Target inhibition of galectin-3 by inhaled TD139 in patients with idiopathic pulmonary fibrosis.

Galectin (Gal)-3 is a profibrotic ß-galactoside-binding lectin that plays a key role in the pathogenesis of idiopathic pulmonary fibrosis (IPF) and IPF exacerbations. TD139 is a novel and potent small-molecule inhibitor of Gal-3.A randomised, double-blind, multicentre, placebo-controlled, phase 1/2a study was conducted to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of inhaled TD139 in 36 healthy subjects and 24 patients with IPF. Six dose cohorts of six healthy subjects were evaluated (4:2 TD139:placebo ratio) with single doses of TD139 (0.15-50 mg) and three dose cohorts of eight patients with IPF (5:3 TD139:placebo ratio) with once-daily doses of TD139 (0.3-10 mg) for 14 days.Inhaled TD139 was well tolerated with no significant treatment-related side-effects. TD139 was rapidly absorbed, with mean time taken to reach maximum plasma concentration (C max) values ranging from 0.6 to 3 h and a plasma half-life (T 1/2) of 8 h. The concentration of TD139 in the lung was >567-fold higher than in the blood, with systemic exposure predicting exposure in the target compartment. Gal-3 expression on alveolar macrophages was reduced in the 3 and 10 mg dose groups compared with placebo, with a concentration-dependent inhibition demonstrated. Inhibition of Gal-3 expression in the lung was associated with reductions in plasma biomarkers centrally relevant to IPF pathobiology (platelet-derived growth factor-BB, plasminogen activator inhibitor-1, Gal-3, CCL18 and YKL-40).TD139 is safe and well tolerated in healthy subjects and IPF patients. It was shown to suppress Gal-3 expression on bronchoalveolar lavage macrophages and, in a concerted fashion, decrease plasma biomarkers associated with IPF progression.

Forced oscillation technique in spinal muscular atrophy.

BACKGROUND: Spinal muscular atrophy (SMA) causes respiratory compromise that is difficult to assess in young children. The forced oscillation technique (FOT) is commercially available for children as young as 2 years of age and is nonvolitional. The aim of this study was to assess the usefulness of FOT in young children with SMA. METHODS: Children with SMA aged < 10 years were recruited. FOT was performed every 3 months for 12 months (five visits). Spirometry and assisted and unassisted peak cough flow (PCF) were performed where possible. Polysomnography was performed on children with type 2 SMA. Clinical information included SMA type, chest infections, Cobb angle, medications, and mobility. Regression analysis assessed relationships between FOT and FVC, PCF, and apnea/hypopnea index (AHI). Analysis of variance sought relationships to clinical characteristics. RESULTS: Twelve children (seven male) were recruited; mean age was 6.26 (± 2.59) years. Respiratory reactance at 8 Hz (Xrs8) (mean z score, +1.41; SD, 1.90; P < .03) and respiratory resistance at 8 Hz (Rrs8) (mean z score, +0.66; SD, 1.34; P = .12) were abnormal. Four children performed spirometry. Linear relationships to Xrs8 exist: FVC (R2, 0.54), unassisted PCF (R2, 0.33), assisted PCF (R2, 0.43), and AHI (R2, 0.32). Over 12 months, Xrs8z score worsened (rate of change of +1.08, P < .001) and Rrs8z score worsened (rate of change +0.51, P < .001). No relationship (P > .05) was found between clinical characteristics and FOT values. CONCLUSIONS: FOT is feasible in young children with SMA, with abnormal values of reactance and resistance on grouped data, worsening over 12 months. Xrs8 is related to respiratory tests used to monitor progress in SMA (FVC, PCF, AHI). Further research on the value of FOT in managing individuals is warranted.

Metabolic and antihypertensive effects of combined angiotensin receptor blocker and diuretic therapy in prediabetic hypertensive patients with the cardiometabolic syndrome.

Hypertensive patients with the cardiometabolic syndrome (CMS) are at increased risk for type 2 diabetes and cardiovascular disease. The authors examined effects of valsartan and hydrochlorothiazide (HCTZ) combined and alone on insulin sensitivity (using homeostasis model assessment-insulin resistance [HOMA-IR]), and inflammatory/metabolic biomarkers in prediabetic hypertensive persons with CMS. Eligible patients entered 16-week therapy with valsartan 320 mg/d (n=189), HCTZ 25 mg/d (n=190), or valsartan/HCTZ 320/25 mg/d (n=187). At the end point, there were no statistically significant differences in HOMA-IR among the 3 groups. HCTZ significantly increased hemoglobin A(1c) and triglyceride concentrations and lowered serum potassium levels vs valsartan. HCTZ also increased plasma aldosterone and C-reactive protein levels. Blood pressure reduction and blood pressure control rates were highest with valsartan/HCTZ. There were no differences between combination valsartan/HCTZ or monotherapies on a measure of insulin sensitivity; however, the negative metabolic effects of HCTZ (increase in triglyceride and hemoglobin A(1c) values) were absent with valsartan/HCTZ, indicating an ameliorating effect of valsartan on these measures.

Safety and efficacy of the oral direct renin inhibitor aliskiren in elderly patients with hypertension.

OBJECTIVES: To evaluate the efficacy, safety and tolerability of aliskiren in elderly patients (> or =65 years old) with essential hypertension. METHODS: In this double-blind, multicenter study, 355 elderly patients with hypertension [office mean sitting systolic blood pressure (msSBP) > or =145-<180 mmHg and mean 24-h ambulatory systolic BP (ASBP) > or =135 mmHg] were randomized to once-daily treatment for 8 weeks with aliskiren 75 mg (n = 91), 150 mg (n = 84), 300 mg (n = 94) or the comparator lisinopril 10 mg (n = 86). The primary efficacy variable was change in mean 24-h ASBP. RESULTS: At endpoint, aliskiren 75 mg, 150 mg, 300 mg and lisinopril 10 mg lowered mean 24-h ASBP (least-squares mean+/-SEM) by 8.4+/-0.8, 7.1+/-0.8, 8.7+/-0.8 and 10.2+/-0.9 mmHg, and mean 24-h ambulatory diastolic BP by 4.5+/-0.5, 3.6+/-0.5, 3.9+/-0.5 and 6.3+/-0.5 mmHg, respectively, with no significant difference between aliskiren doses. The trough-to-peak ratio for ASBP reduction with aliskiren 75 mg, 150 mg, 300 mg and lisinopril 10 mg was 0.77, 0.64, 0.79 and 0.87, respectively. All treatments lowered office msSBP and mean sitting diastolic BP (msDBP) compared with baseline. A significantly greater proportion of patients receiving aliskiren 300 mg achieved BP control (msSBP/msDBP <140/90 mmHg) compared with those receiving aliskiren 75 mg (36.2% vs 24.2%, p = 0.033). There was no evidence of dose-related increases in the rate of adverse events with aliskiren treatment. CONCLUSIONS: Aliskiren, a novel direct renin inhibitor, provides effective 24-h BP lowering with no evidence of dose-related increases in the incidence of adverse events in elderly patients with hypertension.