Sex Differences in Drug Disposition

Physiological, hormonal, and genetic differences between males and females affect the prevalence, incidence, and severity of diseases and responses to therapy. Understanding these differences is important for designing safe and effective treatments. This paper summarizes sex differences that impact drug disposition and includes a general comparison of clinical pharmacology as it applies to men and women

Full breastfeeding and paediatric cancer

Aim: It has been suggested that there is an inverse association between breastfeeding and the risk of childhood cancer. We investigated the association between full breastfeeding and paediatric cancer (PC) in a case control study in Spain. Methods: Maternal reports of full breastfeeding, collected through personal interviews using the Paediatric Environmental History, were compared among 187 children 6 months of age or older who had PC and 187 age-matched control siblings. Results: The mean duration of full breastfeeding for cases were 8.43 and 11.25 weeks for controls. Cases had been significantly more often bottle-fed than controls (odds ratio (OR) 1.8; 95% confidence interval (CI) 1.1-2.8). Cases were significantly less breastfed for at least 2 months (OR 0.5; 95% CI 0.3-0.8), for at least 4 months (OR 0.5; 95% CI 0.3-0.8), and for 24 weeks or more (OR 0.5; 95% CI 0.2-0.9). Conclusions: Breastfeeding was inversely associated with PC, the protection increasing with the duration of full breastfeeding. Additional research on possible mechanisms of this association may be warranted. Meanwhile, breastfeeding should be encouraged among mothers

The interactions of age, genetics, and disease severity on tacrolimus dosing requirements after pediatric kidney and liver transplantation

Purpose: In children, data on the combined impact of age, genotype, and disease severity on tacrolimus (TAC) disposition are scarce. The aim of this study was to evaluate the effect of these covariates on tacrolimus dose requirements in the immediate post-transplant period in pediatric kidney and liver recipients. Methods: Data were retrospectively collected describing tacrolimus disposition, age, CYP3A5 and ABCB1 genotype, and pediatric risk of mortality (PRISM) scores for up to 14 days post-transplant in children receiving liver and renal transplants. Initial TAC dosing was equal in all patients and adjusted using therapeutic drug monitoring. We determined the relationship between covariates and tacrolimus disposition. Results: Forty-eight kidney and 42 liver transplant recipients (median ages 11.5 and 1.5 years, ranges 1.5-17.7 and 0.05-14.8 years, respectively) received TAC post-transplant. In both transplant groups, younger children (<5 years) needed higher TAC doses than older children [kidney: 0.15 (0.07-0.35) vs. 0.09 (0.02-0.20) mg/kg/12h, p = 0.046, liver: 0.12 (0.04-0.32) vs. 0.09 (0.01-0.18) mg/kg/12h, p

Hypothyroxinemia and pregnancy

El pdf del artículo es el manuscrito de autor.[Objective]: To evaluate the peer-reviewed literature on iodine deficiency and hypothyroxinemia in pregnancy. [Methods]: We review published studies on isolated hypothyroxinemia in pregnancy, methodology of free thyroxine (T 4) assays, impact of iodine deficiency on free T4 levels, and status of ongoing prospective randomized trials of isolated hypothyroxinemia during pregnancy. [Results]: Hypothyroxinemia during pregnancy is common. Studies have demonstrated the pivotal role exerted by maternal T4 on fetal brain development and the negative impact of hypothyroxinemia on neurobehavioral performance in offspring. Two intervention studies have demonstrated a positive effect on neurodevelopment in children of mothers promptly supplemented with iodine compared with the neurodevelopment in children of nonsupplemented mothers. Free T4 assays presently in clinical use have limitations. Preliminary results of the Controlled Antenatal Thyroid Study (CATS) are somewhat mixed, and the National Institutes of Health Maternal Fetal Medicine Thyrotropin Study (TSH Study) will be completed in 2015. Knowledge regarding the impact of isolated hypothyroxinemia has progressed, but major questions remain. An optimal diagnostic test for free T4 during pregnancy (accurate, inexpensive, and widely available) remains elusive. Trimester-specific normative data and normal ranges from different geographic regions do not exist. [Conclusions]: Data published to date are insufficient to recommend levothyroxine therapy in pregnant women with isolated hypothyroxinemia. Adequate iodine intake should be recommended before conception and early in pregnancy. © 2011 AACE.Peer Reviewe

The Use of TSH in Determining Thyroid Disease: How Does It Impact the Practice of Medicine in Pregnancy?

During the last four decades, there have been considerable advances in the efficacy and precision of serum thyroid function testing. The development of the third generation assays for the measurement of serum thyroid stimulating hormone (TSH, thyrotropin) and the log-linear relationship with free thyroxine (T4) established TSH as the hallmark of thyroid function testing. While it is widely accepted that TSH outside of the normal range is consistent with thyroid dysfunction, a vast multitude of additional factors must be considered before an accurate clinical diagnosis can be made. This is especially important during pregnancy, when the thyroid is under considerable additional pregnancy-related demands requiring significant maternal physiological changes. This paper examines serum TSH measurement in pregnancy and some associated potential confounding factors

IMMULITE (R) 2000 age and sex-specific reference intervals for alpha fetoprotein, homocysteine, insulin, insulin-like growth factor-1, insulin-like growth factor binding protein-3, C-peptide, immunoglobulin E and intact parathyroid hormone

OBJECTIVES: To determine age and sex-specific pediatric reference intervals for serum alpha fetoprotein, homocysteine, insulin, insulin-like growth factor-I, insulin-like growth factor binding protein-3, C-peptide, immunoglobulin E and parathyroid hormone. DESIGN AND METHODS: The study was conducted at both Children’s National Medical Center and Georgetown University, Washington D.C. Results for the above analytes were obtained from the Children’s National Medical Center laboratory information system over the period of 1/5/2001–3/8/2007.Patient results using the IMMULITE 2000® were accessed and used to establish reference intervals for the analytes studied. All patient identifiers were removed except age and sex. Analysis of the data was performed at Georgetown University in the Bioanalytical Core Laboratory. The data was analyzed using the Hoffmann approach, and was computer adapted. The number of patient samples studied varied with each analyte and were: Alpha fetoprotein (557), homocysteine (924), insulin-like growth factor-1 (1352), insulin-like growth factor binding protein-3 (711), insulin (3239), C-peptide (267), immunoglobulin E (2691) and parathyroid hormone (513). RESULTS AND CONCLUSIONS: This study provides pediatric reference intervals for the eight analytes for children from birth to 18 years of age. All the analytes exhibited at least some age dependence. Sex differences between early and late childhood and adolescence were also frequently found

Tandem mass spectrometry improves the accuracy of free thyroxine measurements during pregnancy

OBJECTIVE: Pregnancy is a time of rapidly changing demands on the thyroid axis, and knowledge of thyroid hormone levels, especially during the first trimester, is important for ensuring maternal and fetal health. The thyroid hormone assays currently in use become more inaccurate at extremes of binding protein concentrations and when heterophilic antibodies are present. Pregnancy is characterized by both these conditions, making accurate determination of free thyroid hormone levels by conventional direct analog immunoassay methods difficult. The objective of this study was to characterize the performance of a novel tandem mass spectrometric assay for free thyroxine during the physiologic conditions of pregnancy. DESIGN: Healthy women without a history of thyroid abnormalities were recruited from the obstetrics and gynecology and endocrinology clinics of a university medical center and their thyroid status was monitored. Free thyroxine levels were assessed by both immunoassay and tandem mass spectrometry during the course of their pregnancy. Serum thyrotropin levels were also measured. The distributions of free thyroid concentrations obtained by the two assays were compared. MAIN OUTCOME: The tandem mass spectrometry and immunoassay values did not correlate well with each other. However, tandem mass spectrometry values correlated well with the current gold standard equilibrium dialysis values. Moreover, the good agreement between equilibrium dialysis and tandem mass spectrometry was maintained across all weeks of gestation. CONCLUSIONS: We conclude that tandem mass spectrometry has a superior performance to immunoassay for the measurement of free thyroxine during pregnancy. Furthermore, it is ideally suited to generating trimester-specific reference intervals for free thyroxine levels. Future studies will determine if it is a better assay to use in most clinical circumstances