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Daily variation of NTBC and its relation to succinylacetone in tyrosinemia type 1 patients comparing a single dose to two doses a day.

ABSTRACT: INTRODUCTION:In hereditary tyrosinemia type 1 (HT1) patients, the dose of NTBC that leads to the absence of toxic metabolites such as succinylacetone (SA) is still unknown. Therefore, the aims of this study were to investigate the variation and concentrations of 2-(2-nitro-4-trifluormethyl-benzyl)-1,3-cyclohexanedione (NTBC) during the day in relation to the detection of SA, while comparing different dosing regimens. METHODS:All patients were treated with NTBC (mean 1.08 ± 0.34 mg/kg/day) and a low phenylalanine-tyrosine diet. Thirteen patients received a single dose of NTBC and five patients twice daily. Home bloodspots were collected four times daily for three consecutive days measuring NTBC and SA concentrations. Statistical analyses were performed by using mixed model analyses and generalized linear mixed model analyses to study variation and differences in NTBC concentrations and the correlation with SA, respectively. RESULTS:NTBC concentrations varied significantly during the day especially if NTBC was taken at breakfast only (p = 0.026), although no significant difference in NTBC concentrations between different dosing regimens could be found (p = 0.289). Momentary NTBC concentrations were negatively correlated with SA (p < 0.001). Quantitatively detectable SA was only found in subjects with once daily administration of NTBC and associated with momentary NTBC concentrations <44.3 ?mol/l. DISCUSSION:NTBC could be less stable than previously considered, thus dosing NTBC once daily and lower concentrations may be less adequate. Further research including more data is necessary to establish the optimal dosing of NTBC.

SUBMITTER: Kienstra NS

PROVIDER: S-EPMC5830494 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Daily variation of NTBC and its relation to succinylacetone in tyrosinemia type 1 patients comparing a single dose to two doses a day.

Kienstra Nienke S NS van Reemst Hannah E HE van Ginkel Willem G WG Daly Anne A van Dam Esther E MacDonald Anita A Burgerhof Johannes G M JGM de Blaauw Pim P McKiernan Patrick J PJ Heiner-Fokkema M Rebecca MR van Spronsen Francjan J FJ

Journal of inherited metabolic disease 20171123 2

<h4>Introduction</h4>In hereditary tyrosinemia type 1 (HT1) patients, the dose of NTBC that leads to the absence of toxic metabolites such as succinylacetone (SA) is still unknown. Therefore, the aims of this study were to investigate the variation and concentrations of 2-(2-nitro-4-trifluormethyl-benzyl)-1,3-cyclohexanedione (NTBC) during the day in relation to the detection of SA, while comparing different dosing regimens.<h4>Methods</h4>All patients were treated with NTBC (mean 1.08 ± 0.34 mg ...[more]

PMID: 29170874

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Project description:Tyrosinemia type I (TYR I) is caused by autosomal recessive fumarylacetoacetate hydrolase deficiency and is characterized by development of severe liver disease in infancy and neurologic crises. If left untreated, most patients die of liver failure in the first years of life. Intervention with medication is effective when initiated during the first month of life. This improvement in the treatment of TYR I patients influenced the decision to include TYR I in the US Secretary of the Department of Health and Human Services' (HHS) Recommended Uniform Screening Panel. However, while tyrosine is routinely measured in newborn screening (NBS) by tandem mass spectrometry (MS/MS), elevated tyrosine levels are not specific to TYR I. To improve the specificity of NBS for TYR I, several assays were developed to measure succinylacetone (SUAC) in dried blood spots (DBS). SUAC is a pathognomonic marker of TYR I, and its detection by NBS MS/MS is possible. This review of the current status of NBS for TYR I in the US is the result of discussions at the HHS Secretary's (Discretionary) Advisory Committee on Heritable Disorders in Newborns and Children about the inconsistent implementation of effective NBS for TYR I in the US. We sought to understand the different TYR I screening practices in US NBS programs. Results indicate that 50 out of 51 NBS programs in the US screen for TYR I, and a successful SUAC performance evaluation scheme is available from the Centers for Disease Control and Prevention. Programmatic and methodological barriers were identified that prevent widespread adoption of SUAC measurements in NBS laboratories. However, since SUAC detection is currently the best approach to NBS for TYR I, a further delay of the addition of SUAC measurement into NBS procedures is discouraged. SUAC measurement should improve both the false positive and false negative rate in NBS for TYR I thereby yielding the desired benefits for affected patients at no expense to the overall population served.

Project description:Strongyloidiasis, caused by an intestinal helminth Strongyloides stercoralis, is common throughout the tropics. It remains an important health problem due to autoinfection, which may result in hyperinfection and disseminated infection in immunosuppressed patients, especially patients receiving chemotherapy or corticosteroid treatment. Ivermectin and albendazole are effective against strongyloidiasis. However, the efficacy and the most effective dosing regimen are to be determined.A prospective, randomized, open study was conducted in which a 7-day course of oral albendazole 800 mg daily was compared with a single dose (200 microgram/kilogram body weight), or double doses, given 2 weeks apart, of ivermectin in Thai patients with chronic strongyloidiasis. Patients were followed-up with 2 weeks after initiation of treatment, then 1 month, 3 months, 6 months, 9 months, and 1 year after treatment. Combination of direct microscopic examination of fecal smear, formol-ether concentration method, and modified Koga agar plate culture were used to detect strongyloides larvae in two consecutive fecal samples in each follow-up visit. The primary endpoint was clearance of strongyloides larvae from feces after treatment and at one year follow-up.Ninety patients were included in the analysis (30, 31 and 29 patients in albendazole, single dose, and double doses ivermectin group, respectively). All except one patient in this study had at least one concomitant disease. Diabetes mellitus, systemic lupus erythrematosus, nephrotic syndrome, hematologic malignancy, solid tumor and human immunodeficiency virus infection were common concomitant diseases in these patients. The median (range) duration of follow-up were 19 (2-76) weeks in albendazole group, 39 (2-74) weeks in single dose ivermectin group, and 26 (2-74) weeks in double doses ivermectin group. Parasitological cure rate were 63.3%, 96.8% and 93.1% in albendazole, single dose oral ivermectin, and double doses of oral ivermectin respectively (P = 0.006) in modified intention to treat analysis. No serious adverse event associated with treatment was found in any of the groups.This study confirms that both a single, and a double dose of oral ivermectin taken two weeks apart, is more effective than a 7-day course of high dose albendazole for patients with chronic infection due to S. stercoralis. Double dose of ivermectin, taken two weeks apart, might be more effective than a single dose in patients with concomitant illness.ClinicalTrials.gov NCT00765024.

Project description:IntroductionMost smoking cessation approaches are modeled on heavy daily smoking. With increasing prevalence of nondaily smoking, it may be necessary to modify these approaches for nondaily smokers.AimsTo provide information about beliefs and attitudes relevant to smoking cessation for nondaily smokers.MethodsSecondary analysis of two prospective studies on young adult smokers (18-24 years of age) provided brief advice to quit smoking. Measures include baseline levels of constructs relevant to smoking cessation counseling and perceived benefits of and barriers to smoking cessation.ResultsParticipants (n = 40 nondaily, 122 daily smokers) were predominantly White (70% and 84%, respectively), gender-balanced (50% and 43% female), full-time college students (89% and 95%). At baseline, nondaily smokers reported lower levels of nicotine dependence (p < .001; nondaily: Fagerström Test for Nicotine Dependence (FTND) = 0.8 ± 1.5, daily: FTND = 3.1 ± 1.9), lower urge to smoke (p < .001), greater self-efficacy when facing external smoking stimuli (p = .03), expecting to experience fewer positive effects (reduced negative affect, p = <.001, stimulation, p = .02), and valuing the importance of smoking effects less (ps < .01) than daily smokers. During counseling, nondaily smokers generated both fewer benefits of cessation (Wald X2(df = 1) = 4.91, p = .027) and fewer barriers (Wald X2(df = 1) = 5.99, p =.014) than daily smokers. Withdrawal was not listed by nondaily smokers as a barrier (p < .01).ConclusionsConstructs relevant to smoking cessation for daily smokers were less salient to young nondaily smokers, compared with moderately addicted young daily smokers, as indicated by responses to standardized scales and by the generation of fewer benefits and barriers in counseling. Interventions may need to find novel ways to engage nondaily smokers, particularly young adult, in smoking cessation efforts.ImplicationsThis study is unique in eliciting benefits and barriers from nondaily smokers as they are about to make a quit attempt. This is a critically important point in time, as this is the point in time in which an action plan is formed and can be informed and enhanced by smoking cessation support. Our study further allowed direct comparison to daily smokers undergoing the same procedures, which allowed the identification of unique factors that may impact nondaily smokers in their quit attempt, which may guide intervention efforts. Use of a mixed method design further strengthen the rigor of this study.

Dataset Information

Daily variation of NTBC and its relation to succinylacetone in tyrosinemia type 1 patients comparing a single dose to two doses a day.

Publications

Daily variation of NTBC and its relation to succinylacetone in tyrosinemia type 1 patients comparing a single dose to two doses a day.

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