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. AUCLSS was calculated using the trapezoidal rule and multiple linear regression (MLR). Unlike more complex modeling methods, MLR does not require sophisticated software or advanced training of personnel. MLR coefficients were estimated in the development subset containing randomly selected 50% of the records and were then used to calculate the AUCLSS of the remaining records (the validation subset). The agreement between dose adjustment recommendations (DAR) based on ISS and LSS, in the validation subset, was evaluated by a Bland-Altman analysis. A DAR deviating from an ISS-based reference by <15% was deemed acceptable. RESULTS: Twelve LSSs were acceptable. Sampling at 0, 120, 180, and 240 minutes after the start of the second infusion (LSS15) yielded the best performance, with DAR deviating from the reference by <10% for 95% of cases; the AUCLSS was determined as follows: AUCLSS = 74.7954 × C(0) + 81.8948 × C(120) + 38.1771 × C(180) + 138.1404 × C(240) + 54.1837. This LSS and LSS13 performed similarly well in an independent external validation. CONCLUSIONS: MLR-based estimates of AUCLSS provide DARs that deviate minimally from the reference. LSSs allow the reduction of patient discomfort, a ∼50% reduction of TDM-related workload for nursing staff and blood loss and a ∼25% reduction in laboratory workload. These benefits may encourage wider use of busulfan TDM, supporting safe and efficacious personalized dosing.

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. Tigecycline should be considered as a possible etiological factor in patients with DIC-like, and this therapy should be withdrawn immediately in suspected cases.

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. In the current study, homogenous antibiotic-loaded soy protein films were cast from aqueous solutions. The antibiotic drug gentamicin was incorporated into the films in order to inhibit bacterial growth, and thus prevent or combat infection, upon its controlled release to the surrounding tissue. The current in vivo study of the dressing material in contaminated deep second-degree burn wounds in guinea pigs (n=20) demonstrated its ability to accelerate epithelialization with 71% epithelial coverage compared to an unloaded format of the soy material (62%) and a significant improved epithelial coverage as compared to the conventional dressing material (55%). Our new platform of antibiotic-eluting wound dressings is advantageous over currently used popular dressing materials that provide controlled release of silver ions, due to its gentamicin release profile, which is safer. Another advantage of our novel concept is that it is based on a biodegradable natural polymer and therefore does not require bandage changes and offers a potentially valuable and economic approach for treating burn-related infections.

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. Ancestral alleles (T) for SLC01B1 rs4149056 (T521C) and SLC01B1 rs11045879 (intron C21273886T) were found to be associated with an increased risk for MTX-related toxicity (p < 0.05 and p = 0.07, respectively), emphasizing the potential importance of employing pharmacogenetic assessment for personalized medicine.

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. METHODS: A retrospective cohort of 176 Crohn's Disease (CD) patients treated with thiopurines (131 with 6MP and 45 with azathioprine) was genotyped for common polymorphisms in GSTM1, GSTT1 and TPMT. Clinical data including SAE, age, ethnicity, gender and smoking status were extracted from patient charts. SAEs evaluated were myelosuppression, hepatotoxicity and pancreatitis. Associations between demographic, clinical, and genetic variables and thiopurine induced SAE were assessed. RESULTS: Twenty-four patients (14%) developed SAE, revealing a significant association between thiopurine induced SAE and GSTM1-null genotype (P=0.05), older age (P=0.016) and active smoking status (P=0.043) and SAE. On multi-variant analysis, past or current smokers were at increased risk for developing thiopurine related SAE (OR 2.915, CI 95%: 1.199- 7.084), specifically pancreatitis (p<0.001). No association was found between TPMT or GSTT1 polymorphisms and the development of SAE. CONCLUSIONS: Active smoking and GSTM1-null genotype appear to be risk factors for thiopurine induced SAEs (i.e. myelosuppression, hepatotoxicity and pancreatitis) in patients with CD. Corroboration of these associations in larger cohorts is warranted.

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. Clinical data were extracted from the medical charts. Odds ratios (ORs) and 95% confidence intervals (CIs) of the association between demographic, clinical, and genetic variables and thiopurine response rates were calculated. RESULTS: The overall response rate to thiopurines was 74% (115/156). The Rac1 SNP rs34932801 heterozygote genotype GC was associated with a lower response rate compared with the wild-type GG genotype (46% versus 76%; OR = 0.26; 95% CI, 0.08-0.91; P = 0.036). Only wild-type homozygotes were found for 5 Rac1 SNPs. None of the other 3 Rac1 SNPs were associated with response to thiopurines. Patients with Montreal B3 behavior pattern responded worse than those with a B1 behavior pattern (59%, versus 80%; OR = 0.37; 95% CI, 0.17-0.83; P = 0.016). Sephardic Jews had a lower response rate to thiopurines compared with Jews of Ashkenazi or mixed ancestry (60% versus 82%; OR = 0.32; 95% CI, 0.15-0.69, P = 0.003). CONCLUSIONS: Rac1 SNP rs34932801carriage, Montreal B3 disease behavior, and a Sephardic Jewish origin were associated with unfavorable response to thiopurines. Corroboration of these associations in larger cohorts is warranted.

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. The purpose of this study was to determine the frequency and distribution of MTHFR polymorphic variants, known to functionally impair MTHFR activity, in the highly heterogeneous Israeli population. MTHFR genotyping was carried out in the representatives of three major demographic groups in Israel by PCR-restriction fragment length polymorphism and high-resolution melting. The relative distribution of variant alleles 677T and 1298C was found to be similar in individuals of Jewish, Druze and Arab Moslem descent (p = 0.09). However, Ashkenazi Jews displayed a 1.9-fold higher frequency of variant 677T and a 1.8-fold lower frequency of variant 1298C compared to non-Ashkenazi Jews (p < 0.001). Distinct differences in the relative frequencies of both polymorphisms were also found between Ashkenazi Jews and Druze (p < 0.01 for C677T, p < 0.01 for A1298C) or Ashkenazi Jews and Arab Moslem (p < 0.01 for C677T, p < 0.05 for A1298C). These data underscore the importance of geographic genetic analysis for a better understanding of human pharmacotherapy and personalized medicine.

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. The main findings of this study were: (1) AML patients carrying the GSTP1 rs1695 variant allele were at risk of developing supra-therapeutic BU-AUC due to reduced BU clearance. (2) Combined polymorphisms in GSTM1 and ABCB1 were associated with BU clearance and AUC rates. In conclusion, GST and ABCB1 genotyping may assist care-givers in personalizing BU dosage with less trial-and-error and may enable preemptive identification of patients at risk for BU toxicity.

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. METHODS: Children receiving vancomycin, (20 mg/kg BID) were included. Patients were divided into 3 groups. Adequacy was defined as trough level ≥ 10mg/L and AUC/MIC > 400. An alternative-dosing regimen was calculated based on individual PK parameters. RESULTS: Seventy-seven pairs (trough, peak) were taken from 51 children. Mean trough level was 3.36 ± 2.58, only 3% fell in therapeutic range, no statistical difference was observed between obese, normal weight or underweight groups. One child had an AUC/MIC > 400. All children recovered. CONCLUSION: PK properties of all weight groups were similar. More frequent and higher doses are needed to achieve the goals of current guidelines.

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. METHODS: A cohort of 606 Israeli IBD patients (453 with Crohn's disease [CD] and 153 with ulcerative colitis [UC]) and 528 ethnically matched healthy controls were genotyped for the null variants of GSTM1 and GSTT1. In patients, phenotype-genotype correlations were examined. RESULTS: Ethnic stratification of healthy controls revealed a higher frequency of GSTT1-null in Jewish and Arab Moslem individuals compared to Druze individuals (P < 0.0005), but no difference in GSTM1-null was found. Comparing IBD patients (both CD and UC) to healthy controls revealed a pattern of lower GSTM1-null and higher GSTT1-null frequencies, which reached significance in Arab Moslem patients. No association was found between NOD2/CARD15 mutation carriage and GSTM1/GSTT1 genotype. No statistically significant association was found between GSTT1-null or GSTM1-null, smoking status, and other phenotypes of CD/UC. CONCLUSIONS: GSTT1-null appears to be associated with IBD, while GSTM1-null appears to be conversely associated with IBD. No association was found between GSTT1-null or GSTM1-null and specific IBD phenotypes.

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. The children were all treated for congenital hemoglobinopathies and were all of Arab Moslem descent. RESULTS: The data demonstrate an association between GSTA1 and GSTP1 genotypes and BU-maximal concentration (C(max)) (P = 0.01, P = 0.02, respectively), area under the concentration-time curve (AUC) (P = 0.02, P = 0.01, respectively) and oral BU clearance/kg body weight (P < 0.02, P = 0.08, respectively). GSTM1-null individuals demonstrated lower BU-AUC/Kg compared to GSTM1-positive individuals. In addition, an association between GVHD and GSTM1-null genotype was found. CONCLUSIONS: GSTA1, GSTP1, and GSTM1 genotyping prior to HSCT in children with congenital hemoglobinopathies may allow better prediction of oral BU kinetics and the need for BU dose adjustment, as well as prediction of transplant related toxicity such as GVHD, thereby improving clinical outcome.

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. Of the surveyed population, 239 and 330 children in the R and K units were hospitalized due to infectious diseases. The antibiotic appropriateness for the R and K units were 84% and 91%, respectively (p>0.5). Total antibiotics Defined Daily Dose (DDD) and Drug Utilization 90% (DU90%) index were 241.7 and 217.5 for the R unit and 388 and 349.2 for the K unit, (p<0.001). Drug Cost 90% indices (DC90%) for the two units were NIS 6,023.5 and NIS 5,955.8; respectively. This study generates up-to-date information on the antimicrobial prescription habits in two different hospitals and suggests that antibiotic treatment in both hospitals appears to be appropriate. Significant lower median antibiotic cost was depicted in the K admission unit in comparison to the R admission unit (11.3 NIS - 40.0 NIS; p<0.01), respectively. Drug use evaluations are useful indicators for following trends of drug prescription, optimizing antibiotic usage and controlling expenditure.

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. RESULTS: Arab Moslems had a higher frequency of warfarin "sensitive" CYP2C9*2, CYP2C9*3 and VKROC1 -1639G>A alleles (0.21, 0.07 and 0.58, respectively) than both Jews (0.13, 0.11 and 0.57, respectively) and Druze (0.12, 0.06 and 0.53, respectively). Statistically significant differences were found in CYP2C9*2 between Druze and Moslems (p=0.01) and between Jews and Moslems (p=0.016) and in CYP2C9*3 between Druze and Jews (p=0.0086). VKORC1(-1639G>A) was the major gene polymorphism associated with warfarin sensitivity in all 3 subpopulations. In contrast, the warfarin "resistant" VKORC1 D36Y allele was very rare in the Israeli population (0-0.015). The results presented demonstrate that allelic variants in CYP2C9 and VKORC1 are very common in Israel with approximately 95% of Jews, approximately 84% of Druze and approximately 91% of Arab Moslems manifesting at least one known warfarin "sensitive" or "resistant" allele. CONCLUSIONS: Individualized genotype based warfarin therapy is highly relevant in the Israeli population due to the high incidence of genetic variations associated with warfarin sensitivity in all 3 non-mixing subpopulations tested.

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. Large amount of data regarding unexpected, sometimes severe pulmonary toxicity during nitrofurantoin therapy should maintain a high index of suspicion for the drug usage among patients with non-resolving pulmonary symptoms. Alternatively, the use of other anti-microbial agents with a better risk-to-benefit ratio should be considered.

General medications utilization and cost patternsin hospitalized children / Utilización general de medicamentos y patrones de costes en niños hospitalizados

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. The electronic data from 252 and 253 hospitalized children in the A and B admission unit were prospectively screened for general medication prescriptions, children on antimicrobials were excluded from the analysis. Their electronic charts were viewed once weekly from October 15, 2007 up to April 7, 2008 using the prescription-point prevalence method. One medication was considered to be one prescription. Results: The general medications prescription number was 790 for 94 children (8.4 prescription/patient) in A and 959 for 88 children (10.9 prescription/patient) in B (p=0.02). The general medications defined daily dose (DDD) and drug utilization 90% (DU90%) index were 2,509.63, 2,259 for A; and 6,110.35, 5,499 for B, respectively. The DU90% index placed salbutamol inhalation with 835 DDD and sodium heparin with 2,102 DDD in the first place for the A and B admission units, respectively. A net increment in medication cost was registered according to the calculated cost from the depicted DU90% when the A (20,263 NIS) and B (6,269 NIS) admission units were compared (p=0.04). Conclusions: A significant difference in the prescription utilization of general medications was shown between the A and B admission units. The A admission unit had lower prescriptions measured by the DU90% index with higher medication cost. Potential drug-drug interactions were depicted in 18 (19%) and 17 (19%) subjects in the A and B admission unit, respectively (AU)

La utilización de medicamentos en el entorno hospitalario puede proporcionar mecanismos para evaluar las tendencias de prescripción de medicamentos, la eficiencia y coste-efectividad de los formularios hospitalarios y examinar sub-poblaciones tales como los niños para los que los hábitos de prescripción son diferentes de los adultos. Objetivos: El objetivo de este estudio descriptivo fue analizar los patrones y costes de la utilización de la medicación general excluyendo los antibióticos, y comparar dos unidades de ingreso pediátricas en un hospital universitario terciario. Métodos: El número total de niños admitidos fue de 1.521 y de 1.467 para las unidades de ingreso A y B, respectivamente. Se escrutaron los datos electrónicos de 252 y 253 niños hospitalizados en las unidades de ingreso A y B, a la búsqueda de la medicación general, excluyendo antibióticos. Sus historiales electrónicos se revisaban una vez a la semana desde el 15 de octubre de 2007 al 7 de abril de 2008 usando el método de prevalencia de prescripción. Se consideró que una medicación era una prescripción. Resultados: el número de medicaciones generales prescritas fue de 790 para 94 niños (8,4 prescripciones/paciente) en A y 959 para 88 niños (10,9 prescripciones/paciente) en B (p=0,02). Las dosis diarias definidas (DDD) y utilización de medicamento90% (DU90%) para la medicación general fueron 2.509.63 y 2.259 para A; and 6.110,35 y 5.499 para B, respectivamente. El índice DU90% situó las inhalaciones con salbutamol con 835 DDD y la heparina sódica con 2.102 DDD en el primer lugar para las unidades A y B de ingreso, respectivamente. Se registró un incremento neto del coste de medicación de acuerdo con el coste calculado de lo dibujado por el DU90% cuando se comparaban las unidades A (20.263 NIS) y B (6.269 NIS) (p=0,04). Conclusiones: Se vio una diferencia significativa en la utilización de prescripciones de medicación general entre las unidades de ingreso A y B. La unidad A tenía menores prescripciones medidas con el índice DU90% de mayor coste. Se identificaron 18 (19%) y 17 (19%) interacciones medicamentosas potenciales en los individuos de las unidades A y B, respectivamente (AU)

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. The electronic data from 252 and 253 hospitalized children in the A and B admission unit were prospectively screened for general medication prescriptions, children on antimicrobials were excluded from the analysis. Their electronic charts were viewed once weekly from October 15, 2007 up to April 7, 2008 using the prescription-point prevalence method. One medication was considered to be one prescription. RESULTS: The general medications prescription number was 790 for 94 children (8.4 prescription/patient) in A and 959 for 88 children (10.9 prescription/patient) in B (p=0.02). The general medications defined daily dose (DDD) and drug utilization 90% (DU90%) index were 2,509.63, 2,259 for A; and 6,110.35, 5,499 for B, respectively. The DU90% index placed salbutamol inhalation with 835 DDD and sodium heparin with 2,102 DDD in the first place for the A and B admission units, respectively. A net increment in medication cost was registered according to the calculated cost from the depicted DU90% when the A (20,263 NIS) and B (6,269 NIS) admission units were compared (p=0.04). CONCLUSIONS: A significant difference in the prescription utilization of general medications was shown between the A and B admission units. The A admission unit had lower prescriptions measured by the DU90% index with higher medication cost. Potential drug-drug interactions were depicted in 18 (19%) and 17 (19%) subjects in the A and B admission unit, 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. RESULTS: Frequencies of TPMT risk alleles differed significantly among the screened Israeli subpopulations: Druze showed fivefold and twofold higher frequencies than Jews and Moslems, respectively. Specifically, allelic frequencies of TPMT*3A were 0.73% (95% CI 0.34-1.45%), 0.79% (95% CI 0.16-2.39%), and 3.19% (95% CI 1.78-5.58%) in Jews, Moslems, and Druze, respectively. Although not found in Jews, TPMT*3C was found at an allelic frequency of 1.05% (95% CI 0.31-2.76%) and 0.75% (95% CI 0.02-2.84%) in Moslems and Druze. TPMT*2 and TPMT*3B were not detected in any of the Israeli subpopulations studied. CONCLUSION: These data indicate that the Israeli population displays a distinct TPMT genetic variability that is comprised of a mix of three major genetically diverse subpopulations, each with its unique TPMT allelic frequency distribution pattern and likelihood of developing an adverse reaction to thiopurine drugs.

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. An intravenous busulfan formula was approved nearly 40 years after the approval of the oral formulation. Busulfan levels expressed as the area under the concentration-time curve (AUC) higher than 1500 microM* minute were reported to increase the risk of developing veno-occlusive disease (VOD), while low levels may result in engraftment failure or disease relapse. VOD occurs in 11-40% of patients undergoing HSCT and is associated with death in 3.3% of patients. Measurement of individual plasma busulfan levels during oral or intravenous dosing to obtain an AUC is likely to provide the necessary elements to monitor the drug disposition, ensuring efficacy and preventing toxicity of patients undergoing HSCT. It is also important to consider the busulfan drug-drug interactions and adverse drug reactions that can develop during the therapeutic process. Busulfan therapeutic drug monitoring and dose-adjustment should be performed in specialized laboratories staffed by well-trained personnel.