Value of therapeutic drug monitoring of endoxifen in Egyptian premenopausal patients with breast cancer given tamoxifen adjuvant therapy: A pilot study.

BACKGROUND: The complex metabolic profile of tamoxifen anticancer drug and polymorphism in its metabolizing enzymes particularly CYP2D6 contribute to the high-observed inter-individual variability in its main active metabolite endoxifen. Therapeutic drug monitoring of endoxifen may play a key role in optimizing tamoxifen therapy, and control of both adverse effects and cancer recurrence. This pilot study aims to assess the clinical benefits of applying endoxifen measurement during tamoxifen therapy in patients with breast cancer. METHODS: Adult premenopausal breast cancer patients ≥ 18 years who received tamoxifen at a fixed dose of 20 mg daily were included. The primary endpoint was to identify the inter-subject variability in serum concentration of the drug and its metabolites especially endoxifen, through fixation of the tamoxifen dose. The secondary endpoint was to check the correlation between endoxifen metabolite concentration and the development of tamoxifen's adverse effects and cancer recurrence. RESULTS: Sixty patients were included in the study with a mean age of 38.4 ± 0.6 years (range: 26-50). The mean concentration of tamoxifen and endoxifen was 181 ± 9.6 ng/mL and 31.49 ng/mL, respectively. The inter-individual variability in concentrations for the drug and its active metabolite as estimated by the coefficient of variation percentage was in 41% and 31%, respectively. Cancer recurrence was observed in a group of patients (n = 16) with an average endoxifen level of 24.48 ng/mL. Another group of patients (n = 25) developed different tamoxifen adverse effects including hot flashes, vaginal bleeding, endometrial thickness, and ovarian cysts with the average endoxifen level of 38.61 ng/mL. The rest of the patients (n = 19) who responded smoothly to the drug with no complications had an average endoxifen level of 31.37 ng/mL. Analysis of variance test showed a significant difference in endoxifen levels between the three groups (p = 0.002). CONCLUSION: The measurement of the endoxifen active metabolite of tamoxifen in breast cancer patients can help dose optimization in light of the observed wide inter-individual variability in drug fixed-dose related concentration of the metabolite. Monitoring of serum concentration of endoxifen can help to reveal, reduce and control tamoxifen's adverse effects and cancer recurrence.

Therapeutic Dilemma in Personalized Medicine.

The practice of medicine depends, over a long time, on identifying therapies that target an entire population. The increase in scientific knowledge over the years has led to the gradual change towards individualization and personalization of drug therapy. The hope of this change is to achieve a better clinical response to given medications and reduction of their adverse effects. Tailoring of medicine on the road of personalized medicine considers molecular and genetic mapping of the individual. However, many factors still impede the smooth application of personalized medicine and represent challenges or limitations in its achievement. In this article, we put some clinical examples that show dilemmas in the application of personalized medicine such as opioids in pain control, fluoropyrimidines in malignancy, clopidogrel as antiplatelet therapy and oral hypoglycemic drugs in Type2 diabetes in adults. Shaping the future of medicine through the application of personalized medicine for a particular patient needs to put into consideration many factors such as patient's genetic makeup and life style, pathology of the disease and dynamic changes in its course as well as interactions between administered drugs and their effects on metabolizing enzymes. We hope in the coming years, the personalized medicine will foster changes in health care system in the way not only to treat patients but also to prevent diseases.

Deprescription in elderly: A spotlight on pharmacoeconomic aspect.

Aging is a complex process and many factors in the elderly, especially multiple diseases and related unnecessary drug use, support a deprescription approach to this age group to save money and health cost. In this review, we have searched for studies related to the pharmacoeconomic aspect of this deprescription approach in the elderly. Few studies are available, but they are promising and effective in paving the way for prospective longitudinal studies to assess the role of deprescription in optimizing the drugs prescribed to aged patients in a way that reduces the costs of both drug adverse effects and/or hospitalization. Awareness of deprescription is important not only to society, but also to hospital stuff and individual patients.

The role of ITPA and ribavirin transporter genes polymorphisms in prediction of ribavirin-induced anaemia in chronic hepatitis C Egyptian patients.

Few data are available concerning the roles of polymorphisms of inosine triphosphatase (ITPA) gene and ribavirin (RBV) transporter genes in the prediction of RBV-induced anaemia among Egyptians with chronic hepatitis C (CHC). Genotyping of three ITPA gene variants and two variants of RBV transporter genes has been performed in 123 patients under pegylated interferon-α/ribavirin treatment. The baseline haemoglobin and ITPA rs1127354 CA/AA have been found as predictors of anaemia at 4, 8 and 12 weeks of RBV therapy. In addition, ITPA rs7270101 AC/CC and age predicted anaemia after 12 weeks of therapy. In conclusion, the ITPA variant rs1127354C>A significantly predict RBV-induced anaemia during the first 3 months of treatment and it is recommended to be assessed before RBV administration.

Cardioprotective effect of atorvastatin alone or in combination with remote ischemic preconditioning on the biochemical changes induced by ischemic/reperfusion injury in a mutual prospective study with a clinical and experimental animal arm.

BACKGROUND: Atorvastatin and remote ischemic preconditioning (RIPC) have beneficial cardiovascular protective effects. The aim of the study was to investigate possible effect of this drug alone and in combination with RIPC on the biochemical changes induced by ischemic/reperfusion injury (I/R) in a combined study with a clinical and experimental animal arm. METHODS: Thirty consecutive patients undergoing elective percutaneous coronary intervention (PCI) were divided into three groups (10 each): group I (control group without any preconditioning), group II (patients who were maintained on atorvastatin (80mg/day) for one month before PCI), and group III (similar to group II but PCI was preceded by RIPC). On the other hand, sixty adult male New Zealand white rabbits were divided into 6 groups (10 each): group I (control), group II (sham), group III (I/R as 30min ischemia followed by 120min reperfusion), group IV (regular atorvastatin 10mg/kg for 40days orally followed by I/R), group V (I/R preceded by RIPC) and group VI (similar to group IV but I/R was preceded by RIPC). Tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), nitric oxide (NO), troponin I (cTnI), creatine kinase MB (CK-MB) and C-reactive protein (CRP) were measured in blood for all study groups. RESULTS: Clinical and experimental parts showed that groups with RIPC combined with atorvastatin pre-treatment showed a synergistic protective effect against I/R injury as evidenced by significant reduction (P<0.001) in the levels of TNF-α, cTnI (in patients) and IL-6, CK-MB and CRP (in rabbits) while the level of NO was significantly (P<0.001) increased compared with other groups. CONCLUSIONS: Pretreatment with atorvastatin combined with RIPC can exert a synergistic cardioprotective effects by reducing the possible biochemical changes related to ischemic reperfusion injury.

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.

The AMPA receptor antagonist perampanel is a new hope in the treatment for epilepsy.

Perampanel is a novel drug recently approved as adjunctive therapy in epileptic patients aged 12 years and older who have drug-resistant partial epilepsy with and without secondary generalization. Pharmacological researches revealed that perampanel reduces neuronal excitability by a non-competitive antagonistic activity against the ionotropic alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors causing modulation of glutamatergic neurotransmission. The pharmacological profile of the drug showed complete absorption following oral administration, and extensive metabolism in the liver by oxidation followed by glucuronidation with an elimination half-life of approximately 53-165 h (average: 105 h), allowing once-daily administration. Randomized placebo-controlled trials demonstrated an effective dose range of the drug, between 4 and 12 mg/day, to significantly reduce seizure frequency in patients with partial-onset seizure that are pharmacoresistant with a favorable tolerability profile. The most frequent adverse events of the drug reported in phase III clinical trials were dizziness, somnolence, fatigue, and headache. However, the data raised from the studies can give a hope that perampanel offers a valuable option as an adjuvant therapy for pharmacoresistant partial-onset and secondarily generalized seizures.

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.

Variability in response to cardiovascular drugs.

Cardiovascular drugs are characterized by wide inter-individual variability in dose/plasma concentration/ response (therapeutic and/or toxic) relationships. Therefore, some patients achieve good therapeutic response to their drug therapy, while others do not. Also, some patients experience adverse effects, which vary from mild to life-threatening. The source of variability in patients' response to cardiovascular drugs may be of pharmacokinetic and/or pharmacodynamic origin. Many factors can potentially affect both of them such as genetics, gender, age, disease state, environmental factors like smoking and food, possible drug-drug interactions, and ethnicity (race). Cardiovascular pharmacogenomics is a new field that focus on the roles of genetic polymorphisms in drug metabolizing enzymes and drug targets in development of variable drug response.

Application of two-point assay of digoxin serum concentration in studying population pharmacokinetics in Egyptian pediatric patients with heart failure: does it make sense?

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.

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.

Study of urinary 6 beta-hydroxycortisol/cortisol ratio in spot urine sample as a biomarker of 3A4 enzyme activity in healthy and epileptic subjects of Egyptian population.

The ratio of urinary 6 beta-hydroxycortisol/cortisol (6 beta-OHC/FC) in morning spot urine samples collected from 8:00 a.m. to 12:00 p.m. was studied using ELIZA kits (Stabiligen) in a group of healthy adult Egyptians (control group) of both sex (n=65, age range: 16-48 years). The frequency distribution of urinary 6 beta-OHC/FC ratio was widely distributed among subjects with higher values in males in comparison to females. No bimodality in either sex was observed. Another group of adult epileptic patients (n=16) was studied for the influence of chronic carbamazepine antiepileptic drug administration on urinary 6 beta-OHC/FC ratio in spot urine samples. The induction property of carbamazepine on CYP3A4 was observed through significant increase (p=0.01) in 6 beta-OHC/FC ratio among epileptic patients in comparison with control subjects. In conclusion, the frequency distribution of urinary 6 beta-OHC/FC ratio among Egyptians shows sexual dimorphism. Also, measurement of urinary 6 beta-OHC/FC ratio provides a simple non-invasive method to monitor CYP3A4 enzyme induction during administration of carbamazepine antiepileptic drug.

Studying long-term effect of phenytoin either alone or combined with ascorbic acid on the anesthetic effect of urethane in rats.

Phenytoin is an anticonvulsant drug known to interact with many other drugs. Previous data suggest that chronic administration of phenytoin delays urethane-induced loss of righting reflex (LRR) and this phenomenon being potentiated by concomitant administration of ascorbic acid (ASC). Therefore, we examined how phenytoin at two different doses combined or not with ASC (fixed dose) interact with both the latency to, and the duration for urethane-induced LRR in experimental rats. The results showed that lower dose of phenytoin (60 mg/kg rat b.i.d.) has significantly shortened the duration of LRR while higher dose of the drug (120 mg/kg b.i.d.) has delayed the latency to LRR (cut-off period of 15 min). Furthermore, addition of ASC to any of the two doses of phenytoin gave results similar to that observed for latency to and duration of LRR when phenytoin was given alone at the higher dose (120 mg/kg b.i.d.). Our data suggest a resistant effect of chronic administration of phenytoin on latency to and/or duration of loss righting reflex induced by urethane in experimental animals. A dose-response relationship of phenytoin in this regard is expected and needs further investigations. The resistant effect of phenytoin on righting reflex has been augmented when ASC was chronically given in combination. This result supports a possible interaction between the two drugs and needs further investigations at both experimental and clinical levels.

Pharmacokinetic modelling of valproic acid from routine clinical data in Egyptian epileptic patients.

OBJECTIVE: This paper describes a developed pharmacokinetic model for the estimation of valproic acid (VPA) clearance (CL) calculated from routine clinical data taken from Egyptian epileptic patients. METHODS: Retrospective clinical data from 81 adult and paediatric epileptic patients with one trough VPA serum concentration per patient were analysed using NONMEM to estimate drug CL and determine the influence of different covariates. A qualification group of 20 epileptic children (3-13 years old) was used to evaluate the final model. RESULTS: The population CL as estimated by base model (no covariates) was 0.581 l h(-1) with inter-individual variability (C.V. %) of 17.4% and SD of residual error was 6.82 mg l(-1). Univariate selection and backward deletion of different covariates led to the development of the final regression model of CL as follows: CL(Lh-1) = 0.101 + 0.151 * CBZ + 0.000248 * VPADD + 0.0968 * age/20 + 0.0803 * INDI, in which CBZ indicates co-administration of carbamazepine, VPADD the daily dose of VPA and INDI uncontrolled epilepsy. The between-subject variability in CL was 23.6% while the standard deviation of the residual error was 5.24 mg l(-1). The model predictions in the qualification group were found to have no bias and satisfactory precision. CONCLUSION: 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.

Therapeutic monitoring of digoxin and antiepileptic drugs in Egypt and Saudi Arabia.

Retrospective analysis was undertaken of serum drug levels determined in 1996 of 580 Egyptian and 1299 Saudi samples and in 2001 of 2361 Saudi samples. Monitored drugs were digoxin, carbamazepine, phenytoin, and valproic acid. The therapeutic drug monitoring results in 1996 showed no differences between the two countries in the rates of subtherapeutic, therapeutic, or toxic drug levels. When the levels of all drugs relative to therapeutic ranges were compared between the 1996 and 2001 Saudi data, a significant decrease in the rate of potentially toxic levels was seen in 2001.

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.

Bayesian estimation of six different sets of carbamazepine pharmacokinetic parameters in Egyptian adult epileptic patients.

The individualization of carbamazepine (CBZ) dosage regimen based on estimation of pharmacokinetic (PK) parameters and measurement of serum drug concentration in epileptic patients can help to control epilepsy. In a retrospective study, the predictive performance of six different sets of CBZ PK parameters selected according to the literature was evaluated in 60 adult epileptic patients. Patients were administered controlled release CBZ (dose range: 200-1200 mg day(-1)) as monotherapy and one steady state serum concentration of the drug was available for each patient. The Bayesian Program of Abbott (PKS system; Abbott Laboratories, Wiesbaden, Germany) was used in the prediction process. Predictive measures included estimation of mean prediction error (mpe) for bias, mean squared prediction error (mspe) and root mean squared prediction error (rmspe) for precision. The analysis showed that three of the investigated six sets achieved the best predictive performance in Egyptian patients and consequently, the PK parameters of any of these three sets can be used by the Bayesian approach as prior information for CBZ dose optimization among the Egyptian adult population.