Correlations between imatinib pharmacokinetics, pharmacodynamics, adherence, and clinical response in advanced metastatic gastrointestinal stromal tumor (GIST): An emerging role for drug blood level testing?

Imatinib is the standard of care for patients with advanced metastatic gastrointestinal stromal tumors (GIST), and is also approved for adjuvant treatment in patients at substantial risk of relapse. Studies have shown that maximizing benefit from imatinib depends on long-term administration at recommended doses. Pharmacokinetic (PK) and pharmacodynamic factors, adherence, and drug-drug interactions can affect exposure to imatinib and impact clinical outcomes. This article reviews the relevance of these factors to imatinib's clinical activity and response in the context of what has been demonstrated in chronic myelogenous leukemia (CML), and in light of new data correlating imatinib exposure to response in patients with GIST. Because of the wide inter-patient variability in drug exposure with imatinib in both CML and GIST, blood level testing (BLT) may play a role in investigating instances of suboptimal response, unusually severe toxicities, drug-drug interactions, and suspected non-adherence. Published clinical data in CML and in GIST were considered, including data from a PK substudy of the B2222 trial correlating imatinib blood levels with clinical responses in patients with GIST. Imatinib trough plasma levels <1100ng/mL were associated with lower rates of objective response and faster development of progressive disease in patients with GIST. These findings have been supported by other analyses correlating free imatinib (unbound) levels with response. These results suggest a future application for imatinib BLT in predicting and optimizing therapeutic response. Nevertheless, early estimates of threshold imatinib blood levels must be confirmed prospectively in future studies and elaborated for different patient subgroups.

BDNF Val66Met polymorphism influence on striatal blood-level-dependent response to monetary feedback depends on valence and agency

Animal work implicates the brain-derived neurotrophic factor (BDNF) in function of the ventral striatum (VS), a region known for its role in processing valenced feedback. Recent evidence in humans shows that BDNF Val66Met polymorphism modulates VS activity in anticipation of monetary feedback. However, it remains unclear whether the polymorphism impacts the processing of self-attributed feedback differently from feedback attributed to an external agent. In this study, we emphasize the importance of the feedback attribution because agency is central to computational accounts of the striatum and cognitive accounts of valence processing. We used functional magnetic resonance imaging and a task, in which financial gains/losses are either attributable to performance (self-attributed, SA) or chance (externally-attributed, EA) to ask whether BDNF Val66Met polymorphism predicts VS activity. We found that BDNF Val66Met polymorphism influenced how feedback valence and agency information were combined in the VS and in the right inferior frontal junction (IFJ). Specifically, Met carriers' VS response to valenced feedback depended on agency information, while Val/Val carriers' VS response did not. This context-specific modulation of valence effectively amplified VS responses to SA losses in Met carriers. The IFJ response to SA losses also differentiated Val/Val from Met carriers. These results may point to a reduced allocation of attention and altered motivational salience to SA losses in Val/Val compared to Met carriers. Implications for major depressive disorder are discussed.

Temporal interrelationships among luteolysis, FSH and LH concentrations and follicle deviation in mares

The effect of altered LH concentrations on the deviation in growth rates between the 2 largest follicles was studied in pony mares. The progestational phase was shortened by administration of PGF2α on Day 10 (Day 0=ovulation; n=9) or lengthened by daily administration of 100 mg of progesterone on Days 10 to 30 (n=11; controls, n=10). All follicles ≥5 mm were ablated on Day 10 in all groups to initiate a new follicular wave. The interovulatory interval was not altered by the PGF2α treatment despite a 4-day earlier decrease in progesterone concentrations. Time required for growth of the follicles of the new wave apparently delayed the interval to ovulation after luteolysis. The FSH concentrations of the first post-ablation FSH surge were not different among groups. A second FSH surge with an associated follicular wave began by Day 22 in 7 of 11 mares in the progesterone group and in 0 of 19 mares in the other groups, indicating reduced functional competence of the largest follicle. A prolonged elevation in LH concentrations began on the mean day of wave emergence (Day 11) in the prostaglandin group (19.2 ± 2.2 vs 9.0 ± 0.7 ng/mL in controls; P<0.05), an average of 4 d before an increase in the controls. Concentrations of LH in the progesterone group initially increased until Day 14 and then decreased so that by Day 18 the concentrations were lower (P<0.05) than in the control group (12.9 ± 1.6 vs 20.2 ± 2.6 ng/mL). Neither the early and prolonged increase nor the early decrease in LH concentrations altered the growth profile of the second-largest follicle, suggesting that LH was not involved in the initiation of deviation. However, the early decrease in LH concentrations in the progesterone group was followed by a smaller (P<0.05) diameter of the largest follicle by Day 20 (26.9 ± 1.7 mm) than the controls (30.3 ± 1.7 mm), suggesting that LH was necessary for continued growth of the largest follicle after deviation. (C) 2000 by Elsevier B.V.

Inhibin B and the ovarian follicular reserve

Inhibins are dimeric glycoproteins composed of an α-subunit and a βA-subunit (inhibin A) or βB-subunit (inhibin B), which inhibits pituitary gonadotropin secretion of FSH. The inhibin B is a product of the cohort of antral follicles. The ovarian follicle number decrease steadily as a function of increasing age, with consequent falls in the levels of inhibin B and increase of FSH levels. It is sufficient to maintain ovulatory function and continued secretion of estradiol. Elevated FSH levels seem to occur late in the sequence of events associated with ovarian failure. The inhibin B, produced by granulosa cells, is the earliest marker of the decline in ovarian follicular reserve across reproductive aging.

Long-term effects of perinatal androgenization on reproductive parameters of male rat offspring androgenization and male rat reproduction

It is known that during sex differentiation, fetal androgens are critical determinants of the male phenotype. Although testosterone is necessary for normal development of male sexual behavior, perinatal androgen treatment can result in disruption of normal male sexual reproduction. Pregnant Wistar rats were administered either corn oil (vehicle) or testosterone propionate at 0.2 mg/kg from gestational day 12 until the end of lactation and the reproductive function of male offspring was evaluated at 90 (adulthood) and 270 (middle age) days of age. Perinatal androgenization in the rat provoked a reduction in sperm production and reserves in adulthood that did not affect fertility and did not persist at more advanced ages, as shown by the results at post-natal day 270. If perinatal androgenization promotes similar effects in humans of reproductive age, the results of the present work can impact male reproduction health, given the less efficient spermatogenesis and lower sperm reserves in the human epididymis, compared to rodents. © Georg Thieme Verlag KG Stuttgart. New York.

Genome-wide association study identifies novel genetic variants contributing to variation in blood metabolite levels

Metabolites are small molecules involved in cellular metabolism, which can be detected in biological samples using metabolomic techniques. Here we present the results of genome-wide association and meta-analyses for variation in the blood serum levels of 129 metabolites as measured by the Biocrates metabolomic platform. In a discovery sample of 7,478 individuals of European descent, we find 4,068 genome- and metabolome-wide significant (Z-test, P<1.09 × 10−9) associations between single-nucleotide polymorphisms (SNPs) and metabolites, involving 59 independent SNPs and 85 metabolites. Five of the fifty-nine independent SNPs are new for serum metabolite levels, and were followed-up for replication in an independent sample (N=1,182). The novel SNPs are located in or near genes encoding metabolite transporter proteins or enzymes (SLC22A16, ARG1, AGPS and ACSL1) that have demonstrated biomedical or pharmaceutical importance. The further characterization of genetic influences on metabolic phenotypes is important for progress in biological and medical research.

Effects of dietary calcium levels and limestone particicle size on the performance, tibia and blood of laying hens

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Effects of acute heat exposure on respiratory metabolism and blood glucose in freshwater fishes, Prochilodus scrofa (curimbatá) and Cyprinus carpio (carp) acclimatized to tropical winter

1. 1. Routine oxygen consumption and blood glucose were determined from freshwater fishes, Prochilodus scrofa and Cyprinus carpio, exposed at high temperatures for 1 hr. 2. 2. Prochilodus scrofa had a significantly higher rate of oxygen consumption at 30°C than at 25°C, and carp higher at 25°C than at 30°C. 3. 3. Blood glucose was significantly higher for Cyprinus carpio than for Prochilodus scrofa at 25 and 30°C; however, after exposure to these temperatures for 1 hr blood glucose did not change significantly for both species. 4. 4. The results suggest that these interspecific variations may be linked to the differences between native and foreign fishes and their way of life. © 1985.

Effects of acute cold exposure on rectal temperature, blood glucose and plasma free fatty acids in alloxan-diabetic rats

These experiments were carried out to study the effects of acute cold exposure (0-2°C/4 hr) on rectal temperature, blood glucose and plasma free fatty acids (FFA) in alloxan-diabetic rats. Male Wistar rats weighing 170-190 g were used and diabetes was induced by i.v. alloxan injection (40 mg/kg body wt). Cold exposure produced severe hypothermia in diabetic rats. After 4 hr of cold, blood glucose of diabetic rats was reduced from 296±16 to 86t±12 mg/dl (P<0.01), and FFA increased slightly, but was not statistically different (P>0.05) from the initial value. As expected, interscapular brown adipose tissue (IBAT) and retroperitoneal and epididymal white adipose tissues were significantly lower in diabetic than in control rats. Cold exposure reduced total IBAT lipids in control but not in diabetic animals. The results of this experiment suggest that diabetic rats were unable to maintain body temperature in the cold, probably because of a failure to generate an adequate amount of heat by nonshivering thermogenesis in brown adipose tissue.

Evaluation of a protein deficient diet in rats through blood oxidative stress biomarkers

Protein malnutrition leads to functional impairment in several organs, which is not fully restored with nutritional recovery. Little is known about the role of oxidative stress in the genesis of these alterations. This study was designed to assess the sensitivity of blood oxidative stress biomarkers to a dietary protein restriction. Male Wistar rats were divided into two groups, according to the diet fed from weaning (21 days) to 60 day old: normal protein (17% protein) and low protein (6% protein). Serum protein, albumin, free fatty acid and liver glycogen and lipids were evaluated to assess the nutritional status. Blood glutathione reductase (GR) and catalase (CAT) activities, plasma total sulfhydryl groups concentration (TSG) as well as plasma thiobarbituric acid reactive substances (TBARs) and reactive carbonyl derivatives (RCD) were measured as biomarkers of the antioxidant system and oxidative damage, respectively. The glucose metabolism in soleus muscle was also evaluated as an index of stress severity imposed to muscular mass by protein malnutrition. No difference was observed in muscle glucose metabolism or plasma RCD concentration between both groups. However, our results showed that the low protein group had higher plasma TBARs (62%) concentration and lower TSG (44%) concentration than control group, indicating increased reactive oxygen species production in low protein group. The enhancement of erythrocyte GR (29%) and CAT (28%) activities in this group also suggest an adaptation to the stress generated by the protein deficiency. Taken together, the results presented here show that the biomarkers used were able to reflect the oxidative stress level induced by this specific protein deficient diet.

Independent impact of glycemia ad blood pressure in albuminuria on high-risk subjects for metabolic syndrome

Background: Microalbuminuria may reflect diffuse endothelial damage. Considering that diabetes and hypertension cause vasculopathy, we investigated associations of albumin-to-creatinine ratio (ACR) with plasma glucose and blood pressure levels in high-risk subjects for metabolic syndrome. Methods: A sample of 519 (246 men) Japanese-Brazilians (aged 60 ± 11 years), who participated in a population-based study, had their ACR determined in a morning urine specimen. Backward models of multiple linear regression were created for each gender including log-transformed values of ACR as dependent variable; an interaction term between diabetes and hypertension was included. Results: Macroalbuminuria was found in 18 subjects. ACR mean values for subjects with normal glucose tolerance, impaired fasting glycemia, impaired glucose tolerance and diabetes were 9.9 ± 6.0, 19.0 ± 35.4, 20.7 ± 35.4, and 33.9 ± 55.0 mg/g, respectively. Diabetic subjects showed higher ACR than the others (p < 0.05). An increase in the proportion of albuminuric subjects was observed as glucose metabolism deteriorated (4.9, 17.0, 23.0 and 36.0%). Stratifying into 4 groups according to postchallenge glycemia (< 7.8 mmol/l, n = 9 1; ≥ 7.8 mmol/l, n = 4 10) and hypertension, hypertensive and glucose-intolerant subgroups showed higher ACR values. ACR was associated with gender, waist circumference, blood pressure, plasma glucose and triglyceride (p < 0.05); albuminuric subjects had significantly higher levels of such variables than the normoalbuminuric ones. In the final models of linear regression, systolic blood pressure and 2-hour glycemia were shown to be independent predictors of ACR for both genders (p < 0.05). In men, also waist was independently associated with ACR. No interaction was detected between diabetes and hypertension. Conclusions: These findings suggest that both glucose intolerance and hypertension could have independent but not synergistic effects on endothelial function - reflected by albumin loss in urine. Such hypothesis needs to be confirmed in prospective studies. © 2004 Dustri-Verlag Dr. K. Feistle.

The relationship between onset of blood lactate accumulation, critical velocity, and maximal lactate steady state in soccer players

The objective of this study was to analyze the validity of the velocity corresponding to the onset of blood lactate accumulation (OBLA) and critical velocity (CV) to determine the maximal lactate steady state (MLSS) in soccer players. Twelve male soccer players (21.5 ± 1.0 years) performed an incremental treadmill test for the determination of OBLA. The velocity corresponding to OBLA (3.5 mM of blood lactate) was determined through linear interpolation. The subjects returned to the laboratory on 7 occasions for the determination of MLSS and CV. The MLSS was determined from 5 treadmill runs of up to 30-minute duration and defined as the highest velocity at which blood lactate did not increase by more than 1 mM between minutes 10 and 30 of the constant velocity runs. The CV was determined by 2 maximal running efforts of 1,500 and 3,000 m performed on a 400-m running track. The CV was calculated as the slope of the linear regression of distance run versus time. Analysis of variance revealed no significant differences between OBLA (13.6 ± 1.4 km·h-1) and MLSS (13.1 ± 1.2 km·h-1) and between OBLA and CV (14.4 ± 1.1 km·h-1). The CV was significantly higher than the MLSS. There was a significant correlation between MLSS and OBLA (r = 0.80), MLSS and CV (r = 0.90), and OBLA and CV (r = 0.80). We can conclude that the OBLA can be utilized in soccer players to estimate the MLSS. In this group of athletes, however, CV does not represent a sustainable steady-state exercise intensity. © 2005 National Strength & Conditioning Association.

Diagnosis of 5α-reductase type 2 deficiency: Contribution of anti-Müllerian hormone evaluation

Aim: To evaluate anti-Müllerian hormone (AMH) levels in patients with clinical and molecular diagnosis of 5α-reductase 2 deficiency. Patients and methods: Data from 14 patients whose age ranged from 21 days to 29 years were analyzed according to age and pubertal stage. Sexual ambiguity was rated as Prader III in 11 patients. LH, FSH, testosterone (T), dihydrotestosterone (DHT) and AMH serum levels were measured in all but two patients, who had been previously submitted to gonadectomy; T and DHT were also measured in 20 age-matched controls. Results: Gonadotropin levels were normal in all but one patient who retained gonads (six of whom had reached puberty) and T/DHT ratio was elevated in all patients when compared to controls. All prepubertal patients had AMH levels < -1 SD for age, while most pubertal patients had AMH levels compatible with pubertal stage. Conclusions: Prepubertal patients with 5α-reductase 2 deficiency have AMH values in the lower part of the normal range. These data indicate that T does not need to be converted to DHT to inhibit AMH secretion by Sertoli cells. © Freund Publishing House Ltd., London.