Pharmacokinetics of intravenous gentamicin in healthy young-adult compared to aged alpacas.

The study objective was to evaluate the effects of age on aminoglycoside pharmacokinetics in eight young-adult (<4 years) and eight aged (≥14 years) healthy alpacas, receiving a single 6.6 mg/kg intravenous gentamicin injection. Heparinized plasma samples were obtained at designated time points following drug administration and frozen at -80°C until assayed by a validated immunoassay (QMS® ). Compartmental and noncompartmental analyses of gentamicin plasma concentrations versus time were performed using WinNonlin (v6.4) software. Baseline physical and hematological parameters were not significantly different between young and old animals with the exception of sex. Data were best fitted to a two-compartment pharmacokinetic model. The peak drug concentration at 30 min after dosing (23.8 ± 2.1 vs. 26.1 ± 2 µg/ml, p = .043) and area under the curve (70.4 ± 10.5 vs. 90.4 ± 17.6 µg hr/ml, p = .015) were significantly lower in young-adult compared to aged alpacas. Accordingly, young alpacas had a significantly greater systemic clearance than older animals (95.5 ± 14.4 and 75.6 ± 16.1 ml hr-1 kg-1 ; p = .018), respectively). In conclusion, a single 6.6 mg/kg intravenous gentamicin injection achieves target blood concentrations of >10 times the MIC of gentamicin-susceptible pathogens with MIC levels ≤2 µg/ml, in both young-adult and geriatric alpacas. However, the observed reduction in gentamicin clearance in aged alpacas may increase their risk for gentamicin-related adverse drug reactions.

Pharmacokinetics and cardiovascular effect of etoricoxib in the absence or presence of St. John's Wort in rats.

The effect of chronic administration of etoricoxib (EXB), in the absence or presence of St. John's Wort (SJW), on its pharmacokinetic parameters and blood pressure was investigated in rats.Rats were divided into 3 groups, each group received daily different oral treatment for 3 weeks. Rats' blood pressures were monitored initially, after 1 and 3 weeks of treatment, and after 1 week of discontinuing dosing of both drugs. EXB pharmacokinetic parameters in the absence or presence of SJW were calculated after 3 weeks.SJW was significantly affected EXB pharmacokinetic parameters. The steady state peak plasma concentration and terminal half-life were reduced by 32% and 91%, respectively, due to a > 3 fold increase in its apparent clearance which is a concentration and time dependent effect. EXB was significantly increased (P<0.001) Rats' blood pressure while, co-administration of EXB and SJW was not significantly affect (P>0.05) rats' blood pressure as compared to the control.Monitoring blood pressure of patients anticipated taking EXB for extended period should be advised. The co-administration of SJW with EXB should be avoided since SJW would greatly reduce EXB concentrations by inducing its metabolism.

Effect of renal impairment on the pharmacokinetics of antimony in hamsters.

Renal failure was experimentally induced in 36 hamsters by intraperitoneal injection with uranyl nitrate (5 mg/kg). Twenty-four h later [during acute renal failure (ARF), as indicated by the serum concentrations of creatinine and urea nitrogen] or 72 h later [during chronic renal failure (CRF)] these hamsters plus 18, uninjected, control hamsters were each given a single, intramuscular dose of sodium stibogluconate (120 mg pentavalent antimony/kg). The pharmacokinetic parameters for the antimonial drug were calculated using a non-compartmental model. Urine was collected for 72 h after similar treatment with the antimonial drug, from another 30 hamsters (10 controls, 10 with ARF, and 10 with CRF), so that the fraction of the antimony administered that was subsequently excreted in the urine could be estimated. Compared with the controls, both the hamsters with ARF and those with CRF had significantly higher maximum concentrations of antimony (C(max)), significantly larger 'areas under the curve' for the plots of blood concentration v. time, and significantly longer plasma half-lives (P < 0.001 for each). The mean (S.D.) values of C(max), for example, were more than three-fold higher in the hamsters with ARF [467.5 (59.04) microg/ml] or CRF [461.1 (68.9) microg/ml] than in the controls [154.01 (17.3) microg/ml]. The systemic clearance of antimony was also significantly lower in the hamsters with CRF than in the control animals [0.051 (0.002) v. 0.296 (0.047) litres/h/kg; P < 0.01]. In addition, the fraction of the antimony administered that was excreted in urine was significantly lower in the animals with ARF (0.25) or CRF (0.08) than in the controls (0.37), indicating significant dysfunction of the kidneys in the hamsters injected with uranyl nitrate. It seems clear that, if severe toxicity is to be avoided, patients with renal dysfunction requiring treatment (for leishmaniasis) with sodium stibogluconate should be given lower doses than similar cases with normal kidney function.

In vivo performance of parenteral theophylline-loaded polyisobutylcyanoacrylate nanoparticles in rats.

Theophylline-loaded polyisobutylcyanoacrylate (PICA) nanoparticles were prepared by emulsifier-free polymerization in aqueous media at ambient conditions. PICA nanoparticles were shown (in vitro) to be a promising controlled delivery system for theophylline. Therefore, this study was conducted to investigate the feasibility of PICA nanoparticles as a parenteral controlled drug delivery system in rats. Wistar rats were given intraperitoneal (i.p.) injections of theophylline solution (4 mg/kg) and theophylline nanospheres suspension (8 mg/kg) on two different occasions. Theophylline serum concentrations were measured by an HPLC assay. The drug solution was rapidly absorbed, distributed, and eliminated. The peak concentration (Cmax), 5.34+/-1.9 mg/l, was achieved 20 min following administration. The mean residence time was 2.94 h, and the apparent clearance was 0.31 (l/h)/kg. After nanospheres administration the mean Cmax, 2.53+/-1.1 mg/l, was attained at 3 h. The drug was successfully maintained around this elevated serum drug concentration up to 11 h in rats. The drug concentration was only reduced to 1.43+/-0.98 mg/l (i.e. reduced by 43.5%) after 20 h of administration. This present study provides evidence that the sorption of theophylline to PICA nanoparticles could control the drug release in rats.

Determination of pefloxacin and its main active metabolite in human serum by high-performance liquid chromatography.

A high-performance liquid chromatographic (HPLC) method is described for the simultaneous determination of a fluoroquinolone, pefloxacin, and its main active metabolite norfloxacin (N-desmethyl metabolite) in serum. Sample preparation involves protein precipitation with acetonitrile. The drugs and the internal standard (acebutolol) were eluted from a 4-microns Novapak C-18 cartridge at ambient temperature with an isocratic mobile phase consisting of 14% acetonitrile in buffer solution, at a flow rate of 2.5 ml/min. The effluent was monitored on a fluorescence detector using excitation and emission wave-lengths of 330 and 440 nm, respectively. Each analysis required no longer than 8 min. Quantification was achieved by measurement of the peak-area ratio of the drugs to the internal standard, and the limit of quantification for both pefloxacin and norfloxacin in serum was 50 ng/ml. The intraday coefficient of variation (CV) ranged from 1.3 to 4.4% and from 2.2 to 7.5% for pefloxacin and norfloxacin, respectively, at the concentration ranges evaluated. The interday CV ranged from 1.1 to 5.9% and from 2.3 to 5.6% for pefloxacin and norfloxacin, respectively, at three concentrations. Relative recovery was 105.5 and 99.5% for pefloxacin and norfloxacin, respectively. Stability tests show that pefloxacin and norfloxacin are stable in serum for at least 3 weeks when stored at -20 degrees C. This method has been used successfully in pharmacokinetic studies in humans.

Integration of hepatitis B immunization in the Expanded Program on Immunization of the Child Survival Project.

The Expanded Program on Immunization (EPI) is a component of the Child Survival Project (CSP) whose objectives are to reduce the incidence rates of six childhood diseases (Measles, Diphtheria, Pertussis, Tetanus, Tuberculosis, Poliomyelitis) and to reduce the number of infant deaths from those diseases by increasing effective vaccination coverage. In 1991, the CSP/EPI developed a national plan to introduce national immunization of infants against hepatitis B in an attempt to control the magnitude and seriousness of the damage which viral hepatitis causes in terms of morbidity, mortality and serious sequelae as hepatitis B is an endemic disease in Egypt causing an important public health problem which requires urgent control. This presentation will discuss the integrated effort undertaken to plan and implement the program, the different challenges it faces, control studies being performed as well as the proposed objectives of the hepatitis B vaccination program.

PIP: The Expanded Program on Immunization (EPI) is a component of the Child Survival Project (CSP). Its objective is to reduce the incidence rates of measles, diphtheria, pertussis, tetanus, tuberculosis, and poliomyelitis by increasing effective vaccination coverage. In 1991, CSP/EPI developed a national plan to introduce national immunization of infants against hepatitis B, which is an endemic disease in Egypt. Hepatitis B virus (HBV) causes acute hepatitis and chronic liver disease. Studies have shown that by maturity most of the population has been infected with hepatitis A and greater than 50% with hepatitis B. The recommended series of 3 intramuscular doses of hepatitis B vaccine induces a protective antibody response (anti HBs) in 90% of healthy adults and 95% of infants, children, and adolescents. Several studies have shown that the currently licensed vaccines produce high rates of seroconversion ( 95%) and induce adequate levels of anti HBs when administered to infants at 2 months, 4 months, and 6 months of age. Scheduling was adjusted to coincide with the currently adopted 2, 4, and 6 month vaccination schedule for oral poliomyelitis virus (OPV) and diphtheria-pertussis-tetanus (DPT) to allow a delay of vaccination from 2 to 3 months following birth. Long term studies of healthy adults and children indicate the immunologic memory remains intact for at least 9 years and confers protection against HBV infection even though anti HBs levels may decline below detectable levels. Safety of hepatitis B vaccines has been verified through experience with millions of doses administered worldwide after licensure. Pain at the injection site (3-29%) and a temperature greater than 37.7 degrees Celsius have been the most frequently reported side effects among adults and children. Nearly 90% of children and 96% of newborns had no reactions to the vaccine. Any presumed risk of adverse events must be balanced against the expected risk of acute and chronic liver disease associated with hepatitis B virus infection.

The influence of liver dysfunction on cyclosporine pharmacokinetics--a comparison between 70 per cent hepatectomy and complete bile duct ligation in dogs.

The influence of experimentally induced hepatic dysfunction on the pharmacokinetics of Cyclosporine A (CsA) was determined in dogs. The pharmacokinetics of oral (PO) and intravenous (IV) CsA were studied before and after 70 per cent hepatectomy or complete bile duct ligation (CBDL). Changes in liver function were monitored by serial measurements of serum bilirubin, and by the maximum removal rate (Rmax) and plasma disappearance rate (ICG-K) of indocyanine green (ICG). Concentrations of CsA in whole blood were measured by HPLC. Seventy per cent hepatectomy caused significant liver dysfunction: the ICG-Rmax decreased by 47.7 +/- 7.1 per cent (mean +/- SD) and the ICG-K decreased by 61.3 +/- 9.7 per cent during the first week after hepatectomy. At the same time, the systemic clearance (CLs) of IV-CsA decreased by 43.9 +/- 8.2 per cent, the area under the concentration curve (AUC) of IV-CsA increased by 35.4 +/- 20.8 per cent and the bioavailability of CsA decreased by 26.4 +/- 14.8 per cent. CBDL also induced significant liver dysfunction: the ICG-Rmax decreased by 39.1 +/- 12.8 per cent and the ICG-K decreased by 65.6 +/- 3.6 per cent in the second week after the operation. During the same period, the AUC of PO-CsA decreased by 69.9 +/- 10.7 per cent and the bioavailability of CsA also decreased markedly by 73.9 +/- 15.6 per cent. These data indicate that hepatic impairment significantly influences the pharmacokinetics of CsA, not only by the changes in intestinal absorption, but also by those in hepatic metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood protein binding of cyclosporine in transplant patients.

The objective of this study was to compare the binding of cyclosporine to blood proteins between four healthy subjects and five liver and eight renal transplant patients. Fresh heparinized blood was obtained, to which sufficient quantities of tritium-labelled cyclosporine and unlabelled cyclosporine were added to blood samples or red blood cell (RBC) suspensions. Concentrations of cyclosporine in whole blood, plasma, RBC suspension, and phosphate buffer were estimated by liquid scintigraphy. The blood:plasma ratio of cyclosporine in transplant patients was significantly lower (P less than .05) than that in healthy volunteers. The RBC:buffer ratio, a measure of affinity of RBCs for cyclosporine, was highest in those with liver transplants and lowest in those with kidney transplants. The unbound fraction of cyclosporine in plasma was less in transplant patients than in healthy volunteers. The results of this study indicate that there are differences in blood protein binding of cyclosporine between transplant patients that may contribute to the differences in the pharmacokinetics and pharmacodynamics of this drug.