Real-life experience with a generic formulation of lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for the Phe508del CFTR mutation.

INTRODUCTION: Cystic fibrosis (CF) is the most frequent recessive autosomal disorder in the Caucasian population. It is caused by mutations that result in a deficient or dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) protein activity. Among CFTR modulators, potentiator compounds increase channel opening, whereas corrector compounds increase CFTR quantity in the cell surface. OBJECTIVE: To report real-life effects of a generic formulation of lumacaftor-ivacaftor use in patients with CF homozygous for the Phe508del CFTR mutation. PATIENTS AND METHODS: Clinical variables (body mass index [BMI], pulmonary exacerbations, sweat test, and pulmonary function) were analyzed in 30 CF patients homozygous for the Phe508del CFTR mutation, treated with lumacaftor-ivacaftor for 12 months, at the Respiratory Center of Hospital de Niños Ricardo Gutiérrez. These clinical variables were compared with those before the use of modulators. RESULTS: A total of 30 patients with CF homozygous for the Phe508del CFTR mutation receiving lumacaftor-ivacaftor therapy were included in this study. The median (interquartile range [IQR]) age at the start of treatment was 10.79 (7.08-14.05) years. Nineteen patients were male. Before treatment, median (IQR) sweat chloride concentration was 80 (72-92) mEq/L, and it had decreased to 74 (68-78) mEq/L (p = .05) 12 months after treatment. Median (IQR) BMI z-score improved from -0.33 (-0.86 to 0.21) to -0.13 (-0.66 to 0.54) (p = .003). A spirometry was performed in 28 of 30 patients. Median (IQR) ppFEV1 was 83.5 (71-91) before treatment and 86.5 (67-103) after treatment (p = .38), 73.3% of patients referred decreased sputum production and 40% reported improvement in their dyspnea at 12 months. Severe pulmonary exacerbations significantly decreased from 60% in the year before treatment, to 30% at 12 months after treatment (p = .037); 13 patients showed an improvement in their exacerbation rates, 2 showed an increased rate, and 15 showed no change. CONCLUSIONS: The use of a generic formulation of lumacaftor-ivacaftor in patients homozygous for the Phe508del CFTR mutation was associated with improvement in nutritional status and respiratory symptoms, and a significant reduction in severe pulmonary exacerbations.

Major benznidazole metabolites in patients treated for Chagas disease: Mass spectrometry-based identification, structural analysis and detoxification pathways.

Benznidazole is the drug of choice for the treatment of Chagas disease, but its metabolism in humans is unclear. Here, we identified and characterized the major benznidazole metabolites and their biosynthetic mechanisms in humans by analyzing the ionic profiles of urine samples from patients and untreated donors through reversed-phase UHPLC-ESI-QTOF-MS and UHPLC-ESI-QqLIT-MS. A strategy for simultaneous detection and fragmentation of characteristic positive and negative ions was employed using information-dependent acquisitions (IDA). Selected precursor ions, neutral losses, and MS3 experiments complemented the study. A total of six phase-I and ten phase-II metabolites were identified and structurally characterized in urine of benznidazole-treated patients. Based on creatinine-corrected ion intensities, nitroreduction to amino-benznidazole (M1) and its subsequent N-glucuronidation to M5 were the main metabolic pathways, followed by imidazole-ring cleavage, oxidations, and cysteine conjugations. This extensive exploration of benznidazole metabolites revealed potentially toxic structures in the form of glucuronides and glutathione derivatives, which may be associated with recurrent treatment adverse events; this possibility warrants further exploration in future clinical trials. Incorporation of this knowledge of the benznidazole metabolic profile into clinical pharmacology trials could lead to improved treatments, facilitate the study of possible drug-drug interactions, and even mitigation of adverse drug reactions.

Presence of benznidazole conjugated metabolites in urine identified by β-glucuronidase treatment

Chagas disease is a serious public health problem in Latin America and, due to migration, in other non-endemic regions. Benznidazole (BNZ) is first choice drug in pediatric therapeutics. However, little is known regarding its metabolism in humans. The aim of the study was to isolate and identify products of human BZN metabolism in urine samples obtained from a pediatric Chagas patient and a healthy adult volunteer both treated with BZN. Urine samples were collected after dose of BNZ. Urine was treated with β-glucuronidase followed by an extraction procedure under two different pH conditions and a HPLC/UV and MS/MS identification of BZN and its metabolites. BZN (m/z 260.09847) was identified in all urine extracts. Peaks from each extracted chromatograms were selected for MS and MS/MS identification. Three compounds structurally related to BZN were identified: BZN-Na+ (m/z 283.08009), N-amine-BZN (m/z 230.12307) and N-hydroxi-amine-BZN (m/z 246.11702). BNZ-Na+ was identified in all extracts, but N-amine-BZN and N-hydroxi-amine-BZN were only observed in those extracts treated with β-glucuronidase. This is the first experimental report showing elimination of BZN N-reduced metabolites in urine. As they were released after treatment with β-glucuronidase it can be suggested that glucuronization plays a role in BNZ metabolism and renal elimination.

Abdominal Cystic Echinococcosis Treated with Albendazole. A Pediatric Cohort Study.

INTRODUCTION: Cystic echinococcosis is endemic in Argentina. The standard pharmacological treatment for the disease is albendazole, but surgery is a common alternative. Even though primary infection occurs mainly in the pediatric population, the optimal therapeutic option in pediatrics is not clearly defined and few pediatric cohorts with cystic echinococcosis treated with albendazole have been described to date. OBJECTIVE: To describe therapeutic response to albendazole in a cohort of pediatric patients with abdominal cystic echinococcosis. POPULATION AND METHODS: Patients (0-18 years old) with abdominal cystic echinococcosis who were treated with albendazole between January 1998 and August 2013. Diagnosis of abdominal cystic echinococcosis was made by ultrasound. All patients received albendazole, 10-15 mg/kg/day. Epidemiological data, symptoms, number, location and outcome of the cysts, serology and treatment received were analyzed. The parameter used to assess treatment response was cyst changes evaluated by ultrasound follow up using the WHO-IWGE classification. RESULTS: A total of 28 patients (with 46 abdominal cysts) were included in the cohort. Mean age at enrolment was 9.4 years and mean duration of follow-up, 23.8 months. All patients resided in rural areas and had had contact with dogs. The asymptomatic form of the disease was the most common presentation. All patients received albendazole (mean duration: 142.5 days), with low incidence of adverse events. Albendazole had a positive effect on most of the cysts. Surgery was performed in 13 patients. CONCLUSION: Treatment with albendazole for uncomplicated cystic echinococcosis cysts is safe and effective, and can potentially reduce the need for surgical intervention.

Pharmacokinetic and pharmacodynamic responses in adult patients with Chagas disease treated with a new formulation of benznidazole.

Pharmacological treatment of Chagas disease with benznidazole (BNZ) is effective in children in all stages, but it is controversial in chronically infected adults. We report the pharmacokinetics and pharmacodynamics in six adult patients with Chagas disease treated with the new BNZ formulation (ABARAX®) in doses between 2.5-5.5 mg/Kg/day. All but one patient had plasmatic BNZ concentrations within the expected range. All patients finalised treatment with nondetectable Trypanosoma cruzi quantitative polymerase chain reaction, which remained nondetectable at the six month follow-up. Our data suggests parasitological responses with the new BNZ and supports the hypothesis that treatment protocols with lower BNZ doses may be effective.

Pharmacokinetic and pharmacodynamic responses in adult patients with Chagas disease treated with a new formulation of benznidazole

Pharmacological treatment of Chagas disease with benznidazole (BNZ) is effective in children in all stages, but it is controversial in chronically infected adults. We report the pharmacokinetics and pharmacodynamics in six adult patients with Chagas disease treated with the new BNZ formulation (ABARAX®) in doses between 2.5-5.5 mg/Kg/day. All but one patient had plasmatic BNZ concentrations within the expected range. All patients finalised treatment with nondetectable Trypanosoma cruziquantitative polymerase chain reaction, which remained nondetectable at the six month follow-up. Our data suggests parasitological responses with the new BNZ and supports the hypothesis that treatment protocols with lower BNZ doses may be effective.

Population PK modelling and simulation based on fluoxetine and norfluoxetine concentrations in milk: a milk concentration-based prediction model.

AIMS: Population pharmacokinetic (pop PK) modelling can be used for PK assessment of drugs in breast milk. However, complex mechanistic modelling of a parent and an active metabolite using both blood and milk samples is challenging. We aimed to develop a simple predictive pop PK model for milk concentration-time profiles of a parent and a metabolite, using data on fluoxetine (FX) and its active metabolite, norfluoxetine (NFX), in milk. METHODS: Using a previously published data set of drug concentrations in milk from 25 women treated with FX, a pop PK model predictive of milk concentration-time profiles of FX and NFX was developed. Simulation was performed with the model to generate FX and NFX concentration-time profiles in milk of 1000 mothers. This milk concentration-based pop PK model was compared with the previously validated plasma/milk concentration-based pop PK model of FX. RESULTS: Milk FX and NFX concentration-time profiles were described reasonably well by a one compartment model with a FX-to-NFX conversion coefficient. Median values of the simulated relative infant dose on a weight basis (sRID: weight-adjusted daily doses of FX and NFX through breastmilk to the infant, expressed as a fraction of therapeutic FX daily dose per body weight) were 0.028 for FX and 0.029 for NFX. The FX sRID estimates were consistent with those of the plasma/milk-based pop PK model. CONCLUSIONS: A predictive pop PK model based on only milk concentrations can be developed for simultaneous estimation of milk concentration-time profiles of a parent (FX) and an active metabolite (NFX).

Benznidazole treatment of chagasic encephalitis in pregnant woman with AIDS.

We report a case of chagasic meningoencephalitis reactivation in a pregnant woman co-infected with Trypanosoma cruzi and HIV that was successfully managed with benznidazole and highly active antiretroviral therapy. Early diagnosis enabled rapid specific treatment that improved the health of the patient and her baby.

Nausea and vomiting of pregnancy: using the 24-hour Pregnancy-Unique Quantification of Emesis (PUQE-24) scale.

With up to 80% of pregnant women experiencing nausea and vomiting of pregnancy (NVP), it is critical to have a graded scale of its severity as a guide for appropriate treatment. In 2002 we introduced the Pregnancy-Unique Quantification of Emesis (PUQE) scoring system, which assessed the severity of nausea and vomiting in pregnancy (NVP) based on three physical symptoms: nausea, vomiting, and retching over the previous 12 hours. We present here validation of an extension of the original PUQE, by assessing NVP over 24 hours. This extension is deemed more clinically relevant, because assessment of symptoms over only 12 hours may encompass sleeping hours and hence may not adequately capture the length and severity of the symptoms. In this study we assessed the external validity of the new PUQE-24 by examining its ability to evaluate several characteristics associated with NVP: (a) ability to take multivitamin supplements; (b) rates of hospitalization and emergency room visits for severe symptoms; (c) sleep patterns; (d) liquid intake; and (e) the woman's self-rated well-being scores. Data collected prospectively from 315 women counselled via the Motherisk NVP line were used for the validation. PUQE-24 showed strong correlation with all parameters examined except for sleep patterns and hydration status. The well-being score, however, correlated significantly with hydration status. Capturing 24 hours rather than 12 hours of symptoms may better direct management of NVP and predict its outcome.

Polymorphism of the ADRB2 gene and response to inhaled beta- agonists in children with asthma: a meta-analysis.

BACKGROUND: About 9% of children have asthma, corresponding to almost 6.8 million children in the USA and 1.1 million in the UK. Asthma exacerbations are the leading cause of pediatric emergency room visits and impose a large burden on the individual, family, and society. There is mounting evidence that therapeutic failure of inhaled beta-agonists is associated with polymorphisms of the beta(2)-adrenergic receptor gene (ADRB2); specifically, mutations leading to amino acid changes at positions 16 and 27, which alter down-regulation of the beta(2)-adrenergic receptor (beta(2)AR), induce resistance to the smooth-muscle relaxing effect of beta(2)-adrenergic agonists. METHODS: We conducted a meta-analysis to examine the association between ADRB2 polymorphisms and the response to inhaled beta(2)-adrenergic agonists in children with asthma. We included all published studies until November 2008, in which asthmatic children underwent testing for acute bronchodilator response, defined as > or = 15% improvement in forced expiratory volume in 1 second (FEV(1)) and single nucleotide polymorphism (SNP) genotyping for positions 16 and/or 27 of the beta(2)AR. Individual and summary odds ratios were calculated using a random effects model. RESULTS: We identified three case-control or family-based studies involving 960 asthmatic children (692 children with negative beta(2)-bronchodilator response, defined as < 15% improvement in FEV(1) and 268 children with positive bronchodilator response). We found a significant association between favorable therapeutic response to inhaled beta(2)-adrenergic agonists in asthmatic children and the Arg/Arg phenotype at position 16 of the beta(2)AR [OR = 1.77; 95% CI (1.01; 3.1); p = 0.029], compared with the Arg/Gly or Gly/Gly phenotypes. The beneficial effect of Arg at position 16 of the beta(2)AR was most pronounced in African-American asthmatic children [OR = 3.54; 95% CI (1.37, 9.13)]. There was no association between clinical response to beta(2)-agonists and polymorphism at amino acid position 27 of the beta(2)AR (OR = 1.04; 95% CI [0.76,1.42]). CONCLUSIONS: Failure of bronchodilator response to inhaled beta-agonists in asthmatic children is associated with the Gly allele (Arg/Gly and Gly/Gly genotypes) at position 16 of the beta(2)-adrenergic receptor. Genetic typing for beta(2)AR polymorphism may help identify children with drug-resistant asthma.

Polymorphism of the MDR1/ABCB1 C3435T drug-transporter and resistance to anticonvulsant drugs: a meta-analysis.

BACKGROUND: Approximately one-third of patients with epilepsy patients have recurrent seizures despite therapy. It has been suggested that therapeutic failure is associated with high expression of the multidrug efflux ABCB1 (MDR1) drug-transporter; specifically, that patients with the 3435CC genotype have higher efflux of anticonvulsants out of brain tissue, with correspondingly lower concentrations in the central nervous system. METHODS: We conducted a meta-analysis to examine the association between MDR1 polymorphisms and the response to anticonvulsants. We included all published studies until September 2007, in which patients with responsive and unresponsive seizure disorders underwent genotyping for ABCB1 C3435T. Individual and summary odds ratios were calculated using a random effects model. A secondary analysis was also performed, stratifying the studies by their ethnic distribution to account for genetic heterogeneity. We also performed a cumulative analysis by date of publication for the included studies using a random effects model. RESULTS: We identified 11 case-control studies involving 3,371 patients (1,646 patients with drug-resistant epilepsy and 1,725 controls). We identified no significant association between anticonvulsant drug resistance and MDR1 polymorphism [odds ratio 1.15; 95% confidence interval (CI) 0.78-1.70; p = 0.48). Subanalysis of studies according to ethnicity yielded similar findings [European cohort: OR = 1.31; 95% CI 0.89-1.94, p = 0.18; Asian cohort: OR = 0.99; 95% CI 0.51-1.89, p = 0.96). CONCLUSIONS: We found no association between ABCB1 genotype and response to anticonvulsant drugs. At the present time, genetic typing for MDR1 polymorphism is not warranted for patients with drug-resistant epilepsy.

Polymorphisms of genes controlling homocysteine levels and IQ score following the treatment for childhood ALL.

INTRODUCTION: One of the causes of long-term morbidity associated with the treatment of acute lymphoblastic leukemia (ALL) is late neurotoxicity manifesting as impairment of higher cognitive functions. Cranial radiation therapy (CRT) and chemotherapeutic agents, particularly methotrexate (MTX), are often suggested to be major contributing factors for its development. Homocysteinemia that arises as a result of MTX-induced folate depletion was proposed to play a role in MTX-related neurotoxicity. Several enzymes are essential to maintain the homocysteine levels. Their different functional forms, associated with common genetic polymorphisms, may modulate homocysteine levels and thereby influence MTX-associated neurotoxicity. OBJECTIVES: To test this hypothesis we assessed whether the variants of the methylene tetrahydrofolate reductase (MTHFR), methionine synthase (MTR), methionine synthase reductase (MTRR), cystathionine beta-synthase (CBS) and endothelial nitric acid synthase (eNOS, NOS3) genes, acting either independently or in conjunction with other risk factors, influenced the cognitive functioning in ALL patients. The influence of the genes was measured by estimating the change in IQ scores over a period of 4 years post ALL diagnosis. RESULTS: Two variants, the CBS 844ins68 polymorphism and NOS3 894T homozygosity, were associated with a change in IQ scores (p = 0.01 and 0.007, respectively). A multivariate model obtained through step-wise selection pointed to the importance of the NOS3 894TT genotype only. This effect appears to be dependent on CRT; IQ decline was apparent among individuals with the 894TT genotype who received radiation therapy (p = 0.03). Furthermore, additional factors affecting IQ were identified, including the treatment administered (i.e., CRT; p = 0.02) and a younger age at diagnosis (p = 0.003), and the modifying effect of the treatment protocols was also noted (p = 0.04). CONCLUSION: The results suggest that NOS3 genotyping might identify individuals that are susceptible to intellectual impairment following ALL treatment.