Limited Sampling Strategies Supporting Individualized Dose Adjustment of Intravenous Busulfan in Children and Young Adults.

Background: Therapeutic drug monitoring (TDM) for busulfan supports dose adjustment during conditioning for stem cell transplantation. The authors aimed to develop and validate limited sampling strategies (LSS) of 4-5 samples for a precise estimation of the area under concentration (AUC)-time curve of busulfan, in plasma as an alternative to an intensive sampling strategy (ISS) requiring 9-10 samples.

Methods: ISS TDM data from 297 patients (≤18 years of age) were used.

Severe Coagulation Disorder and Thrombocytopenia Associated with Tigecycline - Case Report and Review of Literature.

Herein, we report a 70-year-old male patient, with recurrent multiple hepatic abscesses, that was admitted to the internal medicine department for treatment of Carbapenem Resistant Escherichia Coli (CRE) bacteremia. The patient was treated with Tigecycline; few days later, he developed "Disseminated Intravascular Coagulation (DIC)" like coagulation study abnormality that seemed to be related to Tigecycline treatment. Upon discontinuing it, the DIC-like condition was resolved.

Biodegradable soy wound dressings with controlled release of antibiotics: Results from a guinea pig burn model.

There is growing interest in the development of biodegradable materials from renewable biopolymers, such as soy protein, for biomedical applications. Soy protein is a major fraction of natural soybean and has the advantages of being economically competitive, biodegradable and biocompatible. It presents good water resistance as well as storage stability.

Risk factors for serious adverse effects of thiopurines in patients with Crohn's disease.

Purpose: Thiopurines are effective in attaining and maintaining remission in patients with inflammatory bowel diseases (IBD). The major drawback of these drugs are their serious adverse effects (SAE), highlighting the importance of preemptive identification of patients at risk. We aimed to examine whether gene polymorphisms in GSTM1, GSTT1 and TPMT, combined with various clinical parameters, can predict thiopurine induced SAE.

Genetic polymorphisms predicting methotrexate blood levels and toxicity in adult non-Hodgkin lymphoma.

Methotrexate (MTX), a folate antagonist employed for treating a wide range of malignancies, has an extensive interpatient variability, resulting in unpredictable toxicity. The present study evaluated the impact of single gene polymorphisms (SNPs: rs1801133 and rs1801131 in the MTHFR gene; rs4149056 and rs11045879 in the SLC01B1 gene; and rs2032582 and rs1045642 in the ABCB1 transporter gene) on MTX blood levels and toxicity in samples from 69 patients with diffuse large-B-cell lymphoma (DLBCL) treated with high dose intravenous (HD IV) MTX, > 2 g/m(2). None of the studied genotypes was found to be associated with a statistically significant risk for elevated MTX levels at 24-48 h after completing therapy with MTX.

Thiopurine effectiveness in patients with Crohn's disease: a study of genetic and clinical predictive factors.

Background: Thiopurines are efficacious in the treatment of Crohn's disease and were recently shown to induce T-cell apoptosis by modulation of Rac1 activation. To assess whether polymorphisms in Rac1 and other apoptosis-related genes, combined with clinical parameters, can predict response to thiopurines.

Methods: A retrospective cohort of 156 thiopurine-treated patients with Crohn's disease was genotyped for 11 single-nucleotide polymorphisms (SNPs): 9 SNPs in Rac1, 1 SNP in the Fas ligand -843 T>C, and 1 SNP in the Caspase-9 93 C>T.

Prospective evaluation of the dosing regimen of vancomycin in children of different weight categories.

Background: Pharmacokinetics (PK), pharmacodynamics and optimal dosing of vancomycin in obese children is not known. Higher trough levels of vancomycin may improve outcomes. This prospective study evaluated the appropriateness of twice-daily regimen for the adherence to guidelines, among obese and non obese children.

Pharmacokinetic and pharmacogenetic analysis of oral busulfan in stem cell transplantation: prediction of poor drug metabolism to prevent drug toxicity.

High dose busulfan (BU) has become a mainstay in conditioning regimens for hematopoietic stem cell transplantation (HSCT), despite its unpredictable response, narrow therapeutic index and severe toxicity. The present study provides an integration of pharmacokinetic and genetic data of 63 adults with acute myeloid leukemia (AML) preconditioned for HSCT with high dose oral BU, with the aim of defining biomarkers predictive of poor BU metabolism. BU area under the concentration time curve (AUC) demonstrated that 76% of the patients achieved target AUC; 24% required dose modification.

Population distribution of methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C risk alleles for methotrexate toxicity in Israel.

Methylenetetrahydrofolate reductase (MTHFR) is a central regulatory enzyme in the folate pathway. Two non-synonymous single nucleotide polymorphisms in MTHFR, C677T (rs1801133) and A1298C (rs1801131) have been associated with reduced MTHFR enzyme activity. These polymorphisms, especially C677T, appear to be linked with methotrexate-related toxicity, particularly hepatotoxicity; thus, pretreatment identification of individuals carrying these polymorphisms may be of clinical relevance.

Non-Jewish Israeli IBD patients have significantly higher glutathione S-transferase GSTT1-null frequency.

Background: The involvement of oxidant/antioxidant imbalance in the development of inflammatory bowel disease (IBD) is well documented. Two members of the glutathione S-transferase (GST) family of enzymes, GSTM1 and GSTT1, known to take part in cellular protection against electrophiles, demonstrate common deletion variants (termed null) associated with impaired enzyme function.

Aim: To evaluate the effect of GSTM1/GSTT1 genotype on IBD susceptibility in a Israeli cohort and to study the correlation between GSTM1/GSTT1 genotype, smoking status, and a variety of clinical characteristics of IBD.

Influence of glutathione S-transferase A1, P1, M1, T1 polymorphisms on oral busulfan pharmacokinetics in children with congenital hemoglobinopathies undergoing hematopoietic stem cell transplantation.

Background: Busulfan (BU), often used in high dose for myeloablation before hematopoietic stem cell transplantation (HSCT), has been implicated in certain HSCT toxicities, including the occurrence of hepatic veno-occlusive disease (HVOD). In addition to weight and age, gene polymorphisms in specific members of the glutathione-transferase (GST) gene family (A1, P1, M1, and T1), involved in BU metabolism, may play a role in the wide inter-patient variability in systemic BU concentrations.

Procedure: The present study integrated clinical data regarding the occurrence of HVOD, graft versus host disease (GVHD), BU pharmacokinetics and GSTA1, GSTP1, GSTM1, and GSTT1 genotypes of 18 children who received BU in their pre-HSCT conditioning regimen.

Appropriate antibiotic prescribing pattern in hospitalized children.

This study analyzes prospectively the antibiotic prescription habits in terms of appropriateness of use and cost pattern effects in the paediatric wards of two different university hospital patient set-ups. Data on demographics, discharge diagnosis, antibiotic utilization and costs were collected prospectively from the children's individual electronic charts at Rambam Health Care Campus (R) and Kaplan Medical Centre (K) in Israel. A total of 505 and 497 children from R and K units, respectively, were screened.

Distribution of CYP2C9 and VKORC1 risk alleles for warfarin sensitivity and resistance in the Israeli population.

Purpose: This study was designed to delineate the relative frequency of CYP2C9 and VKORC1 polymorphisms known to affect warfarin response in the highly heterogeneous Israeli population.

Methods: Frequencies of CYP2C9 allelic variants CYP2C9*2, CYP2C9*3 and of VKORC1 single nucleotide polymorphisms (snps) -1639G>A and D36Y were determined in genomic DNA of 438 healthy unrelated Israeli volunteers of Jewish, Druze and Arab Moslem descent, using allele specific PCR-RFLP. Genotyping results obtained were confirmed by probe free High Resolution Melt (HRM) Technology.

Hyperimmune gammaglobulin for the treatment of West Nile virus encephalitis.

Background: West Nile virus, the etiologic agent of West Nile fever, is an emerging mosquito-borne disease. WNV was recognized as a cause of severe human meningoencephalitis in elderly patients during outbreaks in various parts of the world.

Objectives: To analyze WNV encephalitis therapy and its outcome after prescribing hyperimmune gammaglobulin therapy.

Nitrofurantoin pulmonary toxicity: neglected threat.

Nitrofurantoin lung toxicity was diagnosed among ten patients receiving 50 mg/day to prevent recurrent urinary tract infection. In six patients a symptomatic period of 3-36 months preceded the diagnosis. All but one patient, with irreversible lung injury at presentation recovered completely, five after drug discontinuation and four after steroids therapy.

General medications utilization and cost patterns in hospitalized children.

Unlabelled: Drug utilization in the in-patient setting can provide mechanisms to assess drug prescribing trends, efficiency and cost-effectiveness of hospital formularies and examine sub-populations such as children for which prescribing habits are different from adults.

Objectives: The aim of this descriptive study was to analyze general medication utilization patterns and costs excluding antimicrobials prescriptions and to compare two pediatric admission units in a tertiary care university hospital.

Methods: The total number of admitted children was 1,521 and 1,467 for the A and B admission units, respectively.

Distribution of TPMT risk alleles for thiopurine [correction of thioupurine] toxicity in the Israeli population.

Background And Objective: Individuals with intermediate or no thiopurine S-methyltransferase (TPMT) activity are at risk of hematotoxicity when treated with standard doses of thiopurines, thus, pretreatment identification of these individuals is of major importance. The purpose of this study was to determine the frequency and distribution of TPMT polymorphic variants, known to functionally impair TPMT activity, in the highly heterogeneous Israeli population.

Methods: TPMT genotyping of individuals representing three major demographic groups in Israel was carried out by PCR restriction fragment length polymorphism and high-resolution melting.

Busulfan use in hematopoietic stem cell transplantation: pharmacology, dose adjustment, safety and efficacy in adults and children.

Busulphan (1, 4-bis [methanesulfonyl-y] butane) is a bi-functional alkylating agent that, in combination with cyclophosphamide, has been commonly used in conditioning regimens before hematological stem cell transplantation (HSCT) for nearly 20 years. Busulfan has a very narrow therapeutic index, and acute toxicity may be related to absorption and disposition of the drug and metabolites. Precise delivery of the oral formulation is compromised by erratic gastrointestinal absorption, particularly in infants and small children.

Antiepileptic drug-induced hypersensitivity syndrome reactions.

Host dependent idiosyncratic drug reactions, otherwise known as unpredictable type B reactions, are of a major concern in clinical practice and drug development. Hypersensitivity syndrome reactions are idiosyncratic in nature and may be induced by a variety of agents including antiepileptic drugs (AEDs). The AEDs hypersensitivity syndrome is a rare but potentially life-threatening syndrome that occurs after exposure to phenytoin, carbamazepine or phenobarbital.

Targeting C-reactive protein levels using high-dose atorvastatin before coronary artery bypass graft surgery.

Background: Statin medication exhibits pleiotropic properties, such as improvement of endothelial function.

Aim: To determine whether a high loading dose of atorvastatin prescribed before and after coronary artery bypass graft (CABG) surgery will attenuate the inflammatory response reflected in kinetic concentrations of C-reactive protein (CRP).

Methods: The individual area under the concentration-time curve (AUC) of CRP concentration was calculated for the first five days after CABG surgery and compared among three groups of patients: group A patients (n=16), who were on chronic statin therapy, were switched to an equivalent therapy of 20 mg atorvastatin daily for 120 h; group B patients (n=15), who were on chronic statin therapy, were switched to 80 mg atorvastatin daily (one dose 24 h before CABG surgery, one on the day of surgery and two further doses after surgery) followed by 40 mg/day up to 120 h after surgery; and group C patients (n=10), who were naive to statin therapy, underwent elective CABG surgery.

Antiepileptic drugs in the treatment of neuropathic pain.

Antiepileptic drugs are an effective treatment for various forms of neuropathic pain of peripheral origin, although they rarely provide complete pain relief. Multiple multicentre randomised controlled trials have shown clear efficacy of gabapentin and pregabalin for postherpetic neuralgia and painful diabetic neuropathy. Theses drugs can be rapidly titrated and are well tolerated.

Immunopathogenesis of hypersensitivity syndrome reactions to sulfonamides.

Cytokines play a role in the immunopathological and molecular mechanisms of sulfonamide-induced hypersensitivity reactions (HSRs). The objective of this study was to analyze the reliability and correlation between the clinical symptoms observed in affected patients (n = 86) because of a sulfonamide-induced HSR and their lymphocyte toxicity assay (LTA) values. Another goal was to determine the cytokine secretion in the patient's sera and their expression in the peripheral blood mononuclear cells (PBMCs) and to explore whether a correlation exists among positive LTA score, cytokine levels, and HSR occurrence.