The population pharmacokinetic model for VPA could be used for a priori recommendation and dose optimisation of that drug in the Egyptian population of epileptic patients.

Genetic polymorphisms in enzymes and transporters involved in the 6-mercaptopurine pathway should be considered during its use to avoid hematological toxicity.

A population pharmacokinetic (PK) study was designed to estimate the PK parameters of digoxin among a selected group of Egyptian pediatric patients (n = 30) with mean age +/- SD and body weight +/- SD of 8.88 +/- 3.01 years and 23.9 +/- 5.8 kg, respectively. All patients had heart failure and were maintained on digoxin given orally. Nonlinear mixed effect modeling software version 5 (NONMEM Project Group, San Francisco, CA) and one-compartment modeling were used for fitting the data. A one-trough steady-state plasma concentration level of digoxin was used in the analysis. The population mean estimates for clearance (CL/f) and volume of distribution (V/f), in which f represents oral bioavailability, were 8.61 L/h and 450 L, respectively. Because of the limited number of samples per patient, regression analysis could not detect a correlation between patient covariates and estimated PK parameters. The analysis did not converge to obtain good parameter estimates. At least two samples per patient should be used to improve the PK estimation and allow better analysis of the relation between the potential covariates and estimated PK parameters.

Heart failure (HF) is a clinical syndrome manifested by signs and symptoms of low cardiac output, pulmonary, and/or systemic congestion. Immunologically, HF is defined as a state of immune activation and persistent inflammation, especially the circulatory levels of inflammatory cytokines have been found to increase. Traditional drugs used in HF have expressed immunomodulatory and/or anticytokine activities that may participate in their therapeutic efficacy in the disease. The angiotensin-converting enzyme inhibitors like captopril and enalapril as well as the angiotensin II receptor antagonist losartan indicated in HF exerted reducing effects on the inflammatory cytokines such as tumor necrosis factor-alpha and interleukin-6 at experimental and clinical levels. Aldosterone antagonists like spironolactone when administered concomitantly with losartan can attenuate angiotensin II-enhanced cytokine production in HF. Carvedilol beta-adrenergic blockers showed a wider spectrum of anti-inflammatory/anticytokine activity that proved to be associated with improvement of cardiac function and ejection fraction in patients with HF. The poor prognosis in HF despite the long experience with its treatment necessitated thinking about new drugs to be added to the traditional ones. Methotrexate and statins are examples of these drugs, especially because they exert immunologic effects. A low dose of methotrexate has been considered as a hopeful adjunct therapy in chronic HF, but large long-term clinical trials are required. Statins showed conflicting results, although they might be useful early after acute ischemic events associated with left ventricular dysfunction or failure, especially in younger patients with less advanced HF.

Digoxin pharmacokinetics (PK) was studied among a selected group of Egyptian pediatric patients (n = 40) with an age range of 0.33 to 15 years. All the patients had heart failure and were maintained on i.v. digoxin (10 microg/kg/d in 2 equal doses). For population PK analysis, 2 serum samples of digoxin were taken per patient. From 30 patients' trough (before the next dose) and 4 hours postdose samples were obtained, while in the other 10 patients, 0.5- and 6-hour postdose samples were taken. Serum concentrations were measured by fluorescence polarization immunoassay. PK modeling was performed using NONMEM software on log-transformed serum digoxin data. The best structural covariate-free model was a linear 2-compartment model with an exponential error model for intersubject variability and an additive model for intrasubject variability. Serum creatinine (SCR) was a significant covariate for clearance. The final population PK parameters were CL (L/h) = 0.388 - [0.78 x (SCR-0.6)], V1 (L/kg) = 1.38, Q (L/h/kg) = 0.48, V2 (L/kg) = 9.11, where CL is the total body clearance, V1 and V2 are the apparent volumes of distribution in the central and peripheral compartments, and Q is intercompartment clearance. A bootstrap resampling for internal validation achieved excellent agreement with the original data sets for PK parameters. In conclusion, 2 points of digoxin concentration allow good regression analysis for clearance-covariate relationship. The inclusion of SCR into the final model might allow better selection of initial maintenance dose of the drug. A prospective study on larger sample size of pediatric patients is recommended for clinical validation of the final model.