Hydrochlorothiazide (HCTZ) is a thiazide diuretic used in adults and children for the treatment o... more Hydrochlorothiazide (HCTZ) is a thiazide diuretic used in adults and children for the treatment of hypertension and edema. The pharmacokinetic (PK) properties of HCTZ in children are not well characterized, particularly among children with obesity who frequently suffer from hypertension and may, therefore, benefit from HCTZ therapy. HCTZ is excreted in the kidney via organic anion transporters 1 and 3 (OAT1 and OAT3). The ontogeny of OAT1 and OAT3 remain unknown, but HCTZ clearance may serve as a surrogate marker of OAT1 and OAT3 maturation. Population PK modeling was performed in NONMEM, and the model was leveraged to conduct dose-exposure simulations. This study examined 83 plasma samples from 49 participants (69% male) taking enteral HCTZ. The median (range) postnatal age was 6.7 years (0.03–19.5 years), and 17 (34%) participants were obese or morbidly obese. The median (range) dose of HCTZ was 0.654 mg/kg (0.11–1.8 kg) and the median number of doses recorded per participant was 5 (1–8). HCTZ PK was well characterized by a 1-compartment PK model. Body weight and a maturation model based on postmenstrual age were significant covariates for apparent clearance, but the presence of obesity was not. Dosing simulations were performed with a standardized 1mg/kg. Simulated exposure (area under the curve and maximum HCTZ concentrations) decreased with age and was likely due to older children receiving the maximum absolute doses of HCTZ. Further studies with more patients in each age group are required to confirm these PK findings of HCTZ in the children.
Adverse drug events are common in critically ill children and often result from systemic or targe... more Adverse drug events are common in critically ill children and often result from systemic or target organ drug exposure. Methods of drug dosing and titration that consider pharmacokinetic alterations may improve our ability to optimally dose critically ill patients and reduce the risk for drug-related adverse events. To demonstrate this possibility, we explored the exposure-response relationship between midazolam and delirium in critically ill children. We retrospectively examined electronic health records (EHRs) of critically ill children <18 years of age hospitalized in the pediatric intensive care unit at Duke University; these children were administered midazolam during mechanical ventilation and had ≥1 Cornell Assessment of Pediatric Delirium (CAPD) score. We used individual-level data extracted from the EHR and a previously published population pharmacokinetic (PK) model developed in critically ill children to simulate plasma concentrations at the time of CAPD scores in 1,00...
Rifampin is active against methicillin-resistant staphylococcal species and tuberculosis (TB). We... more Rifampin is active against methicillin-resistant staphylococcal species and tuberculosis (TB). We performed a multicenter, prospective pharmacokinetic (PK) and safety study of intravenous rifampin in infants of <121 days postnatal age (PNA).
Dried blood spot (DBS) is a practical sampling strategy for pharmacokinetic studies in neonates. ... more Dried blood spot (DBS) is a practical sampling strategy for pharmacokinetic studies in neonates. The utility of DBS to determine the population pharmacokinetics (pop-PK) of ampicillin, as well as accuracy versus plasma samples, was evaluated. An open-label, multicenter, opportunistic, prospective study was conducted in neonates. Ampicillin concentrations from plasma and DBS (CONCPlasma and CONCDBS) were measured by liquid chromatographic tandem mass spectrometry and analyzed using pop-PK and statistical (including transformation) approaches. A total of 29 paired plasma and DBS samples from 18 neonates were analyzed. The median (range) gestational age and postnatal age were 37 (27-41) weeks and 8 (1-26) days, respectively. The geometric mean of CONCDBS to CONCPlasma ratio was 0.56. Correlation analysis demonstrated strong association between CONCPlasma and CONCDBS (r = 0.902, analysis of variance P < 0.001). Using linear regression transformation, the estimated CONCPlasma (eCONCPl...
Antimicrobial agents and chemotherapy, Jan 11, 2018
Solithromycin is a novel fluoroketolide antibiotic, which was under investigation for the treatme... more Solithromycin is a novel fluoroketolide antibiotic, which was under investigation for the treatment of community-acquired bacterial pneumonia (CABP). A phase 1 study was performed to characterize the pharmacokinetics (PK) and safety of solithromycin in children. Eighty-four subjects (median age 6 years [range 4 days - 17 years]) were administered intravenous (IV) or oral (capsules or suspension) solithromycin (IV 6-8 mg/kg; capsules/suspension 14-16 mg/kg on Day 1 and 7-15 mg/kg on Days 2-5). PK samples were collected after first and multi-dose administration. Data from 83 subjects (662 samples) were combined with previously collected adolescent PK data (N=13, median [range] age 16 years (12-17)) following capsule administration to perform a population PK analysis. A 2-compartment PK model characterized the data well, and post-menstrual age was the only significant covariate after accounting for body size differences. Dosing simulations suggested that 8 mg/kg IV daily and oral dosin...
How mitochondrial metabolism is altered by oncogenic tyrosine kinases to promote tumor growth is ... more How mitochondrial metabolism is altered by oncogenic tyrosine kinases to promote tumor growth is incompletely understood. Here, we show that oncogenic HER2 tyrosine kinase signaling induces phosphorylation of mitochondrial creatine kinase 1 (MtCK1) on tyrosine 153 (Y153) in an ABL-dependent manner in breast cancer cells. Y153 phosphorylation, which is commonly upregulated in HER2 breast cancers, stabilizes MtCK1 to increase the phosphocreatine energy shuttle and promote proliferation. Inhibition of the phosphocreatine energy shuttle by MtCK1 knockdown or with the creatine analog cyclocreatine decreases proliferation of trastuzumab-sensitive and -resistant HER2 cell lines in culture and in xenografts. Finally, we show that cyclocreatine in combination with the HER2 kinase inhibitor lapatinib reduces the growth of a trastuzumab-resistant HER2 patient-derived xenograft. These findings suggest that activation of the phosphocreatine energy shuttle by MtCK1 Y153 phosphorylation creates a ...
Major depressive disorder (MDD) is a heterogeneous disease. Efforts to identify biomarkers for su... more Major depressive disorder (MDD) is a heterogeneous disease. Efforts to identify biomarkers for sub-classifying MDD and antidepressant therapy by genome-wide association studies (GWAS) alone have generally yielded disappointing results. We applied a metabolomics-informed genomic research strategy to study the contribution of genetic variation to MDD pathophysiology by assaying 31 metabolites, including compounds from the tryptophan, tyrosine, and purine pathways, in plasma samples from 290 MDD patients. Associations of metabolite concentrations with depressive symptoms were determined, followed by GWAS for selected metabolites and functional validation studies of the genes identified. Kynurenine (KYN), the baseline plasma metabolite that was most highly associated with depressive symptoms, was negatively correlated with severity of those symptoms. GWAS for baseline plasma KYN concentrations identified SNPs across the beta-defensin 1 (DEFB1) and aryl hydrocarbon receptor (AHR) genes t...
Background: The combination of a microtubule stabilizing agent and an mTOR inhibitor has been ide... more Background: The combination of a microtubule stabilizing agent and an mTOR inhibitor has been identified as a synergistic combination in preclinical models. Additional studies have further evaluated the impact of treatment sequence with paclitaxel and rapamycin where administration of rapamycin after paclitaxel was associated with synergy. In our preclinical studies, apoptosis was greater with the combination of ixabepilone and temsirolimus than with either single agent. Thus, a Phase I study of the combination of Ixabepilone (IXB) and Temsirolimus (TEM) was performed to determine the maximum tolerated dose (MTD), describe the toxicity profile and characterize the pharmacokinetics of each agent in patients with advanced cancer. Methods: Eligible patients included adults with a histologically confirmed solid tumor malignancy that was metastatic or unresectable who have received ≤ 2 chemotherapy regimens and had ECOG PS ≤ 2 with adequate bone marrow, renal and hepatic function. Using ...
Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 15, 2018
To determine the dose limiting toxicities (DLT), maximum tolerated dose (MTD), and recommended ph... more To determine the dose limiting toxicities (DLT), maximum tolerated dose (MTD), and recommended phase II dose (RP2D) of veliparib in combination with weekly topotecan in patients with solid tumors. Correlative studies were included to assess the impact of topotecan and veliparib on poly(ADP-ribose) levels in peripheral blood mononuclear cells, serum pharmacokinetics of both agents, and potential association of germline repair gene mutations with outcome. Eligible patients had metastatic nonhematologic malignancies with measurable disease. Using a 3 + 3 design, patients were treated with veliparib orally twice daily on days 1-3, 8-10, and 15-17 and topotecan intravenously on days 2, 9, and 16 every 28 days. Tumor responses were assessed by RECIST. Of 58 patients enrolled, 51 were evaluable for the primary endpoint. The MTD and RP2D was veliparib 300 mg twice daily on days 1-3, 8-10, and 15-17 along with topotecan 3 mg/m on days 2, 9, and 16 of a 28-day cycle. DLTs were grade 4 neutrop...
We undertook a 2-part, phase I, double-blind, placebo-controlled study to evaluate the safety and... more We undertook a 2-part, phase I, double-blind, placebo-controlled study to evaluate the safety and pharmacokinetics of multiple intravenous infusions of sirukumab, a human anti-interleukin-6 monoclonal antibody, in patients with cutaneous lupus erythematosus (CLE) or systemic lupus erythematosus (SLE). In part A, patients with histologically confirmed CLE were randomized to 4 infusions of placebo or 1, 4, or 10 mg/kg sirukumab every 2 weeks. In part B, SLE patients diagnosed according to American College of Rheumatology criteria with a score of 5-12 on the Safety of Estrogens in Lupus Erythematosus National Assessment version of the SLE Disease Activity Index were randomized to 4 infusions of placebo or 10 mg/kg sirukumab every 2 weeks. We treated 31 CLE patients (23 with sirukumab, 8 with placebo) and 15 SLE patients (10 with sirukumab, 5 with placebo). Adverse events (AEs) occurred more often with sirukumab than placebo in CLE patients (91% versus 63%) and in SLE patients (90% versus 80%). Sirukumab led to sustained, dose-independent decreases in white blood cell counts, absolute neutrophil counts (neutropenia), and platelet counts (thrombocytopenia) and to minor elevations in total cholesterol levels. The majority of infections were mild respiratory infections. which were reported similarly across CLE cohorts but more often in sirukumab-treated than in placebo-treated SLE patients. Two serious AEs of infection occurred (pneumonia in the 10 mg/kg-treated group and iatrogenic wound infection in the 4 mg/kg-treated group). Sirukumab showed linear pharmacokinetics in CLE patients. Systemic exposure and half-life were comparable between CLE and SLE patients. No patient developed antibodies to sirukumab through 22 weeks. C-reactive protein and serum amyloid A mean concentrations were suppressed with sirukumab from week 1 to week 14. Treatment with intravenous sirukumab infusions was generally well tolerated in both CLE and SLE patients with mild, stable, active disease. Sirukumab demonstrated linear pharmacokinetics over the dose range studied and comparable systemic exposure and half-life in CLE and SLE patients.
Hydrochlorothiazide (HCTZ) is a thiazide diuretic used in adults and children for the treatment o... more Hydrochlorothiazide (HCTZ) is a thiazide diuretic used in adults and children for the treatment of hypertension and edema. The pharmacokinetic (PK) properties of HCTZ in children are not well characterized, particularly among children with obesity who frequently suffer from hypertension and may, therefore, benefit from HCTZ therapy. HCTZ is excreted in the kidney via organic anion transporters 1 and 3 (OAT1 and OAT3). The ontogeny of OAT1 and OAT3 remain unknown, but HCTZ clearance may serve as a surrogate marker of OAT1 and OAT3 maturation. Population PK modeling was performed in NONMEM, and the model was leveraged to conduct dose‐exposure simulations. This study examined 83 plasma samples from 49 participants (69% male) taking enteral HCTZ. The median (range) postnatal age was 6.7 years (0.03‐19.5 years), and 17 (34%) participants were obese or morbidly obese. The median (range) dose of HCTZ was 0.654 mg/kg (0.11‐1.8 kg) and the median number of doses recorded per participant was 5 (1‐8). HCTZ PK was well characterized by a 1‐compartment PK model. Body weight and a maturation model based on postmenstrual age were significant covariates for apparent clearance, but the presence of obesity was not. Dosing simulations were performed with a standardized 1mg/kg. Simulated exposure (area under the curve and maximum HCTZ concentrations) decreased with age and was likely due to older children receiving the maximum absolute doses of HCTZ. Further studies with more patients in each age group are required to confirm these PK findings of HCTZ in the children.
Hydrochlorothiazide (HCTZ) is a thiazide diuretic used in adults and children for the treatment o... more Hydrochlorothiazide (HCTZ) is a thiazide diuretic used in adults and children for the treatment of hypertension and edema. The pharmacokinetic (PK) properties of HCTZ in children are not well characterized, particularly among children with obesity who frequently suffer from hypertension and may, therefore, benefit from HCTZ therapy. HCTZ is excreted in the kidney via organic anion transporters 1 and 3 (OAT1 and OAT3). The ontogeny of OAT1 and OAT3 remain unknown, but HCTZ clearance may serve as a surrogate marker of OAT1 and OAT3 maturation. Population PK modeling was performed in NONMEM, and the model was leveraged to conduct dose-exposure simulations. This study examined 83 plasma samples from 49 participants (69% male) taking enteral HCTZ. The median (range) postnatal age was 6.7 years (0.03–19.5 years), and 17 (34%) participants were obese or morbidly obese. The median (range) dose of HCTZ was 0.654 mg/kg (0.11–1.8 kg) and the median number of doses recorded per participant was 5 (1–8). HCTZ PK was well characterized by a 1-compartment PK model. Body weight and a maturation model based on postmenstrual age were significant covariates for apparent clearance, but the presence of obesity was not. Dosing simulations were performed with a standardized 1mg/kg. Simulated exposure (area under the curve and maximum HCTZ concentrations) decreased with age and was likely due to older children receiving the maximum absolute doses of HCTZ. Further studies with more patients in each age group are required to confirm these PK findings of HCTZ in the children.
Adverse drug events are common in critically ill children and often result from systemic or targe... more Adverse drug events are common in critically ill children and often result from systemic or target organ drug exposure. Methods of drug dosing and titration that consider pharmacokinetic alterations may improve our ability to optimally dose critically ill patients and reduce the risk for drug-related adverse events. To demonstrate this possibility, we explored the exposure-response relationship between midazolam and delirium in critically ill children. We retrospectively examined electronic health records (EHRs) of critically ill children <18 years of age hospitalized in the pediatric intensive care unit at Duke University; these children were administered midazolam during mechanical ventilation and had ≥1 Cornell Assessment of Pediatric Delirium (CAPD) score. We used individual-level data extracted from the EHR and a previously published population pharmacokinetic (PK) model developed in critically ill children to simulate plasma concentrations at the time of CAPD scores in 1,00...
Rifampin is active against methicillin-resistant staphylococcal species and tuberculosis (TB). We... more Rifampin is active against methicillin-resistant staphylococcal species and tuberculosis (TB). We performed a multicenter, prospective pharmacokinetic (PK) and safety study of intravenous rifampin in infants of <121 days postnatal age (PNA).
Dried blood spot (DBS) is a practical sampling strategy for pharmacokinetic studies in neonates. ... more Dried blood spot (DBS) is a practical sampling strategy for pharmacokinetic studies in neonates. The utility of DBS to determine the population pharmacokinetics (pop-PK) of ampicillin, as well as accuracy versus plasma samples, was evaluated. An open-label, multicenter, opportunistic, prospective study was conducted in neonates. Ampicillin concentrations from plasma and DBS (CONCPlasma and CONCDBS) were measured by liquid chromatographic tandem mass spectrometry and analyzed using pop-PK and statistical (including transformation) approaches. A total of 29 paired plasma and DBS samples from 18 neonates were analyzed. The median (range) gestational age and postnatal age were 37 (27-41) weeks and 8 (1-26) days, respectively. The geometric mean of CONCDBS to CONCPlasma ratio was 0.56. Correlation analysis demonstrated strong association between CONCPlasma and CONCDBS (r = 0.902, analysis of variance P < 0.001). Using linear regression transformation, the estimated CONCPlasma (eCONCPl...
Antimicrobial agents and chemotherapy, Jan 11, 2018
Solithromycin is a novel fluoroketolide antibiotic, which was under investigation for the treatme... more Solithromycin is a novel fluoroketolide antibiotic, which was under investigation for the treatment of community-acquired bacterial pneumonia (CABP). A phase 1 study was performed to characterize the pharmacokinetics (PK) and safety of solithromycin in children. Eighty-four subjects (median age 6 years [range 4 days - 17 years]) were administered intravenous (IV) or oral (capsules or suspension) solithromycin (IV 6-8 mg/kg; capsules/suspension 14-16 mg/kg on Day 1 and 7-15 mg/kg on Days 2-5). PK samples were collected after first and multi-dose administration. Data from 83 subjects (662 samples) were combined with previously collected adolescent PK data (N=13, median [range] age 16 years (12-17)) following capsule administration to perform a population PK analysis. A 2-compartment PK model characterized the data well, and post-menstrual age was the only significant covariate after accounting for body size differences. Dosing simulations suggested that 8 mg/kg IV daily and oral dosin...
How mitochondrial metabolism is altered by oncogenic tyrosine kinases to promote tumor growth is ... more How mitochondrial metabolism is altered by oncogenic tyrosine kinases to promote tumor growth is incompletely understood. Here, we show that oncogenic HER2 tyrosine kinase signaling induces phosphorylation of mitochondrial creatine kinase 1 (MtCK1) on tyrosine 153 (Y153) in an ABL-dependent manner in breast cancer cells. Y153 phosphorylation, which is commonly upregulated in HER2 breast cancers, stabilizes MtCK1 to increase the phosphocreatine energy shuttle and promote proliferation. Inhibition of the phosphocreatine energy shuttle by MtCK1 knockdown or with the creatine analog cyclocreatine decreases proliferation of trastuzumab-sensitive and -resistant HER2 cell lines in culture and in xenografts. Finally, we show that cyclocreatine in combination with the HER2 kinase inhibitor lapatinib reduces the growth of a trastuzumab-resistant HER2 patient-derived xenograft. These findings suggest that activation of the phosphocreatine energy shuttle by MtCK1 Y153 phosphorylation creates a ...
Major depressive disorder (MDD) is a heterogeneous disease. Efforts to identify biomarkers for su... more Major depressive disorder (MDD) is a heterogeneous disease. Efforts to identify biomarkers for sub-classifying MDD and antidepressant therapy by genome-wide association studies (GWAS) alone have generally yielded disappointing results. We applied a metabolomics-informed genomic research strategy to study the contribution of genetic variation to MDD pathophysiology by assaying 31 metabolites, including compounds from the tryptophan, tyrosine, and purine pathways, in plasma samples from 290 MDD patients. Associations of metabolite concentrations with depressive symptoms were determined, followed by GWAS for selected metabolites and functional validation studies of the genes identified. Kynurenine (KYN), the baseline plasma metabolite that was most highly associated with depressive symptoms, was negatively correlated with severity of those symptoms. GWAS for baseline plasma KYN concentrations identified SNPs across the beta-defensin 1 (DEFB1) and aryl hydrocarbon receptor (AHR) genes t...
Background: The combination of a microtubule stabilizing agent and an mTOR inhibitor has been ide... more Background: The combination of a microtubule stabilizing agent and an mTOR inhibitor has been identified as a synergistic combination in preclinical models. Additional studies have further evaluated the impact of treatment sequence with paclitaxel and rapamycin where administration of rapamycin after paclitaxel was associated with synergy. In our preclinical studies, apoptosis was greater with the combination of ixabepilone and temsirolimus than with either single agent. Thus, a Phase I study of the combination of Ixabepilone (IXB) and Temsirolimus (TEM) was performed to determine the maximum tolerated dose (MTD), describe the toxicity profile and characterize the pharmacokinetics of each agent in patients with advanced cancer. Methods: Eligible patients included adults with a histologically confirmed solid tumor malignancy that was metastatic or unresectable who have received ≤ 2 chemotherapy regimens and had ECOG PS ≤ 2 with adequate bone marrow, renal and hepatic function. Using ...
Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 15, 2018
To determine the dose limiting toxicities (DLT), maximum tolerated dose (MTD), and recommended ph... more To determine the dose limiting toxicities (DLT), maximum tolerated dose (MTD), and recommended phase II dose (RP2D) of veliparib in combination with weekly topotecan in patients with solid tumors. Correlative studies were included to assess the impact of topotecan and veliparib on poly(ADP-ribose) levels in peripheral blood mononuclear cells, serum pharmacokinetics of both agents, and potential association of germline repair gene mutations with outcome. Eligible patients had metastatic nonhematologic malignancies with measurable disease. Using a 3 + 3 design, patients were treated with veliparib orally twice daily on days 1-3, 8-10, and 15-17 and topotecan intravenously on days 2, 9, and 16 every 28 days. Tumor responses were assessed by RECIST. Of 58 patients enrolled, 51 were evaluable for the primary endpoint. The MTD and RP2D was veliparib 300 mg twice daily on days 1-3, 8-10, and 15-17 along with topotecan 3 mg/m on days 2, 9, and 16 of a 28-day cycle. DLTs were grade 4 neutrop...
We undertook a 2-part, phase I, double-blind, placebo-controlled study to evaluate the safety and... more We undertook a 2-part, phase I, double-blind, placebo-controlled study to evaluate the safety and pharmacokinetics of multiple intravenous infusions of sirukumab, a human anti-interleukin-6 monoclonal antibody, in patients with cutaneous lupus erythematosus (CLE) or systemic lupus erythematosus (SLE). In part A, patients with histologically confirmed CLE were randomized to 4 infusions of placebo or 1, 4, or 10 mg/kg sirukumab every 2 weeks. In part B, SLE patients diagnosed according to American College of Rheumatology criteria with a score of 5-12 on the Safety of Estrogens in Lupus Erythematosus National Assessment version of the SLE Disease Activity Index were randomized to 4 infusions of placebo or 10 mg/kg sirukumab every 2 weeks. We treated 31 CLE patients (23 with sirukumab, 8 with placebo) and 15 SLE patients (10 with sirukumab, 5 with placebo). Adverse events (AEs) occurred more often with sirukumab than placebo in CLE patients (91% versus 63%) and in SLE patients (90% versus 80%). Sirukumab led to sustained, dose-independent decreases in white blood cell counts, absolute neutrophil counts (neutropenia), and platelet counts (thrombocytopenia) and to minor elevations in total cholesterol levels. The majority of infections were mild respiratory infections. which were reported similarly across CLE cohorts but more often in sirukumab-treated than in placebo-treated SLE patients. Two serious AEs of infection occurred (pneumonia in the 10 mg/kg-treated group and iatrogenic wound infection in the 4 mg/kg-treated group). Sirukumab showed linear pharmacokinetics in CLE patients. Systemic exposure and half-life were comparable between CLE and SLE patients. No patient developed antibodies to sirukumab through 22 weeks. C-reactive protein and serum amyloid A mean concentrations were suppressed with sirukumab from week 1 to week 14. Treatment with intravenous sirukumab infusions was generally well tolerated in both CLE and SLE patients with mild, stable, active disease. Sirukumab demonstrated linear pharmacokinetics over the dose range studied and comparable systemic exposure and half-life in CLE and SLE patients.
Hydrochlorothiazide (HCTZ) is a thiazide diuretic used in adults and children for the treatment o... more Hydrochlorothiazide (HCTZ) is a thiazide diuretic used in adults and children for the treatment of hypertension and edema. The pharmacokinetic (PK) properties of HCTZ in children are not well characterized, particularly among children with obesity who frequently suffer from hypertension and may, therefore, benefit from HCTZ therapy. HCTZ is excreted in the kidney via organic anion transporters 1 and 3 (OAT1 and OAT3). The ontogeny of OAT1 and OAT3 remain unknown, but HCTZ clearance may serve as a surrogate marker of OAT1 and OAT3 maturation. Population PK modeling was performed in NONMEM, and the model was leveraged to conduct dose‐exposure simulations. This study examined 83 plasma samples from 49 participants (69% male) taking enteral HCTZ. The median (range) postnatal age was 6.7 years (0.03‐19.5 years), and 17 (34%) participants were obese or morbidly obese. The median (range) dose of HCTZ was 0.654 mg/kg (0.11‐1.8 kg) and the median number of doses recorded per participant was 5 (1‐8). HCTZ PK was well characterized by a 1‐compartment PK model. Body weight and a maturation model based on postmenstrual age were significant covariates for apparent clearance, but the presence of obesity was not. Dosing simulations were performed with a standardized 1mg/kg. Simulated exposure (area under the curve and maximum HCTZ concentrations) decreased with age and was likely due to older children receiving the maximum absolute doses of HCTZ. Further studies with more patients in each age group are required to confirm these PK findings of HCTZ in the children.
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Papers by felix boakye-agyeman