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Introduction: Proton Pump inhibitors (PPIs) are commonly used for a variety of acid related disorders. Despite the overall effectiveness and safety profile of PPIs, some patients do not respond adequately or develop treatment related adverse events. This variable response among patients is in part due to genotype variability of CYP2C19, the gene encoding the CYP450 (CYP2C19) isoenzyme responsible for PPIs metabolism. Areas covered: This article provides an overview of the pharmacokinetics and mechanism of action of the currently available PPIs, including the magnitude of CYPC19 contribution to their metabolism. Additionally, the role of CYP2C19 genetic variability in the therapeutic effectiveness or outcomes of PPI therapy is highlighted in details, to provide supporting evidence for the potential value of CYP2C19 genotype-guided approaches to PPI drug therapy. Expert opinion: There is a large body of evidence describing the impact of CYP2C19 variability on PPIs and its potential role in individualizing PPI therapy, yet, CYP2C19 pharmacogenetics has not been widely implemented into clinical practice. More data are needed but CYP2C19 genotype-guided dosing of PPIs is likely to become increasingly common and is expected to improve clinical outcomes, and minimize side effects related to PPIs.

Introduction: Short- and long-acting β agonists (SABA and LABA) are bronchodilators for treating asthma. Bronchodilator response (BDR) is quantified by measuring air expired in the first second during a forced expiratory maneuver, prior to and following inhalation of SABA. BDR has been associated with a significant degree of heterogeneity, in part attributable to genetic variation. Heritability, the proportion of phenotypic variability accounted for by genetic variation is estimated to account for 50% of pulmonary function and 28.5% for BDR., Areas Covered: A MEDLINE search for English articles published from January 1990 to June 2014 was completed using the terms: bronchodilator, bronchodilator response, short-acting bronchodilator, long-acting bronchodilator, β2 adrenergic receptor gene (ADRB2), asthma and pharmacogenomics. The effects of ADRB2 variants on BDR and the safety of SABA and LABA + inhaled corticosteroids have been studied with equivocal results. Single and candidate gene studies have identified variants in other genes that alter response to bronchodilators. Associations were recently observed between hospital admission rates and two rare ADRB2 polymorphisms: Thr164Ile and a 25 base pair insertion-deletion at nucleotide -376. This was the first report of life-threatening events associated with LABA being linked to rare ADRB2 variants., Expert Opinion: Pharmacogenomic studies over the last two decades clearly demonstrate that polymorphisms alter patient response to bronchodilators in patients with asthma.

Objective: The relationship between weight status and asthma characteristics in children remains inadequately defined. Very little has been published on the risk of exacerbation, physician perception of severity, and the level controller treatment prescribed to underweight and obese children with asthma in a real-world setting., Methods: We assessed the diagnostic severity, pulmonary function, exacerbation prevalence, and controller treatment level in 10,559 new asthma patients seen at one of four pediatric asthma subspecialty clinics among three BMI groups. Participants were analyzed by body mass index (BMI)-percentile based on Centers for Disease Control & Prevention classification. Multivariable logistic regression models were used to assess the associations between BMI-percentile cohort group and asthma outcomes. RESULTS. Underweight asthmatics were rare (2.5%) relative to obese asthmatics but appeared to have the greatest impairment in forced vital capacity and had the greatest controller treatment burden. Obese asthmatic children made up 26.2% of our cohort and were more likely to have severe disease (odds ratio (OR) 1.40, 95% confidence interval (CI) 1.06-1.85) and airflow obstruction (OR 1.36, 95% CI 1.16-1.59) compared to normal weight asthmatics. Obese asthmatics were not at greater risk for exacerbation (OR 1.41, 95% CI 0.64-3.11) or high treatment burden (OR 1.03, 95% CI 0.83-1.28). CONCLUSIONS. Obesity is more common than underweight status among children with asthma. Both underweight and obese children with asthma have worse lung function and asthma-related outcomes compared to similar normal weight children, though the phenotypic characteristics of underweight and obese asthmatics differed considerably.

Objective: To determine whether high BMI-percentile is associated with misdiagnosis of asthma among children referred to an asthma specialist., Methods: We queried the electronic records of children 8 to 18 years of age seen by a Nemours pediatric pulmonologist. All visits during a 6-year period with the chief complaint of asthma, or an asthma-like symptom such as wheeze, cough, or dyspnea, were included. We collected spirometry, blood counts, and immunoglobulin E (IgE) if available. We determined whether the child had referring physician-diagnosed asthma, specialist-diagnosed asthma, or both. Specialist-diagnosed asthmatics who met additional objective "gold-standard" criterion were labeled strict-criterion asthma., Results: Prevalence of high BMI-percentile was extremely common in all defined asthma groups, even those meeting strict criteria for diagnosis. Referring physician-diagnosed asthmatics did not have higher rates of obesity, and referring physician-diagnosed asthmatics had objective indicators of asthma that were the same as asthmatics diagnosed by a specialist. There was good diagnostic correlation between referring physicians and asthma specialists that was not affected by BMI. Among specialist-diagnosed asthmatics, increased BMI-percentile associated with significantly reduced forced expiratory volume in 1 second (FEV(1)), forced expiratory flow during the middle half of the forced vital capacity (FEF(25 - 75)), and FEV(1)/forced vital capacity (FVC); and significantly increased total blood leukocytes, neutrophils, and platelets compared to leans. For all 2,258 referrals, the estimated odds ratio of receiving a specialist-diagnosis of asthma increased by 0.4% with each increasing BMI percentile., Conclusions: Referring physicians do not appear to erroneously diagnose children with asthma due to overweight status. Our data confirm that overweight status is extremely high in children with true asthma and likely increases the risk for true asthma. Although these data cannot discern causality, high BMI-percentile is associated with greater airflow obstruction and elevated markers of systemic inflammation that could contribute to underlying mechanisms of asthma.

Patients with end-stage renal disease (ESRD) are at high risk for cardiovascular disease (CVD) and therefore should be treated according to ACC/AHA Guidelines. Scant data are available concerning the actual use of cardioprotective drugs in this population. The use of angiotensin-converting enzyme inhibitors (ACE-I), beta-blockers, aspirin, and statins was assessed in 271 (72% males, 66% Caucasians) high-risk ESRD patients on hemodialysis. The study population comprised 27% smokers, 95% with hypertension, 38% with diabetes, and 44% with dyslipidemia; 44% of patients had overt CVD at baseline, including 9% with heart failure, 9% with prior myocardial infarction, and 3% with previous myocardial revascularization. One-third of all patients were not receiving any cardioprotective drugs; among those patients who were, 42% were on one drug, 21% were on two, 3.7% were on three, and 1.5% were on four. The most prescribed agent was ACE-I (35.8%), followed by aspirin (30.6%), and beta-blockers (28.0%). The use of statins was remarkably and significantly low (4.1%) (p < 0.001), even in the higher risk subgroups (patients with diabetes or macrovascular disease). ACE-I plus aspirin was the most prescribed combination (8.5%). Cardioprotective agents recommended for risk-factor modification by the ACC/AHA Guidelines for their well-established efficacy in the general population were underutilized in this cohort of high-risk hypertensive hemodialysis patients, despite an elevated prevalence of clinically evident CVD. Speculatively, this fact may be relevant to better understand the known increased cardiovascular morbidity-mortality associated with chronic renal disease.

Obesity is a risk factor for being diagnosed with asthma, but there is conflicting evidence on whether obesity is a risk factor for lung function abnormalities characteristic of asthma. We studied a cohort of 488 subjects, 47% of whom were obese. Obese and non-obese subjects with asthma had similar airflow limitation and bronchodilator responsiveness, but obese participants had increased sleep disturbance and gastroesophageal reflux disease, higher cytokine levels, and a trend towards increased exacerbations when treated with theophylline. Obese and non-obese asthmatics have similar lung function abnormalities, but comorbidities and altered responses to medications may significantly affect asthma control in obese people.

Our goal was to explore associations between ss2 adrenergic receptor polymorphisms and markers of asthma severity in African American and Caucasian patients with asthma. Polymorphisms at loci -1023, -654, -47, 46, 79, 491, and 523 were genotyped and haplotypes were imputed in 143 African Americans and 336 Caucasians. C523A genotype associated with percentage of African Americans (but not of Caucasians) having an asthma exacerbation: AA, AC, and CC genotypes were 17, 29, and 40%, respectively (p = 0.018). Symptom scores, pulmonary function, and rescue inhaler use paralleled exacerbation prevalence. We conclude the 523 A allele modifies asthma severity in African Americans.

Unlabelled: Lymphatic drainage plays an important role in the uptake of particulates in the respiratory system, being also associated to the spreading of lung cancer through metastasis development. In recent years solid lipid nanoparticles (SLN) have been proposed as carriers of anti-tumoural drugs, for their low toxicity and surface characteristics make them suitable for either imaging (gamma-scintigraphy) or therapy upon encapsulation of cytotoxic drugs. Assessment of inhaled radiolabelled SLN biodistribution is described in the present work., Methods: Nanoparticles (200 nm) were radiolabelled with 99mTc using the lipophilic chelator D,L-hexamehylpropyleneamine oxime (HMPAO). Biodistribution studies were carried out following aerosolisation and administration of a 99mTc-HMPAO-SLN suspension to a group of adult male Wistar rats. A 60 min dynamic image acquisition was performed in a gamma-camera, followed by static image collection at 30 min intervals up to 4 h postinhalation. Radiation counting was performed in organ samples, collected after the animals were sacrificed., Results: The data show an important and significant uptake of the radiolabelled SLN into the lymphatics after inhalation, and a high rate of distribution in periaortic, axillar and inguinal lymph nodes., Conclusion: Results indicate that SLN could be effective colloidal carriers for lymphoscintigraphy or therapy upon pulmonary delivery.

Background: Left ventricular hypertrophy is common in renal transplant patients but the factors influencing its development remain to be determined. The present investigation was conducted to study the effect of blood pressure load on the left ventricular mass of recently transplanted patients using 24-h ambulatory blood pressure monitoring (ABPM)., Methods: We studied 30 renal transplant (RT) patients (36.1+/-13.7 years old, 11 males, 26 Whites, 4 diabetics, 15 under antihypertensive medication, 21 recipients of cadaver donors, and all treated with steroids, cyclosporin and azathioprine and with adequate (serum creatinine < 1.8 mg/100 ml) renal function). The median duration of dialysis treatment before transplant was 37 months, and the studies were performed during the first 40 days post-transplantation. Blood pressure was measured after a 15-min rest (casual blood pressure) and during a 24-h period with a SpaceLabs apparatus. Echocardiograms were obtained from all patients., Results: Mean left ventricular mass index (LVMI) was 153+/-44 g/m2; casual systolic and diastolic BP (mmHg) was 152+/-25 and 92+/-13, whereas systolic and diastolic 24-h BP was 133+/-12 and 85+/-8, respectively. The systolic sleeping BP/awake systolic BP (SSBP/ASBP) ratio was 0.94+/-0.07, and 73% of the patients did not show a significant (>10%) fall of systolic blood pressure during sleep. Multivariate analysis showed that awake systolic blood pressure was the only variable that independently influenced LVMI after adjusting for confounding factors (regression coefficient = 0.49, p = 0.01). Casual systolic and diastolic BP, sleeping systolic and diastolic blood pressure, 24-h heart rate, age, race, gender, smoking, body mass index, duration of dialysis, diabetes, antihypertensive and immunosuppressive drugs and levels of hematocrit, creatinine and serum lipids did not correlate with LVMI., Conclusion: The data indicate that left ventricular hypertrophy during the early post-transplant period is mainly influenced by awake blood pressure load. They also suggest that ABPM may be more useful in the diagnosis and management of post-transplant hypertension than casual BP. The findings emphasize the importance of rigid blood pressure control in renal transplant recipients.

We examined the effect of duration of beta 2-adrenergic receptor (beta 2AR) occupancy by isoproterenol on specific binding of 125I-lodocyanopindolol (125I-ICYP) in membranes from rat L6 myoblasts. Ten minute exposure caused a time-and concentration-dependent maximal decrease in 125I-ICYP binding 24 hours after exposure equal to that following continuous exposure (p < 0.05). Low temperature, concanavalin A, H89 and ICl 118,551 blocked the decline in 125I-ICYP binding during the first hour following exposure probably representing receptor sequestration to a compartment or change to a form incapable of ligand binding. Compared to controls, receptor binding 4 and 24 hours following exposure was reduced 56 +/- 8.7% and 72 +/- 8.8%, respectively (p < 0.05), and was blocked by ICl 118,551 but not CGP12177. Isoproterenol-induced, but not forskolin-stimulated, cAMP accumulation was reduced 35% 24 hours following exposure (p < 0.05). 125I-ICYP binding in intact L6 cells 4 and 24 hours after exposure were respectively 56 +/- 8.9 and 61 +/- 13% of controls (p < 0.05). Following agonist exposure, CHO cell membranes expressing human beta 2ARs exhibited 125I-ICYP binding 85 +/- 2.0% and 6 +/- 2.8% of control values 4 and 24 hours, respectively (p < 0.05). A model predicting that full occupation of the beta 2AR activates receptor degradation explains our results that agonist-induced down-regulation of beta 2AR does not require continuous presence of the agonist.

Patients who die during the first three months on dialysis are not systematically included in the American and European statistics. In contrast, only a few patients survive more than 10 years on this modality of renal replacement therapy. The factors determining these two extreme forms of outcome are poorly understood. We tested the hypothesis that a few variables, easily obtainable at the initiation of dialysis, would identify those individuals at high and low risk of early death. We retrospectively studied 23 patients who died within 90 days of initiating dialysis and 20 patients who survived more than 10 years. These patients were admitted for dialysis to a Brazilian center between July 1, 1976 and February 28, 1997. The baseline variables assessed which were thought to influence survival, were: age, sex, race, body weight, etiology of renal disease, blood pressure, comorbid conditions, hematocrit and serum electrolytes, albumin, creatinine, urea, and urea/creatinine ratio. Univariate analysis showed that patients who died early were older (56.2 +/- 15.6 vs. 42.1 +/- 10.4 years, p < 0.01), had lower serum creatinine (10.6 +/- 2.9 vs. 13.7 +/- 3.7 mg/dL, p < 0.01) and albumin (3.3 +/- 0.9 vs. 4.0 +/- 0.5 g/dL) and a higher urea/creatinine ratio (18.4 +/- 5.8 vs. 13.5 +/- 4.8, p < 0.01) compared with subjects surviving more than 10 years. Early death patients also had more cases of diabetes (35% vs. 0%, p < 0.01) and less chronic glomerulonephritis (9% vs. 35%, p < 0.05). Multivariate analysis showed that age (p < 0.01, CI 1.02 to 1.15, odds ratio 1.1) and urea/creatinine ratio (p < 0.01, CI 1.03 to 1.38, odds ratio 1.2) were positively and independently related to outcome. In the early death group, malnutrition was an important cause of death (17% of all deaths). Compared to baseline data, long-term survivors, at the last follow up, presented reduced systolic blood pressure and increased hematocrit and unchanged body weight, serum albumin and urea/creatinine ratio. These results, based on easily accessible initial variables, suggest that early death on dialysis is influenced by age and by indices related to the nutritional condition of the patients. They also highlight the importance of a potentially correctable risk factor in a population with an elevated prevalence of premature death.

Serum lipoprotein(a) [Lp(a)] concentrations in chronic renal failure patients were investigated in relation to the degree of renal insufficiency, treatment by maintenance hemodialysis, and correction of uremia by renal transplantation with or without cyclosporin immunosuppression. Fast serum levels of Lp(a) (mg/100 mL) were determined in 34 chronic renal failure patients not in need of maintenance dialysis (16 with serum creatinine 2.0-4.0 mg/100 mL; 18 with serum creatinine higher than 4.0 mg/100 mL), 40 patients treated by hemodialysis, 55 successful renal transplant recipients (28 under cyclosporin treatment and 27 receiving no cyclosporin), and 34 healthy controls. Age and sex distributions were similar among groups. Pregnant women; non-White individuals; subjects with obesity, diabetes, nephrotic syndrome, and hepatic and thyroid diseases; and those treated with oral contraceptives or lipid-lowering drugs were excluded from the study. Compared to controls, median Lp(a) was increased in nondialyzed renal failure patients (11 vs. 47.5 p < 0.001) and this was the only lipid abnormally observed in the group. There was no significant difference in Lp(a) levels between nondialized renal failure patients with serum creatinine 2.0-4.0 and > 4.0 mg/100 mL (47 vs. 49, NS). Moreover, Pearson correlation coefficient (r = 0.01, NS) showed that Lp(a) values were not related to serum creatinine in nondialyzed patients, In hemodialysis subjects Lp(a) concentrations (median = 29) were intermediate between those observed in nondialyzed patients and controls but the differences were not significant. Lp(a) levels in renal transplant patients treated with cyclosporin (median = 6) and not receiving cyclosporin (median = 13) were similar and did not differ from controls. Serum Lp(a) increases and attains maximum levels with mild/moderate reduction in renal function, and does not seem to change through late renal failure stages or in relation to the introduction of maintenance hemodialysis treatment. Correction of uremia by successful renal transplant caused normalization of Lp(a) levels regardless of the use of cyclosporin. Increased Lp(a) levels may be the earliest and more consistent lipid alteration seen in predialysis renal failure.

The relationship between the Ki of the B2 adrenoceptor and EC50 values characterizing receptor down-regulation induced by isoproterenol and six beta antagonists classified as having weak to strong intrinsic sympathomimetic activity (ISA) was determined using L6 myoblasts. It was hypothesized that if receptor loss induced by beta antagonists with ISA was mediated through cAMP, EC50 = Ki. EC50/Ki ratios for (-)isoproterenol, (-) and (+) celiprolol were 0.006, 0.01 and 0.08, respectively (p < 0.05); ratios for (-)pindolol and dilevalol were 19 and 9.5, respectively (p < 0.05). EC50/Ki ratios for acebutalol and (-)alprenolol were not significantly different from 1.0. Isoproterenol and dilevalol maximally down-regulated receptor density 89 and 83%, respectively, followed by (+)celiprolol, 54%; (-)celiprolol, 53%; acebutalol, 41%; (-)pindolol, 36% and (-)alprenolol, 31%. Receptor loss was blocked in each case by ICI118,551 or sotalol. A sensitive radioimmunoassay failed to detect increased cAMP accumulation following pretreatment with concentrations of acebutalol, (-)alprenolol, celiprolol and (-)pindolol 100 times their respective Ki values. Isoproterenol and dilevalol stimulated cAMP accumulation 100- and 2-fold over basal, respectively. We conclude that receptor loss induced by beta antagonists with ISA is mediated through the beta 2 adrenoceptor and in at least some cases is cAMP-independent.