results were all within or close to the normal range used in our institution. Acid-base management was performed using alpha-stat regulation and no problems occurred in this series of patients. Average pO 2 was 155mmHG+/-53 with a mean O 2 transfer of 90.7ml and a maximum of 185ml. The heat exchange performance was very good, with a mean coefficient of heat exchange of 0.54+/-0.11 and a maximum of 0.87.     

Pharmacokinetics of propionyl-L-carnitine in humans: evidence for saturable tubular reabsorption

AIMS: Propionyl-L-carnitine (PLC) is an endogenous compound which, along with L-carnitine (LC) and acetyl-L-carnitine (ALC), forms a component of the endogenous carnitine pool in humans and most, if not all, animal species. PLC is currently under investigation for the treatment of peripheral artery disease, and the present study was conducted to assess the pharmacokinetics of intravenous propionyl-L-carnitine hydrochloride. METHODS: This was a placebo-controlled, double-blind, parallel group, dose-escalating study in which 24 healthy males were divided into four groups of six. Four subjects from each group received propionyl-L-carnitine hydrochloride and two received placebo. The doses (1 g, 2 g, 4 g and 8 g) were administered as a constant rate infusion over 2 h and blood and urine were collected for 24 h from the start of the infusion. PLC, ALC and LC in plasma and urine were quantified by h.p. l.c. RESULTS: All 24 subjects successfully completed the study and the infusions were well tolerated. In addition to the expected increase in PLC levels, the plasma concentrations and urinary excretion of LC and ALC also increased above baseline values following intravenous propionyl-L-carnitine hydrochloride administration. At a dose of 1 g, PLC was found to have a mean (+/- s.d.) half-life of 1.09 +/- 0.15 h, a clearance of 11.6 +/- 0.24 l h-1 and a volume of distribution of 18.3 +/- 2.4 l. None of these parameters changed with dose. In placebo-treated subjects, endogenous PLC, LC and ALC underwent extensive renal tubular reabsorption, as indicated by renal excretory clearance to GFR ratios of less than 0.1. The renal-excretory clearance of PLC, which was 0.33 +/- 0.38 l h-1 under baseline condition, increased (P < 0. 001) from 1.98 +/- 0.59 l h-1 at a dose of 1 g to 5.55 +/- 1.50 l h-1 at a dose of 8 g (95% confidence interval for the difference was 2.18,4.97). As a consequence, the percent of the dose excreted unchanged in urine increased (P < 0.001) from 18.1 +/- 5.5% (1 g) to 50.3 +/- 13.3% (8 g). The renal-excretory clearance of LC and ALC also increased substantially after PLC administration and there was evidence for renal metabolism of PLC to LC and ALC. CONCLUSIONS: Intravenous administration of propionyl-L-carnitine hydrochloride caused significant increases in the renal excretory clearances of PLC, LC and ALC, due to saturation of the renal tubular reabsorption process - as a consequence there was a substantial increase with dose in the fraction excreted unchanged in urine. Despite the marked increase in the renal clearance of PLC, total clearance remained unchanged, suggesting a compensatory reduction in the clearance of the compound by non excretory routes.     

Plasma Epstein‐Barr virus DNA for pediatric Burkitt lymphoma diagnosis,prognosis and response assessment in Malawi

Point‐of‐care tools are needed in sub‐Saharan Africa (SSA) to improve pediatric Burkitt lymphoma (BL) diagnosis and treatment. We evaluated plasma Epstein–Barr virus (pEBV) DNA as a pediatric BL biomarker in Malawi. Prospectively enrolled children with BL were compared to classical Hodgkin lymphoma (cHL) and nonlymphoma diagnoses. Pediatric BL patients received standardized chemotherapy and supportive care. pEBV DNA was measured at baseline, mid‐treatment, and treatment completion. Of 121 assessed children, pEBV DNA was detected in 76/88 (86%) with BL, 16/17 (94%) with cHL, and 2/16 (12%) with nonlymphoma, with proportions higher in BL versus nonlymphoma (p < 0.001) and similar in BL versus cHL (p = 0.69). If detected, median pEBV DNA was 6.1 log₁₀copies/mL for BL, 4.8 log₁₀copies/mL for cHL, and 3.4 log₁₀copies/mL for nonlymphoma, with higher levels in BL versus cHL (p = 0.029), and a trend toward higher levels in BL versus nonlymphoma (p = 0.062). pEBV DNA declined during treatment in the cohort overall and increased in several children before clinical relapse. Twelve‐month overall survival was 40% in the cohort overall, and for children with baseline pEBV detected, survival was worse if baseline pEBV DNA was ≥6 log₁₀copies/mL versus <6 log₁₀copies/mL (p = 0.0002), and also if pEBV DNA was persistently detectable at mid‐treatment versus undetectable (p = 0.041). Among children with baseline pEBV DNA detected, viremia was the only significant risk factor for death by 12 months in multivariate analyses (adjusted hazard ratio 1.35 per log₁₀copies/mL, 95% CI 1.04–1.75, p = 0.023). Quantitative pEBV DNA has potential utility for diagnosis, prognosis, and response assessment for pediatric BL in SSA.     

Liquid chromatographic determination of lipophilicity with application to a homologous series of barbiturates

A graphical method for determining the lipophilicity of the members of a homologous series of barbituric acids, from a consideration of their reverse-phase HPLC retention data, is described. The HPLC parameter used as the index of lipophilicity, RQ, is shown not only to form excellent correlations with the more commonly employed indices of lipophilicity, Rm and log P, but also to have a predictive capability for those log P values that had not previously been determined experimentally.     

In Vitro Reporter Gene Transfection via Plasmid DNA Delivered by Metered Dose Inhaler

Aerosolised DNA administration could potentially advance the treatment of inheritable lung diseases, lung malignancies and provide genetic immunisation against infection. Jet nebulisation, the current standard for introducing DNA formulations into the lung, is inherently inefficient. Pressurised metered dose inhalers (pMDIs) offer a potentially more efficacious and convenient alternative, especially for repeat administration. We aim to modify a novel low-energy nanotechnology process to prepare surfactant-coated pDNA nanoparticles for pulmonary gene delivery via a pMDI. Water-in-oil microemulsions containing green fluorescent protein reporter plasmid were snap-frozen and lyophilised. Lyophilised pDNA, in some cases following a surfactant wash, was incorporated into pMDIs with hydrofluoroalkane 134a (HFA134a) propellant and ethanol as cosolvent. To assess biological functionality, A549 human lung epithelial cells were exposed to aerosolised pDNA particles in the presence of dioleoyl-trimethylammonium propane (DOTAP). Transfection studies demonstrated that pDNA biological functionality was maintained following aerosolisation. In vitro toxicity assays (MTT) showed no significant cell viability loss following aerosolised pDNA treatment. We have demonstrated that pDNA particles can be incorporated into an HFA134a formulation and aerosolised using a standard valve and actuator. Particles prepared by this novel process have potential for stable and efficient delivery of pDNA to the lower respiratory tract via standard pMDI technology.     

Neutralization of <Emphasis Type="Italic">Neisseria meningitidis</Emphasis> outer membrane vesicles

Introduction  

We aimed to determine the neutralization of Neisseria meningitidis outer membrane vesicles (blebs) by humoral and cellular elements of whole blood.