Variability In Blood Concentrations Research Articles

Determining Plasma Tacrolimus Concentrations Using High-Performance LC-MS/MS in Renal Transplant Recipients.

Whole-blood therapeutic drug monitoring of tacrolimus is conducted to maintain tacrolimus concentrations within a safe and effective range. Changes in hematocrit cause variability in blood concentrations of tacrolimus because it is highly bound to erythrocytes. Measuring plasma concentrations may eliminate this variability; however, current methods have limitations owing to the use of cross-reactive immunoassays, plasma separation at nonbiological temperatures, and lack of clinical validation. This study aimed to develop and validate a clinically applicable method to measure plasma tacrolimus concentrations in renal transplant recipients and to examine the concentration differences between genotypic CYP3A5 expressors and nonexpressors. Plasma tacrolimus concentrations were measured in 9 stable renal transplant recipients who were genotypic CYP3A5 expressors or nonexpressors. Tacrolimus was extracted from plasma using solid-phase extraction, and liquid chromatography-tandem mass spectrometry was used for detection and quantitation. This assay was sensitive, selective, and linear between 100 and 5000 ng/L, with intraassay and interassay imprecision and inaccuracy <10% and <5% respectively. The extraction recovery of tacrolimus and ascomycin was 74%. Matrix ion suppression effects were 31.5% and 35% with overall recovery of 50.6% and 48.3% for tacrolimus and ascomycin, respectively. Whole-blood concentrations accounted for approximately 46% of the variation in plasma concentrations in CYP3A5 expressors and nonexpressors. No difference in dose-adjusted whole-blood and plasma concentrations was observed between CYP3A5 expressors and nonexpressors. This assay is clinically applicable with excellent performance and demonstrated that tacrolimus plasma concentrations highly correlated with whole-blood concentrations.

Biomarcadores de actividad física y el deporte

Biomarkers measure the body's adaptation to physical training through variations in blood concentrations. These modifications can be benign and reversible or negative, hence the importance of studying their implications. Lactate is an indicator of exercise intensity through the variation of its blood concentration, which increases in more intense exercise. In low intensity exercise, lactate and glucose concentrations gradually decrease, because they use fatty acids as the predominant energy source before glycolysis. High lactate concentrations favor the colonization of Veillonella at intestinal level, improving running time by the metabolic conversion of lactate to propionate and its disposition as an energy source directly, without the effect of first hepatic passage. Troponin is specific for diagnosing cardiac injury. It increases asymptomatically after intense training, proportional to the time and intensity of training. The post-exercise increase is greater in less trained athletes, in athletes adapted to high-intensity intermittent exercise, it rises significantly after intermittent exercise and not after continued exercise, evidencing the a Biomarkers measure the body's adaptation to physical training through variations in blood concentrations. These modifications can be benign and reversible or negative, hence the importance of studying their implications. Lactate is an indicator of exercise intensity through the variation of its blood concentration, which increases in more intense exercise. In low intensity exercise, lactate and glucose concentrations gradually decrease, because they use fatty acids as the predominant energy source before glycolysis. High lactate concentrations favor the colonization of Veillonella at intestinal level, improving running time by the metabolic conversion of lactate to propionate and its disposition as an energy source directly, without the effect of first hepatic passage. Troponin is specific for diagnosing cardiac injury. It increases asymptomatically after intense training, proportional to the time and intensity of training. The post-exercise increase is greater in less trained athletes, in athletes adapted to high-intensity intermittent exercise, it rises significantly after intermittent exercise and not after continued exercise, evidencing the adaptation of the organism to a specific type of exercise. There are typical post-exercise biochemical alterations, characterized by an increase in total creatine kinase and its fractions. It occurs after strenuous exercise that can cause muscle overload, muscle fiber rupture and inflammation, releasing these biochemical markers into the bloodstream. Different high-intensity and high-performance sports disciplines produce increased lactate dehydrogenase indicating risk of injury due to deterioration of muscle fibers.daptation of the organism to a specific type of exercise. There are typical post-exercise biochemical alterations, characterized by an increase in total creatine kinase and its fractions. It occurs after strenuous exercise that can cause muscle overload, muscle fiber rupture and inflammation, releasing these biochemical markers into the bloodstream. Different high-intensity and high-performance sports disciplines produce increased lactate dehydrogenase indicating risk of injury due to deterioration of muscle fibers. Received for review: August 2021Accepted for publication: October 2021Correspondence: 8 de octubre 3020. C.P.11600. Montevideo, Uruguay. Tel: (+598) 24876666 ext. 1663. Contact e-mail: vortizalfonzo@gmail.com

Clinical impact of variability in blood concentrations of calcineurin inhibitors in heart transplant: a double-edged sword

Clinical impact of variability in blood concentrations of calcineurin inhibitors in heart transplant: a double-edged sword

Patterns of mercury exposure and relationships with isotopes and markers of oxidative status in chicks of a Mediterranean seabird

The Mediterranean basin is a hotspot of mercury (Hg) contamination owing to intense anthropogenic emissions, volcanic activity and oligotrophic conditions. Little work has been done to assess the sources of Hg exposure for seabirds and, particularly, the physiological consequences of Hg bioaccumulation. In this study, we (i) describe the individual and temporal variation in blood concentration of total Hg (THg) over three breeding seasons, (ii) identify the factors that affect the THg exposure and (iii) determine the individual- and population-level connections between THg and blood-based markers of oxidative status in chicks of Scopoli’s shearwaters (Calonectris diomedea) breeding on the island of Linosa in the southern Mediterranean. We carried out the work on chicks near fledging because they are fed with prey captured near the colony, thus their Hg levels reflect local contamination. The concentration of THg in erythrocytes varied from 0.23 to 4.29 μg g−1 dw. Chicks that were fed upon higher trophic level prey (i.e., higher δ15N values) had higher THg levels. Individual variation in THg concentrations was not explained by parental identity, sex nor δ13C values. There was significant variation in THg among chicks born from the same mother in different years. We found significant correlations between THg and markers of oxidative status; however, these correlations were no longer significant when we took into account the annual variation in mean values of all metrics. Males with higher values of body condition index had higher blood THg, while THg and body condition index were not correlated in females. Our data indicate that THg levels were moderate to high if compared to other seabirds. However, there is little evidence for harmful short-term detrimental effects owing to THg exposure.

Therapeutic drug monitoring of cyclosporine and tacrolimus in Myanmar kidney transplant patients

IntroductionRenal transplantation is one of the best options for patients suffering from end stage renal disease (ESRD). Cyclosporine and Tacrolimus are mainly applied in immunosuppressive therapy after transplantation of liver, kidney, heart, and other organs. The used of immunosuppressant drugs improve the survival of transplanted organs and reduce organ rejection. Because of their narrow therapeutic index and significant inter-individual variability in blood concentrations, they need to monitor carefully. Therapeutic drug monitoring of tacrolimus and cyclosporine were needed to optimize the outcome in patients after renal transplantations. Maintaining the drugs levels reduce the risks of toxicity or rejection, respectively. ObjectiveThe aim of this study is to identify the optimum blood trough level for cyclosporine and tacrolimus in Myanmar kidney transplant recipients. Materials and methodA retrospective cross sectional design was used and data collected from 50 patients who underwent kidney transplantation and receiving either cyclosporine or tacrolimus within six months after kidney transplantation. Among them 15 and 35 patients are taking cyclosporine and tacrolimus, respectively. For cyclosporine or tacrolimus trough-level monitoring, whole blood sample was drawn 15 min before the next dose and measured by immunoassay method. ResultsThe results showed that majority of cyclosporine and tacrolimus whole blood levels based on C0 (before the dose) concentration were achieved the therapeutic range. ConclusionTherefore, drugs concentration and the recommended clinical conditions should be routinely monitored to adjust the treatment and reduce adverse reactions. Therapeutic drug monitoring of cyclosporine and Tacrolimus are important for the benefits of renal transplant patients in Myanmar.

Estimation of Blood Oxygen Saturation in the Circulation Circuit for Extracorporeal Membrane Oxygenation

Extracorporeal membrane oxygenation (ECMO) is a treatment that supports heart and lung functions with a circulation circuit external to the body. In ECMO, it is important to monitor blood oxygen saturation (SO 2 ) in the circulation tube. As a means of continuous SO 2 measuring, a special connector is inserted into the circuit. However, this method is unsuitable for emergency treatment. Therefore, it is necessary to measure blood SO 2 in the tube without the connector. However, this creates problems for SO 2 estimation, due to varying blood concentration and flow velocity, hemolysis, and wall thickness of the tube. Therefore, we developed a SO 2 estimation method that can calibrate the variation in blood concentration. The method is based on a conversion model between absorbance and SO 2 (CAS), which varies depending on the concentration. In this method, the CAS for the SO 2 estimation is estimated by CAS corresponding to two blood samples prepared in advance with different concentrations. The experiment for SO 2 estimation was conducted with a spectroscope, a halogen light source, and a cut tube. We confirmed that the average error of estimated SO 2 against the SO 2 values measured by a gas analysis was 3.8% within a blood volume concentration range from 50 to 90%. In future work, to improve the estimation accuracy, we will improve our method by investigating other factors that may affect the accuracy.

Population pharmacokinetics of cyclosporine A in Japanese renal transplant patients: comprehensive analysis in a single center.

Cyclosporine A (CyA), a potent immunosuppressive agent used in renal transplantation, has a narrow therapeutic window and a large variability in blood concentrations. This study aimed to develop a population pharmacokinetic (PPK) model of CyA in living-donor renal transplant patients at a single center and identify factors influencing CyA pharmacokinetics (PK). A total of 660 points (preoperative) and 4785 points (postoperative) of blood concentration data from 98 patients who underwent renal transplantation were used. Pre- and postoperative CyA model structure and PPK parameters were separately estimated with a non-linear mixed-effect model, and subsequently, covariate analysis of postoperative data were comprehensively estimated, including preoperative PK parameters. A two-compartment model with first-order absorption and absorption lag time was selected in this study. Aspartate aminotransferase, body surface area (BSA), pretransplant area under the whole blood concentration-time curve/dose, and postoperative days were identified as the covariates on oral clearance. BSA was selected as a covariate of the distribution volume of the central compartment. In addition, diabetes mellitus was selected as a covariate of the first-order absorption rate. This PPK study used the largest number of blood concentration data among previous reports of living-donor renal transplant patients. Moreover, all patients received the same immunosuppressive regimen in a single center. Therefore, the validity of the selected covariates is reliable with high precision. The developed PPK model and selected covariates provide useful information about factors influencing CyA PK and greatly contributes to the identification of the most suitable dosing regimen for CyA.

Surface-Enhanced Raman Scattering in Tunable Bimetallic Core-Shell

In this paper, optical properties of multilayer spherical core-shell nanoparticles based on quasi-static approach and plasmon hybridization theory are investigated. Calculations show that light absorption spectrum of bimetallic multilayer core-shell has three intense plasmon resonance peaks, which are more suitable for multiplex biosensing based on surface-enhanced Raman scattering (SERS) and localized surface plasmon resonance (LSPR). The plasmon resonance peaks in bimetal nanshells are optimized by tuning the geometrical parameters. In addition, the optimal geometry is discussed to obtain the Raman enhancement factor in bimetallic multilayer nanoshell. SERS enhancement factor is calculated with consideration of dampings due to both the electron scattering and the radiation at the boundary and modified Drude model in dielectric function of bimetallic nanoshell. It is shown that bimetallic nanoshell with the small size exhibits strong SERS enhancement factor (~6.63 × 105) with additional collision dampings and ~2.9 × 109 with modified Drude model which are suitable for biosensing applications. In addition, any variation in blood concentration and oxygen level can be detected by this bimetallic core-shell nanoparticle with sensitivity of Δλ/Δn = 264.91 nm/RIU.

Pharmacogenetics of dabigatran etexilate interindividual variability

IntroductionDabigatran etexilate is given in fixed doses without coagulation monitoring for the prevention of blood clots in at risk adults. A high inter-individual variability in blood concentrations of the active metabolite of dabigatran has been reported. ABCB1 and CES1 exert an important effect in the metabolism of dabigatran etexilate and allele variants at these two loci are likely to play a pivotal role.To investigate whether screening for polymorphisms within the ABCB1 and the CES1 genes would explain a portion of the inter-individual variability in blood concentrations of the active metabolite of dabigatran. Material and methodsIn a cohort of patients who had atrial fibrillation and on anticoagulant prophylaxis with dabigatran etexilate, we investigated whether genotypes at rs4148738 (ABCB1), rs8192935 (CES1), and rs2244613 (CES1) loci would affect plasma dabigatran trough and peak concentrations. Results and discussionAmong 92 patients (median age: 72.0years, range: 52–92) analyzed, no clinical variable or genotype was associated with a significant difference in dabigatran peak concentrations. As for trough concentrations, in addition to creatinine clearance, and sex a significant association with the CES1 SNP rs8192935 (p=0.023) was detected. The mean adjusted plasma levels were higher among patients with the CC genotype (86.3ng/dl) than in those carrying the T allele (62.1ng/dl). No significant effect was found for the ABCB1 SNP rs4148738.The CES1 SNP rs8192935 significantly influenced the dabigatran trough concentrations and carriers of the T allele showed significantly lower concentrations than did carriers of the CC genotype.

Hexachlorobenzene Contamination In An Austrian Alpine Valley

Introduction: In Austria, hexachlorobenzene (HCB) was used for agricultural purposes until 1992. In 2011, a cement factory located in a small valley was mandated to burn contaminated slaked lime from a hazardous waste site. When HCB levels exceeded legal standards for foodstuffs from that valley in 2014, concerned citizens sent blood samples and breast milk to Germany. Some were informed their HCB values exceeded German reference values. We were mandated to assess the risk, to establish Austrian reference values and to study routes of exposure. Methods: To establish Austrian reference values, stored blood samples from the Austrian Nutrition and Health Survey 2012 were analyzed. Possible routes of exposure were examined by analyzing samples (soil, air, food, Nordic spruce needles). Based on an individual assessment (e.g. food intake) local residents were invited to provide blood samples. Results: Austrian reference levels were similar to German values from approximately ten years ago. Out of 120 blood samples taken from residents in the exposed valley, 21 exceeded new established Austrian reference values. Highest concentrations were detected among those who mainly consumed food produced in the valley. Residents living closest to the factory had the highest blood HCB-concentrations. Air samples (up to 5.1 ng/m³) and spruce needles (30-50 ng/g dry weight) indicated high exposure in vicinity of the kiln over the last 10-13 months. Based on these findings, a direct route from air to the soil (up to 0.8 ng/g) and through the cattle feed and food for human consumption (esp. milk, meat) could well explain the variability in blood concentrations of HCB. Discussion: Despite the detection of high blood concentrations of HCB in 21 of 120 sampled, daily uptake over the course of one-year was determined to be well below the acceptable daily intake defined by WHO for lifelong exposure. Nevertheless, risk communication to concerned citizens remains a significant challenge.

Effect of zinc on liver cirrhosis with hyperammonemia: A preliminary randomized, placebo-controlled double-blind trial

ObjectiveTo our knowledge, no randomized study has shown whether zinc replacement therapy is effective for hyperammonemia in liver cirrhosis; therefore, we performed a double-blind, placebo-controlled trial to examine efficacy and safety of the zinc replacement therapy. MethodsPatients with liver cirrhosis and hyperammonemia (at or above the institutional reference value) and hypozincemia (≤65 μg/dL) were enrolled in the outpatient units of the participating institutions and were randomly divided to receive placebo (P group) or zinc acetate preparation at a dose of 3 capsules/d for a total zinc content of 150 mg/d (Z group) by the envelope method. Of the 18 enrolled patients, 6 dropped out; thus, the analyses included 12 patients (5 in the P group and 7 in the Z group). Variations in blood concentrations of zinc and ammonia as well as liver function test results were compared. ResultsBlood zinc levels significantly increased in the Z group (P = 0.0037; Friedman test) but not the P group. Blood ammonia levels significantly decreased in the Z group (P = 0.0114; Friedman test) but not the P group. The percent change in blood ammonia level also revealed significant reduction at the eighth week in the Z group (P = 0.0188: Mann-Whitney test). No serious adverse events attributable to the zinc preparation were noted. ConclusionAlthough this study is preliminary and includes a small sample, it is, to our knowledge, the first randomized controlled trial to show that zinc supplementation for 3 mo seems effective and safe for treating hyperammonemia in liver cirrhosis. Studies with a larger sample size are needed to confirm our findings.

Most Blood Biomarkers Related to Vitamin Status, One-Carbon Metabolism, and the Kynurenine Pathway Show Adequate Preanalytical Stability and Within-Person Reproducibility to Allow Assessment of Exposure or Nutritional Status in Healthy Women and Cardiovascular Patients1–3

Knowledge of stability during sample transportation and changes in biomarker concentrations within person over time are paramount for proper design and interpretation of epidemiologic studies based on a single measurement of biomarker status. Therefore, we investigated stability and intraindividual vs. interindividual variation in blood concentrations of biomarkers related to vitamin status, one-carbon metabolism, and the kynurenine pathway. Whole blood (EDTA and heparin, n = 12) was stored with an icepack for 24 or 48 h, and plasma concentrations of 38 biomarkers were determined. Stability was calculated as change per hour, intraclass correlation coefficient (ICC), and simple Spearman correlation. Within-person reproducibility of biomarkers was expressed as ICC in samples collected 1–2 y apart from 40 postmenopausal women and in samples collected up to 3 y apart from 551 patients with stable angina pectoris. Biomarker stability was similar in EDTA and heparin blood. Most biomarkers were essentially stable, except for choline and total homocysteine (tHcy), which increased markedly. Within-person reproducibility in postmenopausal women was excellent (ICC > 0.75) for cotinine, all-trans retinol, cobalamin, riboflavin, α-tocopherol, Gly, pyridoxal, methylmalonic acid, creatinine, pyridoxal 5′-phosphate, and Ser; was good to fair (ICC of 0.74–0.40) for pyridoxic acid, kynurenine, tHcy, cholecalciferol, flavin mononucleotide, kynurenic acid, xanthurenic acid, 3-hydroxykynurenine, sarcosine, anthranilic acid, cystathionine, homoarginine, 3-hydroxyanthranilic acid, betaine, Arg, folate, total cysteine, dimethylglycine, asymmetric dimethylarginine, neopterin, symmetric dimethylarginine, and Trp; and poor (ICC of 0.39–0.15) for methionine sulfoxide, Met, choline, and trimethyllysine. Similar reproducibilities were observed in patients with coronary heart disease. Thus, most biomarkers investigated were essentially stable in cooled whole blood for up to 48 h and had a sufficient within-person reproducibility to allow one-exposure assessment of biomarker status in epidemiologic studies. The Western Norway B Vitamin Intervention Trial was registered at clinicaltrials.gov> as NTC00354081.

Genetic Determinants of Dabigatran Plasma Levels and Their Relation to Bleeding

Fixed-dose unmonitored treatment with dabigatran etexilate is effective and has a favorable safety profile in the prevention of stroke in atrial fibrillation patients compared with warfarin. We hypothesized that genetic variants could contribute to interindividual variability in blood concentrations of the active metabolite of dabigatran etexilate and influence the safety and efficacy of dabigatran. We successfully conducted a genome-wide association study in 2944 Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) participants. The CES1 single-nucleotide polymorphism rs2244613 was associated with trough concentrations, and the ABCB1 single-nucleotide polymorphism rs4148738 and the CES1 single-nucleotide polymorphism rs8192935 were associated with peak concentrations at genome-wide significance (P<9×10(-8)) with a gene-dose effect. Each minor allele of the CES1 single-nucleotide polymorphism rs2244613 was associated with lower trough concentrations (15% decrease per allele; 95% confidence interval, 10-19; P=1.2×10(-8)) and a lower risk of any bleeding (odds ratio, 0.67; 95% confidence interval, 0.55-0.82; P=7×10(-5)) in dabigatran-treated participants, with a consistent but nonsignificant lower risk of major bleeding (odds ratio, 0.66; 95% confidence interval, 0.43-1.01). The interaction between treatment (warfarin versus all dabigatran) and carrier status was statistically significant (P=0.002), with carriers having less bleeding with dabigatran than warfarin (hazard ratio, 0.59; 95% confidence interval, 0.46-0.76; P=5.2×10(-)5) in contrast to no difference in noncarriers (hazard ratio, 0.96; 95% confidence interval, 0.81-1.14; P=0.65). There was no association with ischemic events, and neither rs4148738 nor rs8192935 was associated with bleeding or ischemic events. Genome-wide association analysis identified that carriage of the CES1 rs2244613 minor allele occurred in 32.8% of patients in RE-LY and was associated with lower exposure to active dabigatran metabolite. The presence of the polymorphism was associated with a lower risk of bleeding. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00262600.

Three-way, three-period, crossover bioequivalence study of single oral dose of three brands of 300 mg phenytoin sodium tablets marketed in India, on healthy Indian human volunteers

Objective:To compare the bioavailability of two brands of phenytoin sodium tablets available in the Indian market using Eptoin™ as the reference.Materials and Methods:A randomized, assessor-blind, three-way crossover design study was carried out over a period of 6 months after approval from the Institutional Review Board (IRB). Twenty-two healthy male participants received a single oral 300 mg oral tablet of either of the formulations with a 2-week washout. Blood samples were collected predose and at regular intervals postdose. Plasma phenytoin levels were estimated by high-performance liquid chromatography. Calculation of Cmax, AUC0-t, and AUC0-∞ was done by the linear trapezoidal rule and 90-110% margin (90% confidence interval (CI)) was used to assess bioequivalence.Results:Twenty volunteers completed the study. It was seen that the log-transformed values of Cmax, AUC0-t, and AUC0-∞ of the test formulations were not within the specified limits.Conclusion:Bioinequivalence of available phenytoin brands indicates that switching brands could lead to variations in blood concentrations and thus impact safety and efficacy. If a brand switch is done for any reason, stringent drug-level monitoring is advised.

Efficacy of Artemether-Lumefantrine in Area of High Malaria Endemicity in India and Its Correlation with Blood Concentration of Lumefantrine

This study was conducted to correlate blood concentrations of lumefantrine with treatment outcome for patients with Plasmodium falciparum malaria when the drug was given without specific instructions for administration with food. Patients with P. falciparum malaria in the highly endemic state of Orissa, India, were enrolled during 2008 and followed-up for 28 days after admistration of artemether-lumefantrine for three days according to a World Health Organization protocol. Drug concentration in whole blood was determined by using blood spots placed on filter paper on day 7. The technology is suitable for field studies. One hundred percent of the patients had an adequate clinical and parasitological response. These results confirm the efficacy of artemether-lumefantrine in persons from poor tribal communities when given without specific instructions regarding co-administration with food, despite high inter-individual variability in blood concentrations of lumefantrine.

A review on therapeutic drug monitoring of immunosuppressant drugs.

: Immunosuppressants require therapeutic drug monitoring because of their narrow therapeutic index and significant inter-individual variability in blood concentrations. This variability can be because of factors like drug-nutrient interactions, drug-disease interactions, renal-insufficiency, inflammation and infection, gender, age, polymorphism and liver mass. Drug monitoring is widely practiced especially for cyclosporine, tacrolimus, sirolimus and mycophenolic acid. CYCLOSPORINE: Therapeutic monitoring of immunosuppressive therapy with cyclosporine is a critical requirement because of intra- and inter-patient variability of drug absorption, narrow therapeutic window and drug induced nephrotoxicity. MYCOPHENOLIC ACID MPA: Some reasons for therapeutic drug monitoring of MPA during post-transplant period include: relationship between MPA pharmacokinetic parameters and clinical outcomes, Inter-patient pharmacokinetic variability for MPA despite fixed MMF doses, alternations of MPA pharmacokinetics during the first months after transplantation, drug- drug interaction and influence of kidney function on MPA pharmacokinetic. SIROLIMUS: A recent review of the pharmacokinetics of sirolimus suggested a therapeutic range of 5 to 10 μg l(-1) in whole blood. However, the only consensus guidelines published on the therapeutic monitoring of sirolimus concluded that there was not enough information available about the clinical use of the drug to make recommendations. TACROLIMUS: Sudies have shown, in kidney and liver transplant patients, significant associations of low tacrolimus concentrations with rejection and of high concentrations with nephrotoxicity. Although the feasibility of a limited sampling scheme to predict AUC has been demonstrated, as yet, trough, or pre-dose, whole blood concentration monitoring is still the method of choice.

Seasonal variation in blood concentrations of interleukin-6, adrenocorticotrophic hormone, metabolites of catecholamine and cortisol in healthy volunteers

We investigated seasonal changes in blood concentrations of interleukin-6 (IL-6), adrenocorticotrophic hormone (ACTH), metabolites of catecholamine (VMA, HVA, and 5-HIAA) and cortisol in humans. Eight volunteers were investigated at four times during the year (February, May, August and October) at latitude 35 degrees N. The mean ambient temperature at the collection periods was higher in the order of summer > autumn approximately spring > winter. Changes in mood were also monitored by a profile of mood states (POMS) questionnaire. The concentration of IL-6 was significantly higher in winter and summer than in spring and autumn. The concentrations of ACTH, HVA and VMA were significantly higher in summer. No seasonal variation was detected in cortisol. There were significant differences among the seasons in subscale tension and anger in the POMS questionnaire; the tension subscale showed significant differences between spring and autumn, with a higher score in spring. The results demonstrate that Il-6, ACTH, HVA and VMA exhibit statistically significant seasonal rhythms, which might have important diagnostic and therapeutic implications.

Biomonitoring Equivalents (BE) dossier for trihalomethanes

Measurements of whole blood concentrations of trihalomethanes (THMs) have been reported in persons in the general population. Risk assessments based on administered doses of THMs have been conducted for both cancer and non-cancer health endpoints by the US Environmental Protection Agency; however, no health-based standards exist for interpreting measured blood concentrations of THMs. Existing physiologically based pharmacokinetic models for laboratory rats, dogs, and humans were used to estimate the average blood concentrations consistent with the points of departure, reference doses (RfDs), and, where applicable, cancer potency estimates to provide biomonitoring equivalents (BEs) for these exposure guidance values. The models were also used to characterize the short term variations in blood concentrations that could result from various exposure regimens, even when exposures remain consistent with the underlying RfDs. The BE values derived in this exercise can be used as one component of a screening-level assessment of future population biomonitoring THM data.

Therapeutic drug monitoring of immunosuppressants: An overview

Immunosuppressant drugs have contributed significantly to the success of organ transplantation. Therapeutic drug monitoring is an integral part of transplant protocols. Immunosuppressants require therapeutic drug monitoring because of their narrow therapeutic index and significant variability in blood concentrations between individuals. The variability in blood concentrations can be because of factors like drug-nutrient interactions, gender influence and polymorphism. Drug monitoring is widely practised especially for cyclosporine, tacrolimus, sirolimus and mycophenolic acid. The accuracy and specificity of the drug measurements are fundamental to the clinical interpretation of the concentration data. The issues surrounding the measurement and interpretation of immunosuppressant drug levels such as body fluids used for drug estimation, protein binding, sampling time and method for assay of the drug are discussed in detail in the article.

COUPLING CONTAMINANTS WITH DEMOGRAPHY: EFFECTS OF LEAD AND SELENIUM IN PACIFIC COMMON EIDERS

We coupled intensive population monitoring with collection of blood samples from 383 nesting Pacific common eiders (Somateria mollisima v-nigrum) at two locations in Alaska (USA) from 2002 to 2004. We investigated annual, geographic, and within-season variation in blood concentrations of lead and selenium; compared exposure patterns with sympatrically nesting spectacled eiders (Somateria fischeri); and examined relationships with clutch size, egg viability, probability of hatching, and apparent survival of adult females. Lead concentrations were elevated in 3.6% of females, and all individuals exhibited elevated selenium, most (81%) at concentrations associated with death in captive waterfowl. Blood lead and selenium concentrations varied both within and among site-years and were lower than those of spectacled eiders. During incubation, blood lead concentrations in females increased significantly (possibly via re-release of stored lead from bone), whereas selenium concentrations decreased (likely because of natural excretion). Probability of a nest containing at least one nonviable egg was positively related to blood selenium in hens, but adverse effects in other life-history variables were not supported. Although reproduction appeared to be sensitive to selenium toxicity, our data suggest that high rates of nonviability are unlikely in this population and that selenium-related reductions to clutch size would be inconsequential at the scale of overall population dynamics. We conclude that Pacific common eiders and other wild marine birds likely have higher selenium tolerances than freshwater species and that interspecific differences in exposure levels may reflect differences in reproductive strategies.