Ehab S. El Desoky

Site-dependent small intestinal absorption of ranitidine

The site-dependent, small intestinal absorption characteristics of ranitidine were estimated by the intestinal steady state perfusion technique (triple lumen tubing system) combined with simultaneous measurement of serum concentrations of ranitidine.Ranitidine 150 mg·1−1 was perfused at 10 ml·min−1 for 180 min in different sites of the small intestine between 65–250 cm beyond the teeth. Each of 9 healthy, male volunteers was examined twice, using perfusion sites in different regions of the small intestine to permit intraindividual comparisons.The absorption rates (μg·30 cm−1·min−1) calculated from intestinal samples showed distinct site-dependence; the highest rates (medians 160–923 μg·30 cm−1·min−1) were found in the most proximal region (duodenojejunal junction), and the most distal perfusion sites (distal jejunum/ileum) showed median rates from 193 to 265 μg·30 cm−1·min−1. In both of these regions there was a significant positive correlation between the net intestinal water flux and the movement of ranitidine. Within the mid-jejunum, every subject showed marked secretion of ranitidine into the gut lumen (medians −338 to −124 μg·30 cm−1·min−1), and in this region there was no influence of water flux on ranitidine movement. The intraluminal results were confirmed by the corresponding site-dependent areas under the serum concentration-time curves (AUC), which decreased with the distance of the perfusion site from the teeth. After the more distal perfusions individual AUCs amounted to 64-16% of the AUCs obtained after more proximal applications.The results demonstrate the small intestine as the site of a gradient of absorption of ranitidine. Changes in net water movement along the small intestine can be assumed to influence the absorption pattern of ranitidine.

Generation of pharmacokinetic data during routine therapeutic drug monitoring : Bayesian approach vs. pharmacokinetic studies

In three groups (each n = 12) of unselected hospitalized patients treated either with digoxin, theophylline, or gentamicin routinely performed TDM measurement of trough steady-state plasma levels (+ peak levels in case of gentamicin) was combined with a pharmacokinetic study at steady state (multiple blood sampling during one dosing interval). Pharmacokinetic parameters (apparent volume of distribution Vd, total plasma clearance CL) needed for individualization of dosage were evaluated by the Bayesian approach and a model-(in)dependent pharmacokinetic program (TOPFIT). Comparison of both methods revealed some small differences in the pharmacokinetic parameters for all three drugs. Mean deviations of the Bayesian estimates from the pharmacokinetic calculations of the three drugs ranged between 20 and 38% for Vd and between 13 and 22% for CL, indicating that the Bayesian approach provided reliable pharmacokinetic estimates for individualizing drug dosage under routine conditions. Therefore, it is suggested that routine TDM combined with Bayesian-based analyses can be regarded as an alternative to pharmacokinetic studies in clinically relevant populations.

Pharmacotherapy of rheumatoid arthritis: an overview

Abstract Objective: The aim of this article was to provide an overview of the pharmacotherapy of rheumatoid arthritis (RA), including traditional drugs and the newer agents. Methods: Primary literature on the pharmacotherapy of RA was identified through a comprehensive MEDLINE ® English-language search from January 1985 to September 2000. Additional studies were identified from a review of the references within these sources. Results: Treatment options for RA are expanding as research has provided a more explicit understanding of the pathophysiology of the disease. For the relief of the signs and symptoms of RA, the new selective cyclooxygenase-2 (COX-2) inhibitors (celecoxib and rofecoxib) are joining the available nonsteroidal anti-inflammatory drugs (NSAIDs). COX-2 inhibitors have fewer associated upper gastrointestinal side effects than traditional NSAIDs. Use of disease-modifying antirheumatic drugs (DMARDs) is now recommended early in the disease. Triple therapy with methotrexate (MTX), sulfasalazine, and hydroxychloroquine is one of the successful combination approaches with DMARDs. Leflunomide, a new second-line DMARD, reduces pyrimidine synthesis and decreases rheumatoid inflammation. Leflunomide is as effective as MTX, but unlike MTX, does not cause bone marrow toxicity. The biologic agents etanercept and infliximab have shown benefit alone and in combination with MTX. They have minimal toxicity, except for injection-site reactions. However, they should be reserved for patients who fail to respond to MTX alone or another DMARD.

Some international approaches to aminoglycoside monitoring in the extended dosing interval era

Aminoglycosides have rightly remained a cost-effective anti-microbial strategy for the treatment of gram-positive infections for some 25 years. However, in recent years there has been a review of the traditional thrice-daily administration regimen in favor of an extended dosing interval strategy that takes into account the individual patients renal function. The general recommendations that have been provided to date have been adopted in various ways internationally. These approaches were a matter of discussion for the Clinical Pharmacokinetics Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology at its congress (Vancouver, Canada; November 1997), and will again be a workshop issue at the Cairns (Australia) congress of the Association (September 1999). The present report provides examples of how these practices have been applied at a group of centers from Canada (2 centers), The Netherlands, Egypt, and Australia. These reports demonstrate a variety of approaches and highlight the need for further research for assessing clinical outcomes from different dosing strategies.

Genetic variants in 6-mercaptopurine pathway as potential factors of hematological toxicity in acute lymphoblastic leukemia patients

AIM We investigated the associations between variants in genes coding for enzymes and transporters related to the 6-mercaptopurine pathway and clinical outcomes in pediatric patients with acute lymphoblastic leukemia. MATERIALS & METHODS Statistical association between gender, age and genotypes of selected SNPs, and the risks of hematological toxicity and relapse were investigated using a Cox proportional hazard model in 70 acute lymphoblastic leukemia patients from upper Egypt. RESULTS We found significant associations between ITPA, IMPDH1, SLC29A1, SLC28A2, SLC28A3 and ABCC4 SNPs and one or more of the hematological toxicity manifestations (neutropenia, agranulocytosis and leukopenia); age was significantly related to relapse. CONCLUSION Genetic polymorphisms in enzymes and transporters involved in the 6-mercaptopurine pathway should be considered during its use to avoid hematological toxicity.

NAT2*5/*5 genotype (341T>C) is a potential risk factor for schistosomiasis-associated bladder cancer in Egyptians.

Arylamine N-acetyl transferase (NAT2) displays extensive genetic polymorphisms that affect the rates of acetylation of drugs and genotoxic compounds such as amine carcinogens. To investigate whether the slow acetylator genotype is a risk factor for development of bladder cancer following schistosomal infection of the urinary tract, the authors determined the frequencies of 3 common polymorphisms in the NAT2 gene (341T>C, 590G>A, and 282C>T), which are associated with impaired acetylation activity, in control subjects (n = 61; mean age 34.3 ± 9.2 years) and in schistosomiasis-associated bladder cancer patients (n = 55; 52 ± 10.9 years) from the Egyptian population. Genotyping was carried out using rapid cycle PCR on the LightCycler, and subjects were assigned to a slow, intermediate, or rapid acetylator phenotype on the basis of the genotypes. The frequencies of the mutant alleles observed in the controls from the present study were similar to those reported previously for both the Egyptian population and other Arab populations. Patients showed a higher prevalence (78.2%) of slow acetylator phenotype than controls (67.2%), but this did not reach statistical significance (P = 0.19). However, there were significantly more individuals who were carriers of 2 mutant 341T>C alleles (NAT2*5/*5 genotype) in the patient group compared with controls (odds ratio 2.6, CI 1.02-6.67, P = 0.026). The alloenzyme encoded by this allele has been shown to display a large reduction in its catalytic activity. In conclusion, these data suggest that the NAT2*5/*5 genotype is a potential risk factor for development of urinary bladder cancer in patients with prior schistosomiasis infection.

Drug Therapy of Heart Failure: An Immunologic View

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.

Population pharmacokinetics of digoxin in Egyptian pediatric patients: impact of one data point utilization.

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.

Population pharmacokinetics of steady-state carbamazepine in Egyptian epilepsy patients.

What is Known and Objective:  Individualization of carbamazepine (CBZ) dosage regimen in patients with epilepsy based on based on therapeutic drug monitoring (TDM) followed by estimation of pharmacokinetic (PK) parameters can help in better control of epilepsy. Our objective was to establish a population (POP) PK model of CBZ for Egyptian adult and pediatric patients with epilepsy.

Aminoglycoside and vancomycin serum concentration monitoring and mortality due to neonatal sepsis in Saudi Arabia.

Objective:  To assess the effectiveness of monitoring of serum concentration of aminoglycosides in neonates.