An exploratory, randomised, placebo-controlled, 14 day trial of the soluble guanylate cyclase stimulator praliciguat in participants with type 2 diabetes and hypertension.

AIMS/HYPOTHESIS: Praliciguat (IW-1973), a soluble guanylate cyclase stimulator, amplifies nitric oxide signalling. This exploratory trial investigated the safety, tolerability, pharmacokinetic profile and pharmacodynamic effects of praliciguat in individuals with type 2 diabetes and hypertension. METHODS: This Phase IIA, double-blind, placebo-controlled trial investigated praliciguat in 26 participants with type 2 diabetes and hypertension on stable glucose- and BP-lowering therapies. Participants were randomly allocated in a 3:5:5 ratio to three groups: placebo (n = 6), praliciguat 40 mg once daily for days 1-14 (n = 10), or praliciguat 20 mg twice daily for days 1-7 then 40 mg once daily for days 8-14 (n = 10). Assessments were made in clinic and included treatment-emergent adverse events, pharmacokinetics, metabolic variables, 24 h BP and heart rate, platelet function, reactive hyperaemia index (RHI) and plasma biomarkers. Participants, the sponsor, the investigator and clinic study staff (except designated pharmacy personnel) were blinded to group assignment. RESULTS: Participants treated for 14 days with praliciguat had least-square mean change-from-baseline differences vs placebo (95% CI) of -0.7 (-1.8, 0.4) mmol/l for fasting plasma glucose, -0.7 (-1.1, -0.2) mmol/l for total cholesterol, -0.5 (-1.0, -0.1) mmol/l for LDL-cholesterol, -23 (-56, 9) for HOMA-IR in those not being treated with insulin, and -5 (-10, 1) mmHg and 3 (-1, 6) beats/min for average 24 h mean arterial pressure and heart rate, respectively. Apart from one serious adverse event (SAE; upper gastrointestinal haemorrhage), praliciguat was well tolerated. Praliciguat did not affect platelet function or RHI. Among exploratory biomarkers, plasma levels of asymmetric dimethylarginine decreased in praliciguat vs placebo recipients. CONCLUSIONS/INTERPRETATION: In participants with type 2 diabetes and hypertension on standard therapies, over 14 days praliciguat was well tolerated, except for a single SAE, and showed positive trends in metabolic and BP variables. These results support further clinical investigation of praliciguat. TRIAL REGISTRATION: ClinicalTrials.gov NCT03091920. FUNDING: This trial was funded by Cyclerion Therapeutics.

Genome-wide association analysis in asthma subjects identifies SPATS2L as a novel bronchodilator response gene.

Bronchodilator response (BDR) is an important asthma phenotype that measures reversibility of airway obstruction by comparing lung function (i.e. FEV(1)) before and after the administration of a short-acting ß(2)-agonist, the most common rescue medications used for the treatment of asthma. BDR also serves as a test of ß(2)-agonist efficacy. BDR is a complex trait that is partly under genetic control. A genome-wide association study (GWAS) of BDR, quantified as percent change in baseline FEV(1) after administration of a ß(2)-agonist, was performed with 1,644 non-Hispanic white asthmatic subjects from six drug clinical trials: CAMP, LOCCS, LODO, a medication trial conducted by Sepracor, CARE, and ACRN. Data for 469,884 single-nucleotide polymorphisms (SNPs) were used to measure the association of SNPs with BDR using a linear regression model, while adjusting for age, sex, and height. Replication of primary P-values was attempted in 501 white subjects from SARP and 550 white subjects from DAG. Experimental evidence supporting the top gene was obtained via siRNA knockdown and Western blotting analyses. The lowest overall combined P-value was 9.7E-07 for SNP rs295137, near the SPATS2L gene. Among subjects in the primary analysis, those with rs295137 TT genotype had a median BDR of 16.0 (IQR = [6.2, 32.4]), while those with CC or TC genotypes had a median BDR of 10.9 (IQR = [5.0, 22.2]). SPATS2L mRNA knockdown resulted in increased ß(2)-adrenergic receptor levels. Our results suggest that SPATS2L may be an important regulator of ß(2)-adrenergic receptor down-regulation and that there is promise in gaining a better understanding of the biological mechanisms of differential response to ß(2)-agonists through GWAS.

Effect of Selenium Nanoparticle Size on IL-6 Detection Sensitivity in a Lateral Flow Device.

Sepsis is the body's response to an infection. Existing diagnostic testing equipment is not available in primary care settings and requires long waiting times. Lateral flow devices (LFDs) could be employed in point-of-care (POC) settings for sepsis detection; however, they currently lack the required sensitivity. Herein, LFDs are constructed using 150-310 nm sized selenium nanoparticles (SeNPs) and are compared to commercial 40 nm gold nanoparticles (AuNPs) for the detection of the sepsis biomarker interleukin-6 (IL-6). Both 310 and 150 nm SeNPs reported a lower limit of detection (LOD) than 40 nm AuNPs (0.1 ng/mL compared to 1 ng/mL), although at the cost of test line visual intensity. This is to our knowledge the first use of larger SeNPs (>100 nm) in LFDs and the first comparison of the effect of the size of SeNPs on assay sensitivity in this context. The results herein demonstrate that large SeNPs are viable alternatives to existing commercial labels, with the potential for higher sensitivity than standard 40 nm AuNPs.

Regulatory haplotypes in ARG1 are associated with altered bronchodilator response.

RATIONALE: ß2-agonists, the most common treatment for asthma, have a wide interindividual variability in response, which is partially attributed to genetic factors. We previously identified single nucleotide polymorphisms in the arginase 1 (ARG1) gene, which are associated with ß2-agonist bronchodilator response (BDR). OBJECTIVES: To identify cis-acting haplotypes in the ARG1 locus that are associated with BDR in patients with asthma and regulate gene expression in vitro. METHODS: We resequenced ARG1 in 96 individuals and identified three common, 5' haplotypes (denoted 1, 2, and 3). A haplotype-based association analysis of BDR was performed in three independent, adult asthma drug trial populations. Next, each haplotype was cloned into vectors containing a luciferase reporter gene and transfected into human airway epithelial cells (BEAS-2B) to ascertain its effect on gene expression. MEASUREMENTS AND MAIN RESULTS: BDR varied by haplotype in each of the three populations with asthma. Individuals with haplotype 1 were more likely to have higher BDR, compared to those with haplotypes 2 and 3, which is supported by odds ratios of 1.25 (95% confidence interval, 1.03-1.71) and 2.18 (95% confidence interval, 1.34-2.52), respectively. Luciferase expression was 50% greater in cells transfected with haplotype 1 compared to haplotypes 2 and 3. CONCLUSIONS: The identified ARG1 haplotypes seem to alter BDR and differentially regulate gene expression with a concordance of decreased BDR and reporter activity from haplotypes 2 and 3. These findings may facilitate pharmacogenetic tests to predict individuals who may benefit from other therapeutic agents in addition to ß(2)-agonists for optimal asthma management. Clinical trial registered with www.clinicaltrials.gov (NCT00156819, NCT00046644, and NCT00073840).

Analytical method validation for assay determination of cannabidiol and tetrahydrocannabinol in hemp oil infused products by RP-HPLC.

A simple quantitative reverse phase high performance liquid chromatographic (RP-HPLC) method has been developed and validated for assay determination of cannabidiol and tetrahydrocannabinol in hemp oil infused products. The RP-HPLC method was developed and optimized for the mobile phase composition, flow rate, column selection and detector wavelength. An isocratic elution of samples were performed on SOLAS 100 Å C18 150 mm × 4.6 mm, 5 µm column with a mobile phase containing 75/25 acetonitrile/water v/v, with a flow rate of 1.5 mL/min by using an ultraviolet-visible (UV/Vis) detector operating at 214 nm. The RP-HPLC method was validated to meet regulatory requirements which covers specificity, accuracy, range, linearity, precision, system suitability and robustness. The validated assay test method was applied successfully to quantify cannabidiol and tetrahydrocannabinol in commercial hemp oil infused products such as tablets, soft gel capsules, plant extract oils, oral drops, tincture, and beverage enhancers. All the test results were found acceptable as per ICH guidelines, and this confirmed the feasibility of this method for its intended use in regular quality control and assay of cannabidiol and tetrahydrocannabinol in hemp oil infused products.

The Anti-Obesity Effect of Porous Silica Is Dependent on Pore Nanostructure, Particle Size, and Surface Chemistry in an In Vitro Digestion Model.

The potential for porous silica to serve as an effective anti-obesity agent has received growing attention in recent years. However, neither the exact pharmacological mechanism nor the fundamental physicochemical properties of porous silica that drive its weight-lowering effect are well understood. Subsequently, in this study, an advanced in vitro digestion model capable of monitoring lipid and carbohydrate digestion was employed to elucidate the effect of porous silica supplementation on digestive enzyme activities. A suite of porous silica samples with contrasting physicochemical properties was investigated, where it was established that the inhibitory action of porous silica on digestive enzyme functionality was strongly dependent on porous nanostructure, particle size and morphology, and surface chemistry. Insights derived from this study validate the capacity of porous silica to impede the digestive processes mediated by pancreatic lipase and α-amylase within the gastrointestinal tract, while the subtle interplay between porous nanostructure and enzyme inhibition indicates that the anti-obesity effect can be optimized through strategic particle design.

Swelling of ionic and nonionic surfactant micelles by high pressure gases.

The influence of different solvent environments on the size, shape, and characteristics of surfactant micelles of Pluronic F127 and CTAB was investigated by small-angle neutron scattering (SANS). SANS experiments were undertaken on dilute micellar surfactant solutions of F127 and CTAB that between them were exposed to liquid and supercritical carbon dioxide, liquid propane, ethane, and heptane under various pressures and temperatures. Swelling of the surfactant micelles could be directly related to the solubility of the solvents within the micelles, especially within their cores. Carbon dioxide produced the largest swelling of the Pluronic F127 micelles, compared to propane and ethane, which mirrors the solubility of the gases in the PPO core of the micelles. Conversely, the extent of swelling of the cores of CTAB micelles was greater with propane compared to carbon dioxide, which again relates to the solubility of the solvents in the alkane core of the CTAB micelles.

Preparation, characterisation and modification of carbon-based monolithic rods for chromatographic applications.

A range of porous carbon-based monolithic (PCM) rods with flow-through pore sizes of 1, 2, 5 and 10 mum, were produced using a silica particle template method. The rods were characterised using SEM and energy-dispersive X-ray spectroscopy, BET surface area and porous structure analysis, dilatometry and thermal gravimetry. SEM evaluation of the carbon monolithic structures revealed an interconnected rigid bimodal porous structure and energy-dispersive X-ray spectroscopy analysis verified the quantitative removal of the embedded silica beads. The specific surface areas of the 1, 2, 5 and 10 mum rods were 178, 154, 84 and 125 m(2)/g after pyrolysis and silica removal, respectively. Shrinkage of the monolithic rods during pyrolysis is proportional to the particle size of the silica used and ranged from 9 to 12%. Mercury porosimetry showed a narrow distribution of pore sizes, with an average of approximately 700 nm for the 1 mum carbon monolith. The suitability of bare and surface oxidised PCM rods for the use as a stationary phase for reversed and normal phase LC was explored. The additional modification of PCM rods with gold micro-particles followed by 6-mercaptohexanoic acid was performed and ion-exchange properties were evaluated.

Porous silica spheres as indoor air pollutant scavengers.

Porous silica spheres were investigated for their effectiveness in removing typical indoor air pollutants, such as aromatic and carbonyl-containing volatile organic compounds (VOCs), and compared to the commercially available polymer styrene-divinylbenzene (XAD-4). The silica spheres and the XAD-4 resin were coated on denuder sampling devices and their adsorption efficiencies for VOCs evaluated using an indoor air simulation chamber. Real indoor sampling was also undertaken to evaluate the affinity of the silica adsorbents for a variety of indoor VOCs. The silica sphere adsorbents were found to have a high affinity for polar carbonyls and found to be more efficient than the XAD-4 resin at adsorbing carbonyls in an indoor environment.

Effects of the Soluble Guanylate Cyclase Stimulator Praliciguat in Diabetic Kidney Disease: A Randomized Placebo-Controlled Clinical Trial.

BACKGROUND AND OBJECTIVES: Impaired nitric oxide signaling through soluble guanylate cyclase has been implicated in the pathophysiology of diabetic kidney disease. Praliciguat, a soluble guanylate cyclase stimulator that amplifies nitric oxide signaling, inhibited kidney inflammation and fibrosis in animal models. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In a phase 2 trial, 156 adults with type 2 diabetes, eGFR 30-75 ml/min per 1.73 m2, and urine albumin-creatinine ratio 200-5000 mg/g treated with renin-angiotensin system inhibitors were randomly allocated 1:1:1 to placebo, 20 mg praliciguat, or 40 mg praliciguat daily for 12 weeks. The primary efficacy and safety outcomes were change from baseline to weeks 8 and 12 in urine albumin-creatinine ratio and treatment-emergent adverse events, respectively. Other outcomes assessed were 24-hour ambulatory BP and metabolic parameters. RESULTS: Of 156 participants randomized, 140 (90%) completed the study. The primary efficacy analysis demonstrated a mean change from baseline in urine albumin-creatinine ratio of -28% (90% confidence interval, -36 to -18) in the pooled praliciguat group and -15% (-28 to 0.4) in the placebo group (difference -15%; -31 to 4; P=0.17). Between-group decreases from baseline to week 12 for praliciguat versus placebo were seen in mean 24-hour systolic BP (-4 mm Hg; -8 to -1), hemoglobin A1c (-0.3%; -0.5 to -0.03), and serum cholesterol (-10 mg/dl; -19 to -1). The incidence of treatment-emergent adverse events was similar in the pooled praliciguat and placebo groups (42% and 44%, respectively). Serious adverse events, events leading to study drug discontinuation, and events potentially related to BP lowering were reported at higher frequency in the 40-mg group but were similar in 20-mg and placebo groups. CONCLUSIONS: Praliciguat treatment for 12 weeks did not significantly reduce albuminuria compared with placebo in the primary efficacy analysis. Nonetheless, the observed changes in urine albumin-creatinine ratio, BP, and metabolic variables may support further investigation of praliciguat in diabetic kidney disease. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: A Study to Evaluate the Soluble Guanylate Cyclase (sGC) Stimulator IW-1973 in Diabetic Nephropathy/Diabetic Kidney Disease as Measured by Albuminuria, NCT03217591.

ARG1 is a novel bronchodilator response gene: screening and replication in four asthma cohorts.

RATIONALE: Inhaled beta-agonists are one of the most widely used classes of drugs for the treatment of asthma. However, a substantial proportion of patients with asthma do not have a favorable response to these drugs, and identifying genetic determinants of drug response may aid in tailoring treatment for individual patients. OBJECTIVES: To screen variants in candidate genes in the steroid and beta-adrenergic pathways for association with response to inhaled beta-agonists. METHODS: We genotyped 844 single nucleotide polymorphisms (SNPs) in 111 candidate genes in 209 children and their parents participating in the Childhood Asthma Management Program. We screened the association of these SNPs with acute response to inhaled beta-agonists (bronchodilator response [BDR]) using a novel algorithm implemented in a family-based association test that ranked SNPs in order of statistical power. Genes that had SNPs with median power in the highest quartile were then taken for replication analyses in three other asthma cohorts. MEASUREMENTS AND MAIN RESULTS: We identified 17 genes from the screening algorithm and genotyped 99 SNPs from these genes in a second population of patients with asthma. We then genotyped 63 SNPs from four genes with significant associations with BDR, for replication in a third and fourth population of patients with asthma. Evidence for association from the four asthma cohorts was combined, and SNPs from ARG1 were significantly associated with BDR. SNP rs2781659 survived Bonferroni correction for multiple testing (combined P value = 0.00048, adjusted P value = 0.047). CONCLUSIONS: These findings identify ARG1 as a novel gene for acute BDR in both children and adults with asthma.

The influence of breathing pattern during nebulization on the delivery of arformoterol using a breath simulator.

BACKGROUND: Patients with obstructive airway conditions, including chronic obstructive pulmonary disease (COPD), use nebulizers for drug delivery. Tidal breathing patterns employed by patients during nebulized drug delivery may vary. It is unclear whether different breathing patterns affect the emitted quantity of nebulized drug. This in vitro study evaluated whether different tidal breathing patterns that encompass a range that could be observed in COPD patients influence the emitted amount of nebulized arformoterol. METHODS: Breath-simulation experiments used a Pari LC Plus nebulizer in combination with the Duraneb 3000 portable aerosol system. Four breathing patterns that could represent a range of tidal volumes and inspiratory and expiratory times observed in patients with COPD were studied. The amount of arformoterol on the inspiratory and expiratory filters, and the residual amount in the nebulizer bowl were determined via high-pressure liquid chromatography. Results are expressed as a percent of the nominal dose (15 microg in 2 mL). RESULTS: The total amount of arformoterol on the inspiratory filter increased with a longer inspiratory phase of tidal breathing (ranging from 8.0% to 13.1%), while the expiratory filter dose remained similar (7.9% to 8.7%). The total emitted dose (expiratory and inspiratory amounts combined) for all patterns was 16.0% to 21.1% of the nominal dose. Retained arformoterol amount (not emitted) ranged from 55.9% to 62.3% of the nominal dose. CONCLUSIONS: These breath-simulation experiments suggest that only about 20% of the nominal 15-microg arformoterol dose was emitted from the nebulizer apparatus with each of the 4 tidal breathing patterns studied, and that a longer inspiratory phase was associated with greater inhaled dose.

Output and aerosol properties of 5 nebulizer/compressor systems with arformoterol inhalation solution.

BACKGROUND: Arformoterol, the (R,R) isomer of formoterol, is approved as an inhalation solution for the treatment of bronchoconstriction in patients with chronic obstructive pulmonary disease. Multiple nebulizer systems are commercially available. Different nebulizers can differ significantly in drug output, which may impact drug delivery and clinical efficacy. This study compared the aerosol properties of arformoterol delivered via 5 commonly used nebulizer systems for the home-care market. METHODS: The delivered dose of arformoterol inhalation solution (15 microg/2 mL) was collected in a glass Dreschel-type apparatus. The delivered amount in fine-droplet fraction was assessed with an Andersen cascade impactor, and droplet size (average median diameter and average percent<5 microm) was evaluated via laser diffraction. Compressor flow rate measurements were taken after 1 min and 6 min by placing the flow meter in line with each system. RESULTS: The Pari LC Plus, Updraft II Opti-Neb, and NebuTech systems delivered similar amounts of the 15-microg nominal dose (from 23% to 25%). The Pari LC Star and Sidestream systems delivered slightly higher doses (31% and 35%, respectively). The nebulizer/compressor systems differed somewhat with respect to droplet size. The NebuTech delivered the lowest fine-droplet fraction (61%) via Andersen cascade impactor, and the smallest percent of droplets<5 microm (40%) via laser diffraction. The Pari LC Star and Sidestream delivered the highest fine-droplet fraction (100% and 93%, respectively), and the greatest percent of droplets<5 microm (84% and 88%). The fine-droplet fractions for the Updraft II Opti-Neb and Pari LC Plus were 93% and 89%, respectively, and the percent of droplets<5 microm was about 67%. Compressor flow rates ranged from 3.2 L/min (Pari LC Plus) to 5.4 L/min (NebuTech). CONCLUSIONS: The results of this study demonstrate that the choice of nebulizer/compressor system can influence the aerosol properties of arformoterol inhalation solution and should be considered when prescribing nebulized medications.

A cumulative dose study of levalbuterol and racemic albuterol administered by hydrofluoroalkane-134a metered-dose inhaler in asthmatic subjects.

BACKGROUND: The short-acting beta(2)-agonists levalbuterol and racemic albuterol are available for administration through a hydrofluoroalkane-134a (HFA) metered-dose inhaler (MDI). OBJECTIVE: This study compared the short-term safety and efficacy of cumulative doses of levalbuterol HFA MDI and racemic albuterol HFA MDI in asthmatic subjects. METHODS: This was a randomized, modified-blind, active-controlled, multicenter, 2-way crossover study. Subjects (n = 49) were randomized to 16 cumulative doses (1x, 2x, 4x, 8x, and 16x) of levalbuterol (45 microg per dose) or racemic albuterol (90 microg per dose) administered over a 2-hour period. After a 7-day washout period, subjects were crossed over to the other treatment. After each dose, safety outcomes and pulmonary function were assessed. RESULTS: Heart rate and (R)-albuterol exposure increased for both racemic albuterol HFA and levalbuterol HFA. For cumulative doses of 8x or greater, racemic albuterol HFA treatment had greater increases in mean heart rate than levalbuterol HFA (least-squares mean [+/- SD] difference at the 8x dose was 2.8 beats/min [95% CI, 0.3-5.3] and at the 16x dose was 3.5 beats/min [95% CI, 0.6-6.4]). (R)-albuterol plasma levels ranged from 10% to 18% higher after racemic albuterol HFA MDI dosing versus after levalbuterol HFA MDI. FEV(1) improvements were similar for both treatments. The relative potencies of the 2 therapies, based on FEV(1), were similar (ratio, 1.1 [90% CI, 0.9-1.2]; Finney method). CONCLUSION: In this study single-day cumulative dosing of asthmatic subjects with levalbuterol HFA MDI or racemic albuterol HFA MDI resulted in similar improvements in FEV(1) and tolerability. Plasma (R)-albuterol levels and mean heart rate were less with levalbuterol HFA MDI.

A Randomized, Placebo-Controlled, Multiple-Ascending-Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Soluble Guanylate Cyclase Stimulator Praliciguat in Healthy Subjects.

Nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) signaling is central to the regulation of several physiological processes, including blood flow and inflammation. Deficient NO signaling is implicated in multiple diseases. sGC stimulators are small molecules that enhance sGC activity, particularly in combination with NO. In a randomized, placebo-controlled phase 1 study, the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple ascending doses of the sGC stimulator praliciguat were assessed in 44 healthy adults. Four cohorts of 11 subjects (8 praliciguat, 3 placebo) received once-daily praliciguat for 14 days before up-titrating for 7 days (treatment sequences: 15/30 mg, 20/40 mg, 30/40 mg, and weight-based). All doses were tolerated. No serious or severe adverse events (AEs) were reported. The most common AEs in praliciguat recipients were headache and symptoms consistent with blood pressure (BP) lowering/vasodilation. There were no laboratory, vital sign, electrocardiographic, or platelet function findings indicative of a safety concern. Pharmacokinetics were dose proportional, with an effective half-life of 24-37 hours, supporting once-daily dosing. Praliciguat produced dose-related increases in plasma cGMP consistent with stimulation of sGC. Repeated once-daily dosing showed sustained decreases in BP. Results support evaluation of praliciguat for the treatment of conditions associated with deficient NO signaling.

Enhancing the dissolution of phenylbutazone using Syloid® based mesoporous silicas for oral equine applications.

Three mesoporous silica excipients (Syloid® silicas AL-1 FP, XDP 3050 and XDP 3150) were formulated with a model drug known for its poor aqueous solubility, namely phenylbutazone, in an attempt to enhance the extent and rate of drug dissolution. Although other forms of mesoporous silica have been investigated in previous studies, the effect of inclusion with these specific Syloid® silica based excipients and more interestingly, with phenylbutazone, is unknown. This work reports a significant enhancement for both the extent and rate of drug release for all three forms of Syloid® silica at a 1:1 drug:silica ratio over a period of 30 min. An explanation for this increase was determined to be conversion to the amorphous form and an enhanced drug loading ability within the pores. Differences between the release profiles of the three silicas were concluded to be a consequence of the physicochemical differences between the three forms. Overall, this study confirms that Syloid® silica based excipients can be used to enhance dissolution, and potentially therefore bioavailability, for compounds with poor aqueous solubility such as phenylbutazone. In addition, it has been confirmed that drug release can be carefully tailored based on the choice of Syloid® silica and desired release profile.

Nebulized arformoterol in patients with COPD: a 12-week, multicenter, randomized, double-blind, double-dummy, placebo- and active-controlled trial.

OBJECTIVE: The aim of this study was to assess the efficacy and tolerability of nebulized arformoterol tartrate (a selective, long-acting beta(2)-adrenergic agonist that is the [R,R] isomer of formoterol) and salmeterol xinafoate versus placebo in patients with chronic obstructive pulmonary disease (COPD). METHODS: This 12-week, multicenter, randomized, double-blind, double-dummy, placebo- and active-controlled trial was conducted at 60 centers across the United States. Male and female patients aged >or=35 years with physician-diagnosed COPD received arformoterol (15 microg BID, 25 microg BID, or 50 microg QD via nebulizer), salmeterol (42 microg BID via metered dose inhaler), or placebo. Pulmonary function was assessed by spirometry; dyspnea, by the Transitional Dyspnea Index (TDI); and health status, by the St. George's Respiratory Questionnaire (SGRQ). Adverse events (AEs) were assessed by site personnel at all clinic visits (screening, first dose at week 0, and at weeks 3, 6, 9, 12, and follow-up). COPD exacerbations were defined as worsening respiratory status requiring a change in medication or an unscheduled provider visit. RESULTS: A total of 717 patients received study medication. The demographic composition of all treatment arms was similar. The mean age was 62.9 years, 58% were men, and mean baseline forced expiratory volume in 1 second (FEV(1)) was 1.2 L (41% predicted). Mean improvement in trough FEV(1) over 12 weeks was significantly greater with all 3 arformoterol doses (15 microg BID, +16.9%; 25 microg BID, +18.9%; 50 microg QD, +14.9%) and for salmeterol (+17.4%) relative to placebo (+6.0%; P < 0.001). There were significantly greater improvements in the mean percentage change in FEV(1) AUC(0-12h) from the predose value over 12 weeks (15 microg BID, 12.7%, 25 microg BID, 13.9%, 50 microg QD, 18.9%; salmeterol, 9.8%) versus placebo (2.7%; P

A comparison of 5-day courses of dirithromycin and azithromycin in the treatment of acute exacerbations of chronic obstructive pulmonary disease.

BACKGROUND: Short-term use of antibiotics has become a common component of the management of acute exacerbations of chronic bronchitis (AECB), particularly in complex cases with productive cough or purulent phlegm. The macrolide antibiotics, particularly second-generation agents such as dirithromycin and azithromycin, are among the antibiotic classes frequently recommended and used to treat upper and lower respiratory infections, including AECB. OBJECTIVE: This study compared the clinical efficacy and tolerability of 5-day courses of dirithromycin and azithromycin given once daily for the treatment of acute exacerbations of chronic obstructive pulmonary disease (COPD). METHODS: This randomized, investigator-blinded, parallel-group clinical trial was conducted at 5 centers in the United States. Eligible patients were adult (age >35 years) smokers or ex-smokers (smoking history of at least 10 pack-years) with chronic bronchitis and an acute exacerbation, defined by the occurrence of increased dyspnea and/or productive cough and feverishness within 48 hours of enrollment. Before randomization, an attempt was made to obtain a sputum specimen from each patient for Gram's staining and culture. Patients were randomized to receive dirithromycin 500 mg QD for 5 days or azithromycin 500 mg QD on day 1 and 250 mg QD on days 2 to 5. Clinical efficacy was assessed separately by patients and physicians at early (days 7-10) and late (days 25-35) posttreatment visits. RESULTS: Eighty-six patients (48 women, 38 men; mean age, 55 years) with a mean smoking history of 31 pack-years were included in the intent-to-treat analysis. Forty-six (54%) patients were randomized to dirithromycin and 40 (47%) patients to azithromycin. Clinical efficacy was reported in a high proportion of patients in both treatment groups, both at the early posttreatment visit (84.8% dirithromycin, 75.7% azithromycin; difference dirithromycin - azithromycin, 9.1%; 95% CI, -8.2 to 26.4) and the late posttreatment visit (95.5% and 86.5%, respectively; difference dirithromycin - azithromycin, 9.0%; 95% CI, -3.7 to 21.6). A similar proportion of patients required a second course of antibiotics over the study period (20.5% dirithromycin, 27.0% azithromycin; difference dirithromycin - azithromycin, -6.6%; 95% CI, -25.2 to 12.1). Only 42 (48.8%) patients were able to produce a sputum sample before receiving study treatment, and of these, only 20 (47.6%) demonstrated a preponderance of neutrophils on Gram's staining. Both treatments were well tolerated. CONCLUSIONS: The results of this study suggest comparable clinical efficacy between 5-day courses of once-daily dirithromycin and azithromycin in acute exacerbations of COPD. There were insufficient data to permit meaningful comparison of the bacteriologic efficacy of these macrolide antibiotics.

Inclusion of fenofibrate in a series of mesoporous silicas using microwave irradiation.

A selection of porous silicas were combined with a model drug using a recently developed, controlled microwave heating process to determine if the application of microwave irradiation could enhance subsequent drug release. Five mesoporous silica types were investigated (core shell, core shell rehydrox, SBA-15, silica gel, SYLOID®) and, for comparison, one non-porous silica (stober). These were formulated using a tailored microwave heating method at drug/excipient ratios of 1:1, 1:3 and 1:5. In addition, all experiments were performed both in the presence and absence of water, used as a fluidising media to aid interaction between drug and support, and compared with results obtained using more traditional heating methods. All formulations were then characterised using differential scanning calorimetry (DSC), powder X-ray diffraction (XRD), scanning electron microscopy (SEM) and Fourier transformation infrared spectroscopy (FT-IR). Pharmaceutical performance was investigated using in vitro drug release studies. A significant enhancement in the release profile of fenofibrate was observed for formulations prepared using microwave heating in the absence of water for five of the six silica based formulations. Of all the formulations analysed, the greatest extent of drug release within the experimental 30 min was the 1:5 core shell rehydrox achieving a total of 86.6 ± 2.8%. The non-porous (stober) particles did not exhibit an increased release of the drug under any experimental conditions studied. This anomaly is thought to be a result of the comparatively small surface area of the silica particles, thus preventing the adsorption of drug molecules.

Comparison of fenofibrate-mesoporous silica drug-loading processes for enhanced drug delivery.

Loading a poorly water-soluble drug onto a high surface area carrier such as mesoporous silica (SBA-15) can increase the drug's dissolution rate and oral bioavailability. The loading method can influence subsequent drug properties including solid state structure and release rate. The objective of this research was to compare several loading processes in terms of drug distribution throughout the mesoporous silica matrix, drug solid state form and drug release properties. A model poorly water-soluble drug fenofibrate was loaded onto SBA-15 using; (i) physical mixing, (ii) melt, (iii) solvent impregnation, (iv) liquid CO2 and (v) supercritical CO2 methods. Physical mixing resulted in heterogeneous drug-loading, with no evidence of drug in the mesopores and the retention of the drug in its crystalline state. The other loading processes yielded more homogeneous drug-loading; the drug was deposited into the mesopores of the SBA-15 and was non-crystalline. All the processing methods resulted in enhanced drug release compared to the unprocessed drug with the impregnation, liquid and SC-CO2 producing the greatest increase at t=30 min.