Corticosteroid pharmacokinetic abnormalities in overweight and obese corticosteroid resistant asthmatics.
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ABSTRACT:
SUBMITTER: Goleva E
PROVIDER: S-EPMC4789098 | biostudies-literature | 2016 Mar-Apr
REPOSITORIES: biostudies-literature
Publications
Corticosteroid pharmacokinetic abnormalities in overweight and obese corticosteroid resistant asthmatics.
Goleva Elena E Covar Ronina R Martin Richard J RJ Leung Donald Y M DY
The journal of allergy and clinical immunology. In practice 20160118 2
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Project description:ObjectivesTo explore the effects of weight change on the risk of metabolic abnormalities in the Chinese population.MethodsA total of 1895 metabolically healthy adults aged 21-78 years completed anthropometric and biological measurements at baseline (2012) and at an eight year follow-up (2020). Based on absolute weight change and relative weight change, the participants were split into five classes. A Cox proportional hazards regression model was used to estimate the relative risk (RR) and 95% confidence intervals (95% CI) for the risk of metabolic abnormalities using stable weight as the reference group. Stratified analysis was used to explore this relationship in participants with different baseline body mass index (BMI) levels.ResultsDuring the follow-up period, 35.41% of the participants retained a stable weight, and 10.71% had metabolic abnormalities. After covariate adjustment, for every kilogram gained over eight years, the risk of developing metabolic abnormalities increased by 22% (RR: 1.094; 95% CI: 1.063-1.127). Compared with stable weight participants, weight gain of 2-4 Kg and weight gain ≥ 4 Kg exhibited significantly higher risks of metabolic abnormalities, with RR of 1.700 (95% CI 1.150-2.513) and 1.981 (95% CI 1.372-2.859), respectively. A weight gain of ≥ 4 Kg had an opposite effect on the overweight/obesity and non-overweight/obesity groups, with an increased risk of metabolic abnormalities only in the non-overweight/obesity group (RR, 2.291; 95% CI, 1.331-3.942). Moreover, weight loss ≥ 4 Kg significantly reduced the risk of metabolic abnormalities only among overweight/obese adults (RR 0.373; 95% CI 0.154-0.906). Similar results were observed in relative body weight change analyses.ConclusionsLong-term excessive body weight gain is positively associated with an increased risk of metabolic abnormalities among adults with non-overweight/obesity, whereas long-term body weight loss is a protective factor for metabolic health among adults with overweight/obesity.
| S-EPMC9808089 | biostudies-literature
Project description:BACKGROUND: It has been suggested that smoking asthmatics benefit less from corticosteroid treatment than never-smoking asthmatics. We investigated differences in blood and sputum inflammatory profiles between ex-, current-, and never-smokers and assessed their ICS treatment response after 2-week and 1-year treatment. METHODS: We analyzed FEV1, PC20 methacholine and PC20 AMP, (differential) cell counts in sputum and blood in ex-, current- and never-smokers at baseline (n=114), after 2-week treatment with fluticasone 500 or 2000 ?g/day (n=76) and after 1-year treatment with fluticasone 500 ?g/day or a variable dose of fluticasone based on a self-management plan (n=64). RESULTS: A total of 114 patients were included (29 ex-, 30 current- and 55 never-smokers. At baseline, ex- and current-smokers had less eosinophils in sputum and blood than never-smokers. Blood neutrophil counts were higher in current- than in never-smokers. A higher number of cigarettes smoked daily was associated with lower blood and sputum eosinophils. After 2-week ICS treatment, FEV1 %predicted improved less in current-smokers than never-smokers (2.4% versus 8.1%, p=0.010) and ex-smokers tended to improve less than never-smokers (4.1%, p=0.067). In contrast, no differences in ICS treatment response in lung function or inflammatory cells were found between the three groups after 1 year. CONCLUSIONS: Ex- and current-smokers have less eosinophils and more neutrophils in their sputum and blood than never-smokers. Although ex- and current-smokers have a reduced short-term corticosteroid treatment response, we did not find a difference in their long-term treatment response.
| S-EPMC3849864 | biostudies-other
Project description:BackgroundResponse to inhaled corticosteroids is highly variable, and the association between DNA methylation and treatment response is not known.ObjectiveTo examine the association between peripheral blood DNA methylation and inhaled corticosteroid response in children with persistent asthma.MethodsEpigenome-wide DNA methylation was analysed in individuals on inhaled corticosteroids in three independent and ethnically diverse cohorts-Childhood Asthma Management Program (CAMP); Children, Allergy, Milieu, Stockholm, Epidemiology (BAMSE); and Genetic Epidemiology of Asthma in Costa Rica Study (GACRS). Treatment response was evaluated using two definitions, the absence of emergency department visits and/or hospitalizations and the absence oral corticosteroid use while on inhaled corticosteroid therapy. CpG sites meeting nominal significance (P < 0.05) for each outcome were combined in a three-cohort meta-analysis with adjustment for multiple testing. DNA methylation was correlated with gene expression using Pearson and partial correlations.ResultsIn 154 subjects from CAMP, 72 from BAMSE, and 168 from GACRS, relative hypomethylation of cg00066816 (171 bases upstream of IL12B) was associated with the absence of emergency department visits and/or hospitalizations (Q = 0.03) in all cohorts and lower IL12B expression (ρ = 0.34, P = 0.01) in BAMSE. Relative hypermethylation of cg04256470 (688 bases upstream of CORT) was associated with the absence of oral corticosteroid use (Q = 0.04) in all cohorts and higher CORT expression (ρ = 0.20, P = 0.045) in CAMP.Conclusion and clinical relevanceDifferential DNA methylation of IL12B and CORT are associated with inhaled corticosteroid treatment response in persistent childhood asthmatics. Pharmaco-methylation can identify novel markers of treatment sensitivity in asthma.
| S-EPMC7085934 | biostudies-literature
Project description:BackgroundIn view of the increased use of metformin in obese adolescents, the aim of this study was to determine the pharmacokinetics of metformin in overweight and obese adolescents.MethodsIn overweight and obese adolescents receiving metformin 500 or 1000 mg twice daily for 37 weeks during a clinical trial, blood samples were collected over 8 h during an oral glucose tolerance test. Population pharmacokinetic modeling was performed using NONMEM.ResultsData for 22 overweight and obese adolescents with a mean total body weight (TBW) of 79.3 kg (range 54.7-104.9), body mass index (BMI) of 29.1 kg/m2 (range 22.9-39.3), and age of 15.9 years (range 11.1-17.5) were analysed. In the model, oral clearance (CL/F) of metformin (1.17 l/min [relative standard error of 6%]) increased significantly with TBW (p < 0.01). More specifically, CL/F increased with both developmental weight (WTfor age and length) and excess body weight (WTexcess), for which an excess weight covariate model was proposed.ConclusionThe CL/F of metformin in obese adolescents (1.17 l/min) is larger than that in non-obese children (0.55 l/min) and similar to that in adults (1.3 l/min) as reported in the literature. This increase may potentially be explained by increased tubular secretion of metformin. These results appear to indicate that adult dosages of metformin could be considered in obese adolescents if pediatric dosages have been therapeutically ineffective. CLINICALTRIALS.GOV: NCT01487993.
| S-EPMC6028885 | biostudies-literature
Project description:BackgroundSingle nucleotide polymorphisms (SNPs) influence a patient's response to inhaled corticosteroids and β2-agonists, and the effect of treatment with inhaled corticosteroids is synergistic with the effect of β2-agonists. We hypothesized that use of inhaled corticosteroids could influence the effect of SNPs associated with a bronchodilator response.ObjectiveTo assess whether, among subjects with asthma, the association of SNPs with bronchodilator response is different between those treated with inhaled corticosteroids versus those on placebo.MethodsA genome-wide association analysis was conducted by using 581 white subjects from the Childhood Asthma Management Program. By using data for 449,540 SNPs, we conducted a gene by environment analysis in PLINK with inhaled corticosteroid treatment as the environmental exposure and bronchodilator response as the outcome measure. We attempted to replicate the top 12 SNPs in the Leukotriene Modifier or Corticosteroid or Corticosteroid-Salmeterol Trial.ResultsThe combined P value for the Childhood Asthma Management Program and Leukotriene Modifier or Corticosteroid or Corticosteroid-Salmeterol Trial populations was 4.8 × 10(-8) for rs3752120, which is located in the zinc finger protein gene ZNF432 and has an unknown function.ConclusionsInhaled corticosteroids appear to modulate the association of bronchodilator response with variant(s) in the ZNF432 gene among adults and children with asthma.
| S-EPMC3943570 | biostudies-literature
Project description:BackgroundThe frequency with which multiple corticosteroid abnormalities occur in cats with aldosterone secreting adrenocortical tumors is unknown.ObjectivesTo evaluate adrenal-derived corticosteroids in cats in which blood samples were submitted for measure of aldosterone.AnimalsTwo hundred ninety-seven cats.MethodsRetrospective study. Analysis of a convenience sample of previously submitted serum or plasma. Progesterone, corticosterone, and cortisol were measured in feline serum or plasma samples submitted to an endocrinology laboratory for aldosterone measurements. Demographics and clinical history were retrieved from submittal forms when provided. Statistical testing was performed to investigate associations among the adrenal corticosteroids.ResultsProgesterone and corticosterone concentrations were strongly correlated (ρ = 0.74; P < .001). Progesterone (median, 5 nmol/L; interquartile range, 3-10 nmol/L) and corticosterone (113 nmol/L, 38-250 nmol/L) in cats with markedly increased aldosterone concentrations (≥3000 pmol/L) were higher than progesterone (1 nmol/L, 1-2 nmol/L) and corticosterone (12 nmol/L, 3-25 nmol/L) in cats with normal aldosterone concentrations (P < .001 for both comparisons). Progesterone concentrations ≥10 nmol/L (normal, ≤2 nmol//L) occurred in 24 of 76 (32%) cats with aldosterone concentrations ≥3000 pmol/L. Cortisol was lower in cats with aldosterone concentrations ≥3000 pmol/L as compared to those with aldosterone concentrations <500 pmol/L (59 nmol/L, 27-103 nmol/L vs 103 nmol/L, 49-182 nmol/L; P = .002).Conclusions and clinical importanceMultiple corticosteroid abnormalities occur in a subset of cats with hyperaldosteronism. The magnitude of increases in progesterone and corticosterone in some cats with hyperaldosteronism is likely to be clinically relevant.
| S-EPMC8478033 | biostudies-literature
Project description:BackgroundIt is known that 15-30% overweight/obese adults do not suffer cardiometabolic consequences. There is limited literature examining factors that can be used to assess cardiometabolic health in overweight/obese children. If such factors can be identified, they would aid in differentiating those most in need for aggressive management.MethodsBaseline data from 7- to 12-year-old, overweight, and obese children enrolled in a weight management program at an urban hospital were analyzed. Homeostatic model assessment for insulin resistance (HOMA-IR) <2.6 was used to define insulin-sensitive and HOMA-IR ≥2.6 was used to defined insulin-resistant participants. Demographics, physical activity measures, and cardiometabolic risk factors were compared between the two phenotypes. Odds ratios (ORs) examining the association between intermediate endpoints (metabolic syndrome [MetS], nonalcoholic fatty liver disease [NAFLD], systemic inflammation, and microalbuminuria) and the two metabolic phenotypes were evaluated.ResultsOf the 362 overweight/obese participants, 157 (43.5%) were insulin sensitive and 204 (56.5%) were insulin resistant. Compared to the insulin-sensitive group, the insulin-resistant group was older (8.6±1.6 vs. 9.9±1.7; p<0.001) and had a higher BMI z-score (1.89±0.42 vs. 2.04±0.42; p=0.001). After multivariable adjustment, compared to the insulin-sensitive group, the insulin-resistant group had higher odds of having MetS (OR, 5.47; 95% confidence interval [CI]: 1.72, 17.35; p=0.004) and NAFLD (OR, 8.66; 95% CI, 2.48, 30.31; p=0.001), but not systemic inflammation (OR, 1.06; 95% CI: 0.56, 2.03; p=0.86) or microalbuminuria (OR, 1.71; 95% CI, 0.49, 6.04; p=0.403).ConclusionsUsing a HOMA-IR value of ≥2.6, clinical providers can identify prepubertal and early pubertal children most at risk. Focusing limited resources on aggressive weight interventions may lead to improvement in cardiometabolic health.
| S-EPMC4485365 | biostudies-literature
Project description:This study evaluated the effects of 2 levels of intake of high-amylose maize type 2 resistant starch (HAM-RS2) on insulin sensitivity (S(I)) in participants with waist circumference ≥89 (women) or ≥102 cm (men). Participants received 0 (control starch), 15, or 30 g/d (double-blind) of HAM-RS2 in random order for 4-wk periods separated by 3-wk washouts. Minimal model S(I) was assessed at the end of each period using the insulin-modified i.v. glucose tolerance test. The efficacy evaluable sample included 11 men and 22 women (mean ± SEM) age 49.5 ± 1.6 y, with a BMI of 30.6 ± 0.5 kg/m2 and waist circumference 105.3 ± 1.3 cm. A treatment main effect (P = 0.018) and a treatment × sex interaction (P = 0.033) were present. In men, least squares geometric mean analysis for S(I) did not differ after intake of 15 g/d HAM-RS2 (6.90 × 10⁻⁵ pmol⁻¹ · L⁻¹ × min⁻¹) and 30 g/d HAM-RS2 (7.13 × 10⁻⁵ pmol⁻¹ · L⁻¹ × min⁻¹), but both were higher than after the control treatment (4.66 × 10⁻⁵ pmol⁻¹ · L⁻¹ × min⁻¹) (P < 0.05). In women, there was no difference among the treatments (overall least squares ln-transformed mean ± pooled SEM = 1.80 ± 0.08; geometric mean = 6.05 × 10⁻⁵ pmol⁻¹ · L⁻¹ × min⁻¹). These results suggest that consumption of 15-30 g/d of HAM-RS2 improves S(I) in men. Additional research is needed to understand the mechanisms that might account for the treatment × sex interaction observed.
| S-EPMC3301990 | biostudies-literature
Project description:BACKGROUNDThe airways of obese asthmatics have been shown to be NO deficient, and this contributes to airway dysfunction and reduced response to inhaled corticosteroids. In cultured airway epithelial cells, L-citrulline, a precursor of L-arginine recycling and NO formation, has been shown to prevent asymmetric dimethyl arginine-mediated (ADMA-mediated) NO synthase (NOS2) uncoupling, restoring NO and reducing oxidative stress.METHODSIn a proof-of-concept, open-label pilot study in which participants were analyzed before and after treatment, we hypothesized that 15 g/d L-citrulline for 2 weeks would (a) increase the fractional excretion of NO (FeNO), (b) improve asthma control, and (c) improve lung function. To this end, we recruited obese (BMI >30) asthmatics on controller therapy, with a baseline FeNO of ≤30 ppb from the University of Colorado Medical Center and Duke University Health System.RESULTSA total of 41 subjects with an average FeNO of 17 ppb (95% CI, 15-19) and poorly controlled asthma (average asthma control questionnaire [ACQ] 1.5 [95% CI, 1.2-1.8]) completed the study. Compared with baseline, L-citrulline increased whereas ADMA and arginase concentration did not (values represent the mean Δ and 95% CI): plasma L-citrulline (190 μM, 84-297), plasma L-arginine (67 μM, 38-95), and plasma L-arginine/ADMA (ratio 117, 67-167). FeNO increased by 4.2 ppb (1.7-6.7 ppb); ACQ decreased by -0.46 (-0.67 to 0.27 points); the forced vital capacity and forced exhalation volume in 1 second, respectively, changed by 86 ml (10-161 ml) and 52 ml (-11 to 132 ml). In a secondary analysis, the greatest FEV1 increments occurred in those subjects with late-onset asthma (>12 years) (63 ml [95% CI, 1-137]), in females (80 ml [95% CI, 5-154]), with a greater change seen in late-onset females (100 ml, [95% CI, 2-177]). The changes in lung function or asthma control were not significantly associated with the changes before and after treatment in L-arginine/ADMA or FeNO.CONCLUSIONShort-term L-citrulline treatment improved asthma control and FeNO levels in obese asthmatics with low or normal FeNO. Larger FEV1 increments were observed in those with late-onset asthma and in females.TRIAL REGISTRATIONClinicalTrials.gov NCT01715844.FUNDINGNIH NHLBI R01 HL146542-01.
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Project description:Echinocandins, such as caspofungin, are commonly used to treat candidemia and aspergillosis. Success rates for candidemia treatment are approximately 70%. Dose optimization may further help improve these success rates, given that the microbial effect of these agents is concentration dependent. There are conflicting data as regards the effect of weight and/or obesity on caspofungin drug concentrations. We designed a prospective study to evaluate the population pharmacokinetics of caspofungin in adults with a weight difference range of 100 kg. Caspofungin pharmacokinetics were best described using a two-compartment pharmacokinetic model. There were 18 subjects studied, of whom half were women. The central volume was typically 4.2 liters but increased by a factor of (weight/53.6)(3/4). The peripheral compartment volume was typically 2.53 liters but increased by a factor of (weight/53.6)(3/2), an unusual power law signature. Similarly, the 3/4 power law best described the relationship between weight and systemic clearance for persons weighing >66.3 kg, whereas intercompartmental clearance was best described by the 3/2 power signature. There are two implications of our findings. First, lower caspofungin area-under-the-concentration-time curves are achieved in obese persons than thinner ones. This suggests that dose optimization in heavier patients may improve clinical success rates. Second, the 3/2 exponent is unusual in fractal geometry-based scaling and warrants further study. Moreover, this suggests that use of a "floating" instead of a fixed exponent may be more useful in studies where weight is under investigation as a potential cause of pharmacokinetic variability within adult patients. (This study protocol was registered at www.clinicaltrials.gov under registration number NCT01062165.).
| S-EPMC3632956 | biostudies-literature