Males and females differ in their response to drug treatment. These differences can be critical in response to drug treatment. It is therefore essential to understand those differences to appropriately conduct risk assessment and to design safe and effective treatments. Even from that modest perspective, how and when we use drugs can result in unwanted and unexpected outcomes. We summarize the sex differences that impact pharmacokinetics and pharmacodynamics and include a general comparison of clinical pharmacology as it applies to men, pregnant and non-pregnant women. Since this is an area rapidly evolving, it is essential for the practitioner to review drug prescribing information and recent literature to understand fully the impact of sex differences in clinical therapeutics.
Active and passive smoking have been associated with an array of adverse effects on health. The development of valid and accurate scales of measurement for exposures associated with health risks constitutes an active area of research. Tobacco smoke exposure still lacks an ideal method of measurement. A valid estimation of the risks associated with tobacco exposure depends on accurate measurement. However, some groups of people are more reluctant than others to disclose their smoking status and exposure to tobacco. This is particularly true for pregnant women and parents of young children, whose smoking is often regarded as socially unacceptable. For others, recall of tobacco exposure may also prove difficult. Because relying on self-report and the various biases it introduces may lead to inaccurate measures of nicotine exposure, more objective solutions have been suggested. Biomarkers constitute the most commonly used objective method of ascertaining nicotine exposure. Of those available, cotinine has gained supremacy as the biomarker of choice. Traditionally, cotinine has been measured in blood, saliva, and urine. Cotinine collection and analysis from these sources has posed some difficulties, which have motivated the search for a more consistent and reliable source of this biomarker. Hair analysis is a novel, noninvasive technique used to detect the presence of drugs and metabolites in the hair shaft. Because cotinine accumulates in hair during hair growth, it is a unique measure of long-term, cumulative exposure to tobacco smoke. Although hair analysis of cotinine holds great promise, a detailed evaluation of its potential as a biomarker of nicotine exposure, is needed. No studies have been published that address this issue. Because the levels of cotinine in the body are dependent on nicotine metabolism, which in turn is affected by factors such as age and pregnancy, the characterization of hair cotinine should be population specific. This review aims at defining the sensitivity, specificity, and clinical utilization of different methods used to estimate exposure to cigarette smoking and environmental tobacco smoke.
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.
BACKGROUND New high-performance liquid chromatography/ tandem mass spectrometry (LC-MS/MS) methods are among the most successful approaches to improve specificity problems inherent in many immunoassays. CONTENT We emphasize problems with immunoassays for the measurement of steroids and review the emerging role of LC-MS/MS in the measurement of clinically relevant steroids. The latest generation of tandem mass spectrometers has superior limits of quantification, permitting omission of previously employed derivatization steps. The measurement of steroid profiles in the diagnosis and treatment of congenital adrenal hyperplasia, adrenal insufficiency, chronic pelvic pain and prostatitis, oncology (breast cancer), and athletes has important new applications. CONCLUSIONS LC-MS/MS now affords the specificity, imprecision, and limits of quantification necessary for the reliable measurement of steroids in human fluids, enhancing diagnostic capabilities, particularly when steroid profiles are available.
Objectives-To describe the interrelationships of thyroid functions based on trimester-specific concentrations in healthy, iodine-sufficient pregnant women across trimesters, and postpartum.Methods-Circulating total 3,5,3′-triidothyronine (T 3 ) and thyroxine (T 4 ) concentrations were determined simultaneously using liquid chromatography tandem mass-spectrometry (LC/MS/MS). Free thyroxine (FT 4 ), thyroid-stimulating hormone (TSH), and thyroglobulin (Tg) were measured using immunoassay techniques. Linear mixed effects models and correlations were calculated to determine trends and associations, respectively, in concentrations.Results and conclusions-Trimester-specific T 3 , FT 4 , TSH, and Tg concentrations were significantly different between the first and third trimesters (all p < 0.05); second and third trimester values were not significantly different for FT 4 , TSH, and Tg (all p > 0.25) although T 3 was significantly higher in the third, relative to the second trimester. T 4 was not significantly different at any trimester (all p > 0.80). With two exceptions, analyte concentrations tended not to be correlated at each trimester and at 1-year postpartum. One exception was that T 3 and T 4 tended to be associated (all p < 0.05) at all time points except the third trimester (ρ = 0.239, p > 0.05). NIH Public Access
Background-Most clinical chemistry laboratories measure free thyroxine (FT4) by an analogue (direct) method. Nevertheless, the validity of analogue FT4 immunoassays has been questioned and patient's results using this approach frequently do not fit in with the clinical presentation. Because of these problems we routinely send out all direct free T4's that are < 2.5th percentile and many that are > 97.5th percentile for measurement by equilibrium dialysis, the gold standard method. In approximately half of these cases, the FT4 by equilibrium dialysis was normal. We developed a rapid, reliable free T4 method employing isotope dilution tandem mass spectrometry and compared our results with both the analogue (direct) free T4 and equilibrium dialysis procedures.Methods-An API-4000 tandem mass spectrometer (Sciex, Toronto, Canada) equipped with TurboIonSpray and Agilent HPLC system was used employing isotope dilution with deuterium labeled internal standard (IS=L-thyroxine-d 2 ). Serum was filtered through the Centrifree YM-30 ultrafiltration device by centrifugation, IS added to the ultrafiltrate, and 400 μL injected onto a C-18 column. After washing, the switch valve is activated and a methanol gradient allows for elution of both T4 and the IS into the LC/MS/MS system. Quantitation was by MRM analysis in the negative mode. Equilibrium dialysis was performed by the Nichols method and analogue free T4 results were obtained on the Dade Dimension RxL.Results-The within-day and between-day CV's were < 7.1% at all concentrations tested. The results correlated well with equilibrium dialysis (Eq Dial=0.971 MS+0.041, n =68, Syx=1.381, r =0.954). A poor correlation was found with the analogue (direct) free T4 method (IA=0.326 MS +6.27, n =154, Syx=1.96, r =0.459). Conclusions-Samples can be processed in batches of 30. The free T4 tandem MS method has a rapid turn-around-time vs the equilibrium dialysis procedure, with a chromatographic run time of 8 min per sample. NIH Public Access
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.
Objective-To establish normal, trimester-specific reference intervals for serum 17β-estradiol, progesterone (P), 17α-hydroxyprogesterone, cortisol, 11-deoxycortisol, androstenedione, DHEA, and DHEAS, measured simultaneously using isotope dilution tandem mass spectrometry. Design-Sequential cohort study.Patient(s)-Healthy women undergoing a normal pregnancy (age, 25-38 years; mean, 30 years) attending a prenatal well clinic at gestation weeks 12, 22, and 32 and approximately 1 year postpartum.Main Outcome Measure(s)-Trimester-specific reference intervals of endogenous steroid hormones analyzed using an isotope dilution tandem mass spectrometer equipped with an atmospheric pressure photoionization source with deuterium-labeled internal standards.Result(s)-Serum estradiol, P, 17α-hydroxyprogesterone, and 11-deoxycortisol increased throughout pregnancy; cortisol increased up to the second trimester and then remained steady, while androstenedione increased by 80 percent by gestation week 12, then remained constant. Serum DHEA-S decreased by 50% by the third trimester. Normal pregnancy depends on pronounced adaptations in pregnancy-related hormone concentrations, characterized by elevated levels of several circulating steroid hormones, which normally increase with the progression of pregnancy (1-6). Endogenous steroid hormone exposure during pregnancy has been of interest in studies of duration of gestation, fetal size, twin pregnancies, control of labor, nausea and vomiting in pregnancy, pregnancyinduced hypertension, and other disease states (5-9). The studies have generally produced weak and inconsistent findings because the hormone levels were either not available or lacked specificity or because surrogate measures of exposure to altered steroid hormone levels were often used to estimate these hormones. Conclusion(s)- NIH Public AccessSteroid hormones are derived from cholesterol. Binding proteins facilitate their transport and increase their half-life but limit their entry into target cells, thereby regulating their biological activity. Binding proteins make precise determination of serum steroid hormone concentrations difficult by interfering with different steroid hormones immunoassays (IAs). Furthermore, the lack of specificity of IAs due to cross reactivity with structurally related molecules is a well-known phenomenon (10-12).In contrast, isotope dilution liquid chromatography-tandem mass spectrometry (LC/MS/MS) is a specific detection method that allows the quantification of the analyte of interest. It also allows for a simpler approach to sample preparation without employing lengthy and timeconsuming extraction and sample derivatization steps. This has been reported in a previous publication, and steroid hormone analysis using isotope dilution LC/MS/MS was compared with the analysis of the same samples using IA techniques (14). Generally, tandem mass spectrometry provides lower values than IA, no doubt because of improved specificity.The reasons for the improved specificity in our tandem mass sp...
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