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1.
Clin Transl Sci ; 14(2): 656-663, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33278322

RESUMO

In previous work, participants with a G970R mutation in cystic fibrosis transmembrane conductance regulator (CFTR) (c.2908G>C) had numerically lower sweat chloride responses during ivacaftor treatment than participants with other CFTR gating mutations. The objective of this substudy was to characterize the molecular defect of the G970R mutation in vitro and assess the benefit of ivacaftor in participants with this mutation. This substudy assessed sweat chloride, spirometry findings, and nasal potential difference on and off ivacaftor treatment in three participants with a G970R/F508del genotype. Intestinal organoids derived from rectal biopsy specimens were used to assess ivacaftor response ex vivo and conduct messenger RNA splice and protein analyses. No consistent or meaningful trends were observed between on-treatment and off-treatment clinical assessments. Organoids did not respond to ivacaftor in forskolin-induced swelling assays; no mature CFTR protein was detected in Western blots. Organoid RNA analysis demonstrated that 3 novel splice variants were created by G970R-CFTR: exon 17 truncation, exons 13-15 and 17 skipping, and intron 17 retention. Functional and molecular analyses indicated that the c.2908G>C mutation caused a cryptic splicing defect. Organoids lacked an ex vivo response with ivacaftor and supported identification of the mechanism underlying the CFTR defect caused by c.2908G>C. Analysis of CFTR mutations indicated that cryptic splicing was a rare cause of mutation misclassification in engineered cell lines. This substudy used organoids as an alternative in vitro model for mutations, such as cryptic splice mutations that cannot be fully assessed using cDNA expressed in recombinant cell systems.


Assuntos
Aminofenóis/administração & dosagem , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/tratamento farmacológico , Quinolonas/administração & dosagem , Adolescente , Adulto , Aminofenóis/efeitos adversos , Biópsia , Linhagem Celular , Células Cultivadas , Criança , Fibrose Cística/genética , Fibrose Cística/patologia , Éxons/genética , Feminino , Humanos , Mucosa Intestinal/citologia , Mucosa Intestinal/patologia , Masculino , Mutação , Organoides , Medicina de Precisão/métodos , Cultura Primária de Células , Quinolonas/efeitos adversos , Splicing de RNA , Reto/citologia , Reto/patologia , Resultado do Tratamento , Adulto Jovem
2.
J Cyst Fibros ; 16(2): 267-274, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28132845

RESUMO

BACKGROUND: This pilot study evaluated the effect of short- and long-term ivacaftor treatment on hyperpolarized 3He-magnetic resonance imaging (MRI)-defined ventilation defects in patients with cystic fibrosis aged ≥12years with a G551D-CFTR mutation. METHODS: Part A (single-blind) comprised 4weeks of ivacaftor treatment; Part B (open-label) comprised 48weeks of treatment. The primary outcome was change from baseline in total ventilation defect (TVD; total defect volume:total lung volume ratio). RESULTS: Mean change in TVD ranged from -8.2% (p=0.0547) to -12.8% (p=0.0078) in Part A (n=8) and -6.3% (p=0.1953) to -9.0% (p=0.0547) in Part B (n=8) as assessed by human reader and computer algorithm, respectively. CONCLUSIONS: TVD responded to ivacaftor therapy. 3He-MRI provides an individual quantification of disease burden that may be able to detect aspects of the disease missed by population-based spirometry metrics. Assessments by human reader and computer algorithm exhibit similar trends, but the latter appears more sensitive. www.clinicaltrials.gov identifier: NCT01161537.


Assuntos
Aminofenóis/administração & dosagem , Fibrose Cística , Imageamento por Ressonância Magnética/métodos , Ventilação Pulmonar , Quinolonas/administração & dosagem , Adulto , Agonistas dos Canais de Cloreto/administração & dosagem , Fibrose Cística/diagnóstico , Fibrose Cística/tratamento farmacológico , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Esquema de Medicação , Monitoramento de Medicamentos/métodos , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Hélio/farmacologia , Humanos , Isótopos/farmacologia , Masculino , Pessoa de Meia-Idade , Mutação , Avaliação de Resultados em Cuidados de Saúde , Projetos Piloto , Ventilação Pulmonar/efeitos dos fármacos , Ventilação Pulmonar/fisiologia , Método Simples-Cego
3.
J Cyst Fibros ; 16(1): 41-44, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27773592

RESUMO

Ivacaftor, a CFTR potentiator that enhances chloride transport by acting directly on CFTR to increase its channel gating activity, has been evaluated in patients with different CFTR mutations. Several previous analyses have reported no statistical correlation between change from baseline in ppFEV1 and reduction in sweat chloride levels for individuals treated with ivacaftor. The objective of the post hoc analysis described here was to expand upon previous analyses and evaluate the correlation between sweat chloride levels and absolute ppFEV1 changes across multiple cohorts of patients with different CF-causing mutations who were treated with ivacaftor. The goal of the analysis was to help define the potential value of sweat chloride as a pharmacodynamic biomarker for use in CFTR modulator trials. For any given study, reductions in sweat chloride levels and improvements in absolute ppFEV1 were not correlated for individual patients. However, when the data from all studies were combined, a statistically significant correlation between sweat chloride levels and ppFEV1 changes was observed (p<0.0001). Thus, sweat chloride level changes in response to potentiation of the CFTR protein by ivacaftor appear to be a predictive pharmacodynamic biomarker of lung function changes on a population basis but are unsuitable for the prediction of treatment benefits for individuals.


Assuntos
Aminofenóis , Cloretos/análise , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Volume Expiratório Forçado/efeitos dos fármacos , Quinolonas , Suor/química , Aminofenóis/administração & dosagem , Aminofenóis/farmacocinética , Biomarcadores/análise , Agonistas dos Canais de Cloreto/administração & dosagem , Agonistas dos Canais de Cloreto/farmacocinética , Ensaios Clínicos como Assunto , Fibrose Cística/diagnóstico , Fibrose Cística/tratamento farmacológico , Fibrose Cística/genética , Humanos , Mutação , Valor Preditivo dos Testes , Quinolonas/administração & dosagem , Quinolonas/farmacocinética , Resultado do Tratamento
4.
Obesity (Silver Spring) ; 20(7): 1426-36, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22421927

RESUMO

The BLOOM-DM (Behavioral Modification and Lorcaserin for Obesity and Overweight Management in Diabetes Mellitus) study evaluated efficacy and safety of lorcaserin for weight loss in patients with type 2 diabetes. Secondary objectives included evaluations of glycemic control, lipids, blood pressure, and quality of life. This 1-year, randomized, placebo-controlled trial enrolled 604 patients 1:1:1 to placebo, lorcaserin 10 mg once daily (QD) or lorcaserin 10 mg twice daily (BID). Patients were treated with metformin, a sulfonylurea (SFU) or both; had glycated hemoglobin (HbA(1c)) 7-10%; were 18-65 years old; and had BMI 27-45 kg/m(2). Patients received diet and exercise counseling. Safety monitoring included serial echocardiograms. Mean (± SD) age was 52.7 ± 8.7; 54.2% were women; 60.5% were white, 20.9% were African American, and 13.8% were Hispanic. Mean (± SD) weight was 103.6 ± 17.8 kg; BMI was 36.0 ± 4.5 kg/m(2). Most patients (91.7%) took metformin; 50.2% took a SFU. More patients lost ≥5% body weight with lorcaserin BID (37.5%; P < 0.001) or lorcaserin QD (44.7%; P < 0.001) vs. placebo (16.1%; modified intent to treat (MITT)/last observation carried forward (LOCF)). Least square mean (± SEM) weight change was -4.5 ± 0.35% with lorcaserin BID and -5.0 ± 0.5% with lorcaserin QD vs. -1.5 ± 0.36% with placebo (P < 0.001 for each). HbA(1c) decreased 0.9 ± 0.06 with lorcaserin BID, 1.0 ± 0.09 with lorcaserin QD, and 0.4 ± 0.06 with placebo (P < 0.001 for each); fasting glucose decreased 27.4 ± 2.5 mg/dl, -28.4 ± 3.8 mg/dl, and 11.9 ± 2.5 mg/dl, respectively (P < 0.001 for each). Symptomatic hypoglycemia occurred in 7.4% of patients on lorcaserin BID, 10.5% on lorcaserin QD, and 6.3% on placebo. Common adverse events were headache, back pain, nasopharyngitis, and nausea. Lorcaserin was associated with significant weight loss and improvement in glycemic control in patients with type 2 diabetes.


Assuntos
Benzazepinas/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hemoglobinas Glicadas/metabolismo , Hipoglicemiantes/uso terapêutico , Obesidade/tratamento farmacológico , Receptor 5-HT2C de Serotonina/efeitos dos fármacos , Redução de Peso/efeitos dos fármacos , Adulto , Idoso , Fármacos Antiobesidade/uso terapêutico , Benzazepinas/farmacologia , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Índice de Massa Corporal , Aconselhamento , Diabetes Mellitus Tipo 2/sangue , Método Duplo-Cego , Ecocardiografia , Feminino , Hemoglobinas Glicadas/efeitos dos fármacos , Humanos , Hipoglicemiantes/farmacologia , Masculino , Pessoa de Meia-Idade , Obesidade/sangue , Qualidade de Vida , Comportamento de Redução do Risco
5.
J Clin Endocrinol Metab ; 96(10): 3067-77, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21795446

RESUMO

CONTEXT: Lorcaserin is a novel selective agonist of the serotonin 2C receptor. OBJECTIVE: Our objective was to evaluate the effects of lorcaserin on body weight, cardiovascular risk factors, and safety in obese and overweight patients. DESIGN AND SETTING: This randomized, placebo-controlled, double-blind, parallel arm trial took place at 97 U.S. research centers. PATIENTS: Patients included 4008 patients, aged 18-65 yr, with a body mass index between 30 and 45 kg/m(2) or between 27 and 29.9 kg/m(2) with an obesity-related comorbid condition. INTERVENTIONS: Patients were randomly assigned in a 2:1:2 ratio to receive lorcaserin 10 mg twice daily (BID), lorcaserin 10 mg once daily (QD), or placebo. All patients received diet and exercise counseling. MAIN OUTCOME MEASURES: The ordered primary endpoints were proportion of patients achieving at least 5% reduction in body weight, mean change in body weight, and proportion of patients achieving at least 10% reduction in body weight at 1 yr. Serial echocardiograms monitored heart valve function. RESULTS: Significantly more patients treated with lorcaserin 10 mg BID and QD lost at least 5% of baseline body weight (47.2 and 40.2%, respectively) as compared with placebo (25.0%, P < 0.001 vs. lorcaserin BID). Least squares mean (95% confidence interval) weight loss with lorcaserin BID and QD was 5.8% (5.5-6.2%) and 4.7% (4.3-5.2%), respectively, compared with 2.8% (2.5-3.2%) with placebo (P < 0.001 vs. lorcaserin BID; least squares mean difference, 3.0%). Weight loss of at least 10% was achieved by 22.6 and 17.4% of patients receiving lorcaserin 10 mg BID and QD, respectively, and 9.7% of patients in the placebo group (P < 0.001 vs. lorcaserin BID). Headache, nausea, and dizziness were the most common lorcaserin-related adverse events. U.S. Food and Drug Administration-defined echocardiographic valvulopathy occurred in 2.0% of patients on placebo and 2.0% on lorcaserin 10 mg BID. CONCLUSIONS: Lorcaserin administered in conjunction with a lifestyle modification program was associated with dose-dependent weight loss that was significantly greater than with placebo.


Assuntos
Fármacos Antiobesidade/uso terapêutico , Benzazepinas/uso terapêutico , Obesidade/tratamento farmacológico , Sobrepeso/tratamento farmacológico , Agonistas do Receptor 5-HT2 de Serotonina/uso terapêutico , Redução de Peso/efeitos dos fármacos , Absorciometria de Fóton , Adolescente , Adulto , Idoso , Fármacos Antiobesidade/efeitos adversos , Benzazepinas/efeitos adversos , Índice de Massa Corporal , Doenças Cardiovasculares/epidemiologia , Método Duplo-Cego , Ecocardiografia , Feminino , Humanos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Sobrepeso/complicações , Receptor 5-HT2C de Serotonina/efeitos dos fármacos , Fatores de Risco , Tamanho da Amostra , Agonistas do Receptor 5-HT2 de Serotonina/efeitos adversos , Adulto Jovem
6.
Br J Clin Pharmacol ; 70(3): 376-82, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20716238

RESUMO

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Cysteamine bitartrate is taken lifelong, every 6 h and for the treatment of cystinosis. Recent studies using cysteamine for for other diseases such as neurodegenerative disorders adopt the same dosing regimen for cysteamine. Regular cysteamine bitartrate (Cystagon) may cause upper gastrointestinal symptoms in some patients. WHAT THIS STUDY ADDS: This is the only study that provides pharmacokinetic data for cysteamine delivered in an enteric-release preparation in normal subjects. EC-cysteamine is very well tolerated and does not cause increased gastrin concentrations, even at relatively high doses. EC-cysteamine at the higher dose results in better drug uptake as measured by Cmax and AUC and is more likely to be effective. AIMS: Cysteamine bitartrate (Cystagon) is the approved treatment for cystinosis. Poor compliance and patient outcome may occur because the drug needs to be taken every 6 h and in some patients causes gastrointestinal symptoms due to hypergastrinaemia. A formulation of cysteamine requiring twice daily ingestion would improve the quality of life for these patients. This study compares the pharmacokinetics and gastrin production following cysteamine bitartrate non-enteric-coated and cysteamine bitartrate enteric-coated in normal healthy subjects. METHODS: Enteric-coated cysteamine was prepared. Following single doses of cysteamine bitartrate non-enteric-coated 450 mg and cysteamine bitartrate enteric-coated 450 mg and 900 mg, serial plasma cysteamine and gastrin concentrations were measured. Two subjects also received cysteamine bitartrate non-enteric-coated 900 mg. Gastrointestinal (GI) symptoms were recorded. RESULTS: Six healthy adults (mean age 20.7 years, range 18-24 years; mean weight 59.3 kg) received drug. All post-dose gastrin concentrations were within the normal range (<100 pg ml(-1)). The tmax following cysteamine bitartrate non-enteric-coated (mean and SD is 75+/-19 min) was shorter than cysteamine bitartrate enteric-coated (220+/-74 min) (P=0.001), but only the Cmax and AUC estimates following 900 mg cysteamine bitartrate enteric-coated were significantly greater than any of the other preparations or doses (P<0.05). One patient had GI symptoms following both 900 mg cysteamine bitartrate non-enteric-coated and cysteamine bitartrate enteric-coated. CONCLUSION: Although patient numbers were low, single high doses of cysteamine bitartrate enteric-coated were better tolerated than similar doses of cysteamine bitartrate non-enteric-coated in the healthy subjects and all had normal gastrin concentrations. The delayed tmax following cysteamine bitartrate enteric-coated suggested that the cysteamine was released enterically.


Assuntos
Cisteamina/administração & dosagem , Cistinose/tratamento farmacológico , Gastrinas/sangue , Protetores contra Radiação/administração & dosagem , Adolescente , Área Sob a Curva , Cisteamina/farmacocinética , Feminino , Humanos , Absorção Intestinal/fisiologia , Masculino , Protetores contra Radiação/farmacocinética , Comprimidos com Revestimento Entérico , Adulto Jovem
7.
J Pediatr ; 156(5): 823-7, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20138296

RESUMO

OBJECTIVE: Cystinosis causes renal and other organ failure. Treatment with 6-hourly cysteamine bitartrate (Cystagon, Mylan, Morgantown, West Virginia) reduces intracellular cystine and the rate of organ deterioration. A recent study showed that an enteric-release cysteamine required less frequent daily dosing. This report describes the long-term use of enteric-coated (EC) cysteamine bitartrate (Cystagon) in children with cystinosis. STUDY DESIGN: After a pharmacokinetic and pharmacodynamic study of EC-cysteamine in children with cystinosis, 5 patients remained on twice-daily treatment. White blood cell cystine levels were measured 12 hours after ingestion every 4 to 8 weeks. These levels were then compared with the patient's previous 6-h post-dose levels taken while on regular cysteamine bitartrate before entering the study. Blood chemistry was also measured. RESULTS: Five children with cystinosis (mean age, 9 years; range, 8 to 17 years) who previously took cysteamine bitartrate (mean dose, 47 mg/kg body wt), received EC-cysteamine for 10 to 27 months (mean dose, 25 mg/kg body wt) and had mean white blood cell cystine levels of 0.77 and 0.71 nmol half-cystine/mg protein, respectively. During the study period, patients maintained adequate growth and there was no significant deterioration in renal or thyroid function. Two children were required to restart acid suppression after 6 months on EC-cysteamine therapy. CONCLUSIONS: Long-term, twice-daily EC-cysteamine, given at approximately 60% of the previous daily dose of cysteamine bitartrate, was effective at maintaining white blood cell cystine levels within a satisfactory range. There was no significant deterioration in renal or thyroid function.


Assuntos
Cisteamina/administração & dosagem , Cistinose/tratamento farmacológico , Adolescente , Criança , Creatinina/sangue , Cistina/sangue , Cistinose/sangue , Esquema de Medicação , Feminino , Humanos , Leucócitos/metabolismo , Masculino , Comprimidos com Revestimento Entérico
8.
J Pediatr ; 156(1): 71-75.e1-3, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19775699

RESUMO

OBJECTIVE: Cystinosis causes renal and other organ failure. Regular 6-hourly cysteamine bitartrate (Cystagon; Mylan, Morgantown, West Virginia) reduces intracellular cystine and the rate of organ deterioration. A formulation of cysteamine requiring less frequent dosing may improve compliance and possibly patient outcome. METHODS: Enteric-release cysteamine was prepared. For a period of 1 month, patients received their regular cysteamine dose every 6 hours (stage I). The patients then underwent pharmacokinetic and pharmacodynamic studies following washout periods using single-doses of cysteamine and enteric-release cysteamine (stage II). Finally, the patients commenced regular enteric-release cysteamine therapy (stage III). Weekly trough white blood cell (WBC) cystine levels were recorded. RESULTS: Seven children with cystinosis (mean age, 11.8 years; range, 8-17 years) who received cysteamine and enteric-release cysteamine (mean dose, 45 and 28.8 mg/kg body weight/day, respectively) had mean WBC cystine levels of 0.7+/-0.3 and 0.41+/-0.22 nmol half-cystine/mg protein in study stages I and III, respectively. Study stage II showed that the mean time (T(max)) to reach the maximum plasma cysteamine level (C(max)) was longer for enteric-release cysteamine than for cysteamine (176 minutes vs 60 minutes; P=.001), but the mean C(max) at the same dose was similar. Mean serum gastrin levels were similar after ingestion of cysteamine and enteric-release cysteamine. CONCLUSIONS: Twelve-hour enteric-release cysteamine, given at approximately 60% of the previous daily dose of cysteamine, was effective in maintaining trough WBC cystine levels within a satisfactory range.


Assuntos
Cisteamina/administração & dosagem , Cistinose/tratamento farmacológico , Protetores contra Radiação/administração & dosagem , Adolescente , Criança , Cisteamina/sangue , Preparações de Ação Retardada , Feminino , Gastrinas/sangue , Humanos , Leucócitos/química
9.
PLoS One ; 4(11): e7714, 2009 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-19888320

RESUMO

Pediatric Crohn's disease is a chronic auto inflammatory bowel disorder affecting children under the age of 17 years. A putative etiopathogenesis of Crohn's disease (CD) is associated with disregulation of immune response to antigens commonly present in the gut microenvironment. Heat shock proteins (HSP) have been identified as ubiquitous antigens with the ability to modulate inflammatory responses associated with several autoimmune diseases. The present study tested the contribution of immune responses to HSP in the amplification of autoimmune inflammation in chronically inflamed mucosa of pediatric CD patients. Colonic biopsies obtained from normal and CD mucosa were stimulated with pairs of Pan HLA-DR binder HSP60-derived peptides (human/bacterial homologues). The modulation of RNA and protein levels of induced proinflammatory cytokines were measured. We identified two epitopes capable of sustaining proinflammatory responses, specifically TNF< and IFN induction, in the inflamed intestinal mucosa in CD patients. The responses correlated positively with clinical and histological measurements of disease activity, thus suggesting a contribution of immune responses to HSP in pediatric CD site-specific mucosal inflammation.


Assuntos
Autoimunidade , Doença de Crohn/imunologia , Epitopos de Linfócito T/química , Proteínas de Choque Térmico/metabolismo , Inflamação , Adolescente , Chaperonina 60/química , Criança , Pré-Escolar , Citocinas/metabolismo , Feminino , Humanos , Masculino , Fenótipo
11.
Br J Clin Pharmacol ; 63(1): 36-40, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17229040

RESUMO

AIMS: Although cysteamine was first used in the treatment of cystinosis in 1976 and approved by the FDA as cysteamine bitartrate (Cystagon) in 1994, surprisingly little pharmacological data are available for this compound. Cysteamine and its related drugs are currently being evaluated for the treatment of Huntington's and Parkinson's disease. The aim of te study was to understand the pharmacokinetics of cysteamine bitartrate following gastrointestinal infusion. METHOD: Cysteamine bitartrate was delivered through a naso-enteric catheter into the stomach (n = 8), small intestine (n = 8) and caecum (n = 4) of normal subjects. Plasma cysteamine concentrations were determined using LC-MS/MS. RESULTS: The rate and extent of drug absorption were assessed by comparing AUC(0, infinity), C(max) and t(max), among the gastrointestinal infusion sites. Total cysteamine exposure, expressed as area under the curve (AUC(0, infinity)) was greatest when the drug was infused into the small intestine (4331.3 +/- 1907.6 min x microM) followed by stomach (3901.9 +/- 1591.9 min x microM) and caecum (3141.4 +/- 1627.6 min x microM). Cysteamine infusion into the small intestine resulted in the most rapid rise to maximal plasma concentrations (t(max) = 21 +/- 0.56 min); t(max) was delayed to 50 +/- 26 min and 64 +/- 26 min after gastric and caecal infusion, respectively. The maximum cysteamine plasma concentration (C(max)) was reached after infusion of the drug into the small intestine (51 +/- 21 microM), which was higher than plasma C(max) concentrations after gastric (39 +/- 16 microM) and caecal infusion (23 +/- 15 microM). CONCLUSIONS: The pharmacokinetic data generated help extend our understanding of cysteamine.


Assuntos
Cisteamina/administração & dosagem , Cistinose/tratamento farmacológico , Nootrópicos/administração & dosagem , Adulto , Área Sob a Curva , Cisteamina/farmacocinética , Cistinose/metabolismo , Feminino , Humanos , Absorção Intestinal/fisiologia , Masculino , Nootrópicos/farmacocinética , Estudos Prospectivos
12.
J Pediatr ; 148(6): 764-9, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16769383

RESUMO

OBJECTIVES: To test the hypothesis that a controlled-release preparation of cysteamine, with fewer daily administrations, would improve the quality of life for patients with cystinosis. STUDY DESIGN: A specifically designed nasoenteric tube was used to administer cysteamine directly into the stomach, small intestine (SI) and colon and serial plasma cysteamine, serum gastrin and leukocyte cystine levels were measured. RESULTS: Eight control subjects (mean age 23.2 years) and 6 subjects with cystinosis (mean age 15.2 years) were studied. Cysteamine absorption (maximum concentration and area under the curve of the concentration-time gradient) was greater from the SI than stomach or cecum (P < .01). Leukocyte cystine depletion was greater after delivery of cysteamine into the SI than stomach or cecum; this effect was associated with the plasma cysteamine maximum concentration and area under the curve (P < .001 and < .02, respectively). Gastrin levels were not affected by site of drug delivery and were elevated only in patients with cystinosis with gastrointestinal symptoms. CONCLUSIONS: The absorption of cysteamine and the effect of this agent on leukocyte cystine depletion are more profound after SI administration. Enteric-coated cysteamine, targeted for SI release, may require fewer daily dosages. Not all patients with cystinosis require acid-suppression therapy.


Assuntos
Cisteamina/administração & dosagem , Cistinose/tratamento farmacológico , Adolescente , Adulto , Área Sob a Curva , Cisteamina/sangue , Cisteamina/farmacocinética , Cistina/análise , Cistinose/metabolismo , Preparações de Ação Retardada , Feminino , Gastrinas/sangue , Humanos , Absorção Intestinal/fisiologia , Leucócitos/química , Masculino , Qualidade de Vida
13.
Pediatr Nephrol ; 20(12): 1786-93, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16133039

RESUMO

Oral cysteamine therapy prevents natural disease progression in children with cystinosis, but it may cause severe gastrointestinal (GI) symptoms through gastric acid-hypersecretion. The purpose of this study was to assess the value of esomeprazole in controlling cysteamine-induced acid-hypersecretion and GI symptoms in children with cystinosis. Subjects underwent upper GI endoscopy and biopsy, serum gastrin and cysteamine measurements as well as acid secretion studies (basal, maximal and peak acid output, BAO, MAO, PAO) before and during esomeprazole therapy. A symptom score (maximum 14 points) was devised to monitor symptoms. Twelve children (mean age 5.8 years) were studied. Cysteamine ingestion resulted in mean MAO and PAO significantly higher than mean BAO, both before and during esomeprazole therapy. PAO was usually within 60 min of cysteamine ingestion. Esomeprazole therapy significantly reduced MAO (P<0.01) and PAO (P<0.01). The mean symptom score fell from 6.4 to 0.7 (P<0.0001) during esomeprazole therapy. The mean final dose of esomeprazole was 1.7 mg/kg per day (range 0.7 mg/kg per day to 2.75 mg/kg per day). Plasma cysteamine levels were not affected by acid-suppression therapy. One child had multi-nucleated parietal cells. Cysteamine-induced gastric acid-hypersecretion and GI symptoms are dramatically reduced with esomeprazole therapy. Esomeprazole does not alter cysteamine absorption and is very well tolerated in children.


Assuntos
Cistinose/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Esomeprazol/uso terapêutico , Ácido Gástrico/metabolismo , Gastroenteropatias/fisiopatologia , Criança , Pré-Escolar , Cisteamina/efeitos adversos , Cisteamina/sangue , Inibidores Enzimáticos/efeitos adversos , Esomeprazol/efeitos adversos , Feminino , Gastrinas/sangue , Gastroenteropatias/induzido quimicamente , Gastroenteropatias/tratamento farmacológico , Gastroscopia , Humanos , Mucosa Intestinal/patologia , Masculino , Estudos Retrospectivos , Índice de Gravidade de Doença
14.
Int J Vitam Nutr Res ; 74(4): 294-300, 2004 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15580812

RESUMO

The effects of added ascorbic acid and particle size on iron absorption from ferric pyrophosphate were evaluated in adult women (9-10 women/study) based on erythrocyte incorporation of iron stable isotopes (57Fe or 58Fe) 14 days after administration. Three separate studies were made with test meals of iron-fortified infant cereal (5 mg iron/meal) and the results are presented as geometric means and relative bioavailability values (RBV, FeSO4 = 100%). The results of study 1 showed that iron absorption was significantly lower from ferric pyrophosphate (mean particle size 8.5 microm) than from FeSO4 in meals without ascorbic acid (0.9 vs. 2.6%, p < 0.0001, RBV 36%) and in the same meals with ascorbic acid added at a 4:1 molar ratio relative to fortification iron (2.3 vs. 9.7%, p < 0.0001, RBV 23%). Ascorbic acid increased iron absorption from ferric pyrophosphate slightly less (2.6-fold) than from FeSO4 (3.7-fold) (p < 0.05). In studies 2 and 3, RBV of ferric pyrophosphate with an average particle size of 6.7 microm and 12.5 pm was not significantly different at 52 and 42% (p > 0.05), respectively. In conclusion, the addition of ascorbic acid increased fractional iron absorption from ferric pyrophosphate significantly, but to a lesser extent than from FeSO4. Decreasing the mean particle size to 6.7 microm did not significantly increase iron absorption from ferric pyrophosphate.


Assuntos
Ácido Ascórbico/administração & dosagem , Difosfatos/farmacocinética , Ferro da Dieta/farmacocinética , Ferro/farmacocinética , Adulto , Disponibilidade Biológica , Difosfatos/química , Eritrócitos/metabolismo , Feminino , Compostos Ferrosos/administração & dosagem , Compostos Ferrosos/farmacocinética , Humanos , Ferro/química , Isótopos de Ferro/sangue , Ferro da Dieta/administração & dosagem , Tamanho da Partícula , Fatores de Tempo
16.
Br J Nutr ; 91(1): 107-12, 2004 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-14748943

RESUMO

Ferric pyrophosphate is a water-insoluble Fe compound used to fortify infant cereals and chocolate-drink powders as it causes no organoleptic changes to the food vehicle. However, it is only of low absorption in man. Recently, an innovative ferric pyrophosphate has been developed (Sunactive Fe trade mark ) based on small-particle-size ferric pyrophosphate (average size 0.3 microm) mixed with emulsifiers, so that it remains in suspension in liquid products. The aim of the present studies was to compare Fe absorption of micronised, dispersible ferric pyrophosphate (Sunactive Fe trade mark ) with that of ferrous sulfate in an infant cereal and a yoghurt drink. Two separate Fe absorption studies were made in adult women (ten women/study). Fe absorption was based on the erythrocyte incorporation of stable isotopes ((57)Fe and (58)Fe) 14 d after the intake of labelled test meals of infant cereal (study 1) or yoghurt drink (study 2). Each test meal was fortified with 5 mg Fe as ferrous sulfate or micronised, dispersible ferric pyrophosphate. Results are presented as geometric means. There was no statistically significant difference between Fe absorption from micronised, dispersible ferric pyrophosphate- and ferrous sulfate-fortified infant cereal (3.4 and 4.1 % respectively; P=0.24) and yoghurt drink (3.9 and 4.2 % respectively; P=0.72). The results of the present studies show that micronised, dispersible ferric pyrophosphate is as well absorbed as ferrous sulfate in adults. The high relative Fe bioavailability of micronised, dispersible ferric pyrophosphate indicates the potential usefulness of this compound for food fortification.


Assuntos
Difosfatos/farmacocinética , Grão Comestível , Alimentos Fortificados , Ferro da Dieta/farmacocinética , Ferro/farmacocinética , Iogurte , Absorção , Adulto , Bebidas , Disponibilidade Biológica , Eritrócitos/metabolismo , Feminino , Compostos Ferrosos/metabolismo , Humanos , Isótopos de Ferro
17.
Am J Clin Nutr ; 79(1): 99-102, 2004 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-14684404

RESUMO

BACKGROUND: Erythorbic acid, a stereoisomer of ascorbic acid with similar physicochemical properties, is widely used as an antioxidant in processed foods. OBJECTIVES: The aims of the present study were to evaluate the effect of erythorbic acid on iron absorption from ferrous sulfate at molar ratios of 2:1 and 4:1 (relative to iron) and to compare the effect of erythorbic acid directly with that of ascorbic acid at a molar ratio of 4:1. DESIGN: Iron absorption from iron-fortified cereal was measured in 10 women on the basis of erythrocyte incorporation of stable iron isotopes ((57)Fe or (58)Fe) 14 d after administration. Each woman consumed 4 ferrous-sulfate-fortified test meals (containing 5 mg Fe/meal) with or without added erythorbic or ascorbic acid. The data were evaluated by use of paired t tests, and the results are presented as geometric means. RESULTS: Iron absorption from the test meal without any added enhancer was 4.1%. The addition of erythorbic acid (at molar ratios of 2:1 and 4:1 relative to iron) increased iron absorption 2.6-fold (10.8%; P < 0.0001) and 4.6-fold (18.8%; P < 0.0001), respectively. The addition of ascorbic acid (molar ratio of 4:1) increased iron absorption 2.9-fold (11.7%; P = 0.0004). At a molar ratio of 4:1, erythorbic acid was 1.6-fold (P = 0.0002) as potent an enhancer of iron absorption as was ascorbic acid. CONCLUSION: Although erythorbic acid is a potent enhancer of iron absorption, its lack of antiscorbutic activity limits its usefulness in iron-fortification programs. However, it may play a major role in enhancing iron bioavailability from mixed diets that include foods preserved with erythorbic acid.


Assuntos
Ácido Ascórbico/farmacologia , Absorção Intestinal/efeitos dos fármacos , Ferro/farmacocinética , Adulto , Grão Comestível , Feminino , Alimentos Fortificados , Humanos , Ferro/sangue , Estereoisomerismo
18.
Br J Nutr ; 90(6): 1081-5, 2003 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-14641967

RESUMO

Ascorbic acid and Na2EDTA enhance Fe absorption from the water-soluble Fe compound FeSO4 but their effect on poorly water-soluble Fe compounds such as ferrous fumarate is less well established. In the present study, the effects of ascorbic acid and Na2EDTA on Fe absorption from ferrous fumarate were evaluated in adult women (ten women/study) from the erythrocyte incorporation of Fe stable isotopes ((57)Fe or (58)Fe) 14 d after administration. Two separate studies were made with test meals of Fe-fortified infant cereal (5 mg Fe/meal). Data were evaluated by paired t tests and the results are presented as geometric means. In study 1a, the comparison between Fe absorption from ferrous fumarate- and FeSO4-fortified cereal showed that adult women absorb Fe as well from ferrous fumarate as from FeSO4 (3.0 and 3.1 % respectively, P=0.85). After addition of Na2EDTA (Na2EDTA:fortification Fe molar ratio of 1:1), Fe absorption from FeSO4 was significantly higher than from ferrous fumarate (5.3 v. 3.3 % respectively, P<0.01; study 1b). In study 2, Fe absorption was compared from ferrous fumarate-fortified meals with and without ascorbic acid added at a 4:1 molar ratio (relative to fortification Fe) and the results showed that ascorbic acid increased Fe absorption from ferrous fumarate significantly (6.3 v. 10.4 %, P=0.02). The results of the present studies show that Fe absorption from ferrous fumarate is enhanced by ascorbic acid but not by Na2EDTA, thus emphasising that not all findings from Fe absorption studies made with FeSO4 can be extrapolated to Fe compounds with different solubility properties.


Assuntos
Ácido Ascórbico/farmacologia , Ácido Edético/farmacologia , Compostos Ferrosos/farmacocinética , Alimentos Fortificados , Ferro da Dieta/farmacocinética , Adulto , Feminino , Aditivos Alimentares/farmacologia , Humanos , Absorção Intestinal/efeitos dos fármacos , Isótopos de Ferro
19.
Am J Clin Nutr ; 78(2): 274-8, 2003 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12885708

RESUMO

BACKGROUND: Fish sauce and soy sauce have been suggested as food vehicles for iron fortification in Asia. NaFeEDTA is a potentially useful fortificant because it can be added to these condiments without causing precipitation during storage. OBJECTIVES: The objectives were to evaluate iron absorption from NaFeEDTA-fortified fish sauce and soy sauce against a reference fortificant (FeSO(4)), to compare iron absorption from NaFeEDTA-fortified fish sauce and soy sauce, and to evaluate the influence of fish sauce and soy sauce per se on iron absorption. DESIGN: Five separate iron-absorption studies were made in adult women (10 women per study). Iron absorption was measured on the basis of erythrocyte incorporation of (57)Fe or (58)Fe 14 d after the intake of labeled meals of rice or rice and vegetables. Fish sauce or soy sauce (10 g) fortified with 5 mg Fe as NaFeEDTA or FeSO(4) was fed with selected meals. The results are presented as geometric means. RESULTS: Iron absorption from NaFeEDTA- and FeSO(4)-fortified fish sauce (3.3% and 3.1%, respectively) and soy sauce (6.1% and 5.6%, respectively) was not significantly different. No significant difference was observed when NaFeEDTA-fortified fish sauce and soy sauce were compared directly (6.7% and 7.9%, respectively). Soy sauce inhibited iron absorption from rice-based meals (8.5% without and 6.0% with soy sauce; P < 0.02), whereas fish sauce did not affect iron absorption significantly. CONCLUSION: The relatively high iron absorption from NaFeEDTA-fortified fish sauce and soy sauce and the acceptable organoleptic properties of NaFeEDTA indicate the potential usefulness of this iron fortificant in fish sauce and soy sauce fortification programs.


Assuntos
Anemia Ferropriva/tratamento farmacológico , Dieta , Ácido Edético/uso terapêutico , Compostos Férricos/uso terapêutico , Óleos de Peixe/uso terapêutico , Ferro da Dieta/farmacocinética , Adulto , Anemia Ferropriva/metabolismo , Disponibilidade Biológica , Desferroxamina , Feminino , Ferritinas/metabolismo , Alimentos Fortificados , Humanos , Absorção Intestinal , Isótopos de Ferro , Ferro da Dieta/administração & dosagem , Estado Nutricional , Ácido Fítico , Glycine max
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