High-performance liquid chromatographic method for the simultaneous determination of pentisomide and its major metabolite N-desisopropylpentisomide in plasma, urine and tissues using solid-phase extraction.
A rapid, sensitive and selective high-performance liquid chromatographic method for the simultaneous determination of pentisomide and its major metabolite desisopropylpentisomide in plasma, urine and tissues has been developed. The method for plasma samples, urine samples and tissue samples, after homogenizing with 50% ethanol, involves extraction of samples via activated Bond-Elut C8 disposable columns with methanol at pH 10 after addition of internal standard, and initially on column washing of samples at pH 10 with water and acetonitrile. The obtained methanolic extract is evaporated to dryness under nitrogen at 25 degrees C; the sample residue is then reconstituted in mobile phase and an aliquot of this solution is injected into the liquid chromatograph. Separation is performed using a Nova-Pak C18 4 microns particle size column operating in combination with radial compression separation unit and a methanol-water-di-sec.-butylamine-phosphoric acid (40:60:0.5:0.2, v/v) pH 3.5 mobile phase with ultraviolet detection at 258 nm. Endogenous substances or a variety of drugs concomitantly used in pentisomide therapy, with the exception of disopyramide, do not interfere with the assay. The mean recovery of pentisomide and desisopropylpentisomide from plasma and urine and from tissues is more than 91 and 86%, respectively. The limit of detection of the assay is 10 ng/ml for both drugs. The intra- and inter-day coefficient of variation for replicate analyses of spiked plasma samples is less than 7 and 8%, respectively. Mean steady-state plasma levels of pentisomide and desisopropylpentisomide in patients on chronic oral therapy are reported.
Relationships Between Ventricular Arrhythmias and Plasma Concentrations of ME3202 (CM7857) in Dogs
Two-stage coronary ligation-, digitalis-, and epinephrine (EPI)-induced ventricular arrhythmias were used to establish minimum effective plasma concentrations of ME3202 in dogs. 2-(2-Diisopropylaminoethyl)-4-methyl-2-(2-pyridyl) pentanamide (ME3202) showed antiarrhythmic effects against arrhythmias in all models. The minimum effective plasma concentrations for arrhythmias induced by 24-h coronary ligation, 48-h coronary ligation, digitalis, and EPI were 4.8 ± 1.0 [after 5 mg/kg intravenously (i.v.)], 5.3 ± 1.3 (after 5 mg/kgi.v.), 4.1 ± 1.1 (after 4 mg/kg i.v.), and 2.5 ± 0.8 (after 5 mg/kg i.v.) μg/ml, respectively (mean ± SD, n = 6 or 7). The minimum effective concentration for EPI-induced arrhythmias was significantly lower than those for the other types of arrhythmias. This profile is similar to those of propafenone and nicainoprol, and since ME3202 had no deleterious effects on blood pressure (BP) or sinus node rate, it is expected to be clinically useful.
Public Hospitals : Options for Reform through Public-Private Partnerships
Globally, health expenditures rose from an average of 3 percent of GDP in 1950 to 8 percent (US$3 trillion) in 1999 (WHO 2000). The increase in spending has been driven by rising income, changing demographic and epidemiological trends, and costly new pharmaceuticals and technology. Although technology is allowing a shift to outpatient care, hospitals still account for 30–50 percent of health expenditures. Public funding has not kept pace with the growth in spending. Much of the increase has been financed from private sources (out-ofpocket payments and private insurance), while the share funded publicly (by tax revenue and national insurance) declined by 6 percent between 1977 and 1997. Constraints on public funding, combined with rising costs, have forced public hospitals to cut costs wherever possible while still endeavoring to guarantee universal (and often free) access to public patients.1 Governments have used different strategies to address these problems, such as shifting financing from general tax revenue to payroll-financed national health insurance, narrowing the basic package of services available to all citizens, linking hospital funding to outputs and efficiency, amalgamating hospitals into networks, increasing autonomy and incentives for management, and reducing the number of hospital beds. Some governments have also turned to public-private partnerships to bring private sector efficiency into public hospitals.