Efficacy and safety of the dipeptidyl peptidase-4 inhibitor PF-734200 added to metformin in Type 2 diabetes.

AIMS: PF-734200 is a potent and selective oral dipeptidyl peptidase-4 (DPP-4) inhibitor. This study assessed the efficacy and safety of PF-734200 at dose rates of 20 and 30 mg/day in subjects with Type 2 diabetes mellitus inadequately controlled on metformin monotherapy. METHODS: This was a placebo-controlled, double-blind, randomized, multicentre, 12 week study. Subjects with Type 2 diabetes mellitus were eligible if screening glycosylated haemoglobin (HbA(1c) ) was 7-11% (53.0-96.7 mmol/mol) and they had been receiving metformin monotherapy for ≥2 months. Subjects receiving metformin and an insulin secretagogue or metformin and thiazolidinedione needed to have a screening HbA(1c) of 6.5-9.5% (47.5-80.3 mmol/mol), measured prior to discontinuing the insulin secretagogue or thiazolidinedione. The primary end-point of the study was a change from baseline to week 12 in HbA(1c) levels. RESULTS: Baseline characteristics for 289 subjects randomized to PF-734200 or placebo groups were similar (mean age 56.5 years, mean body mass index 32.2 kg/m(2) and mean HbA(1c) 8.2%, 66.1 mmol/mol). In the predefined per protocol data set, least-squares mean HbA(1c) at week 12 was reduced by 0.79 (8.6 mmol/mol 95% confidence interval -1.10 to -0.49, -12.0 to -5.4 mmol/mol) and 0.92% (10.1 mmol/mol; -1.23 to -0.61, -13.4 to -6.7 mmol/mol) in the 20 and 30 mg groups, respectively, compared with placebo. Differences from placebo were statistically significant (P<0.0001), but the differences between the 20 and 30 mg groups were not. The intent-to-treat analysis yielded similar findings. CONCLUSIONS: The HbA(1c) was significantly and meaningfully reduced by both doses of PF-734200, but 20 mg appears to be the more appropriate therapeutic dose for Type 2 diabetes mellitus, contingent upon confirmation by long-term controlled studies.

Effects of inhaled human insulin on airway lining fluid composition in adults with diabetes.

Inhaled human insulin (Exubera (human insulin of rDNA origin) Inhalation Powder) causes small, early and reversible changes in pulmonary function in subjects with diabetes mellitus. The present study assessed whether changes occur in cellular and soluble constituents of airway lining fluid consistent with inflammation as a possible cause for Exubera-associated lung function alterations. Two 31-week, open-label, sequential design phase 2 studies were conducted, one with 20 subjects with type 1 and one with 24 subjects with type 2 diabetes. After run-in, all subjects received subcutaneous insulin for 12 weeks, followed after 1 week by 12 weeks of Exubera. Bronchoalveolar lavage fluid cell counts and protein constituents were determined at baseline, after 12 weeks of subcutaneous insulin and after 12 weeks of Exubera. Baseline cellular and soluble constituents of lavage fluid were similar to those reported for nondiabetic adults. Exubera produced no consistent clinically or statistically significant changes in total or differential lavage fluid cell counts or protein concentrations, even though Exubera-associated changes in pulmonary function are known to be fully manifest within 12 weeks. Therefore, 12 weeks of Exubera treatment is not associated with evidence of pulmonary inflammation. The treatment effects on lung function observed in Exubera trials are not caused by lung inflammation.

Relationship between airway obstruction and respiratory symptoms in adult asthmatics.

STUDY OBJECTIVES: To characterize the relationship between symptoms and the degree of airway obstruction as determined by the FEV1 and peak expiratory flow (PEF) in a cohort of adult patients attending a university-based urban asthma clinic. DESIGN: Each of six current asthma symptoms, including cough, dyspnea, wheeze, chest tightness, sputum production, and nocturnal awakening was rated by patients on a 0 (none) to 4 (constant) scale at initial and first follow-up clinic evaluations. Spirometry and PEF were measured at the initial clinic visit and PEF was measured at all follow-up visits. PATIENTS: Sixty-seven adult patients with chronic asthma. MEASUREMENTS AND RESULTS: Asthma symptoms did not correlate with the degree of airway obstruction as determined by the FEV1 (percent predicted FEV1 vs total symptoms: r=0.143; p=0.263; n=70) and only correlated poorly with PEF (percent predicted PEF vs total symptoms: r=0.384; p=0.0029; n=58). Subjective wheezing was the best individual predictor of the level of airway obstruction in this group of patients. When reassessed an average of 7.9 weeks later, patients reported significant improvement in several symptoms, including those of wheeze, chest tightness, dyspnea, and nocturnal awakening. However, this symptomatic improvement was not associated with improvement in the level of airway obstruction. CONCLUSIONS: Asthma symptoms correlate poorly with the level of airway obstruction as determined by the FEV1 and PEF. Following treatment, subjective improvement in asthma symptoms may occur without improvement in the level of airway obstruction. These results support the recommendation to measure airway obstruction objectively when assessing adult patients with chronic asthma.

A Dose-Ranging Study of the DPP-IV Inhibitor PF-734200 Added to Metformin in Subjects With Type 2 Diabetes*.

The purpose of this phase 2, multicentre, randomized, double-blind, placebo-controlled, 12-week dose-ranging study was to assess the efficacy, safety, and tolerability of the dipeptidyl peptidase-IV (DPP-IV) inhibitor PF-734200 in adult subjects with type 2 diabetes who were on a stable dose of metformin. Men and women with inadequate glycaemic control with metformin as their sole diabetes medication were randomized to placebo or PF-734200 2 mg, 5 mg, 10 mg, or 20 mg every day. A population subset underwent mixed meal tolerance tests (MMTT) at baseline and week 12. A total of 301 subjects were treated. At week 12, PF-734200 doses of ≥5 mg produced a statistically significant reduction in haemoglobin A (1C) (HbA (1c)) compared with placebo. The mean (95% confidence interval) placebo-adjusted changes in HbA (1c) were -0.31% (-0.70 to 0.08), -0.74% (-1.12 to -0.36), -0.70% (-1.02 to -0.38), and -0.75% (-1.07 to -0.43) for the 2 mg, 5 mg, 10 mg, and 20 mg doses, respectively. PF-734200 20 mg significantly reduced glucose area under the curve following MMTT (-12.8% [-22.9 to -2.7]; p=0.003) compared with placebo. The reductions observed with other doses were not statistically significant. PF-734200 was safe and well tolerated at all doses tested when added to metformin. PF-734200 safely and effectively lowered HbA (1c) in subjects receiving metformin. The 20 mg dose provided the greatest improvements in post-prandial glucose.

Effect of salbutamol on dry air- and acetylcholine-induced bronchoconstriction in the canine lung periphery.

We examined the effect of salbutamol on dry airflow-induced bronchoconstriction (AIB) and acetylcholine-induced bronchoconstriction (Ach-IB) in the canine lung periphery using a wedged bronchoscope technique. Collateral system resistance (Rcs) and airway wall temperature (Taw) were monitored in a peripheral lung segment before, during and after airflow challenge. Rcs before and after aerosolized acetylcholine was recorded in a contralateral lung segment. Intravenous salbutamol (2.5 micrograms.kg-1) significantly attenuated the peak fall in Taw during airflow challenge and the peak rise in Rcs following challenge. Intravenous salbutamol attenuated Ach-IB to a similar degree. Significant systemic effects were recorded following i.v. salbutamol. In contrast, aerosolized salbutamol (50 micrograms) minimally decreased the fall in Taw during airflow challenge, while virtually eliminating AIB. The same dose of aerosolized salbutamol only partially attenuated Ach-IB. Aerosolized salbutamol did not affect mean arterial pressure or heart rate. Intravenous salbutamol may in part inhibit AIB by increasing pulmonary blood flow, secondary to its systemic circulatory effects, and decrease heat and water loss during airflow challenge. In contrast, aerosolized salbutamol abolished AIB, while only minimally effecting airway cooling. These data suggest that AIB is a result of mediator release and/or smooth muscle contraction.

Mechanisms of asthma.

In recent years, our understanding of basic mechanisms of asthma has increased significantly. This article reviews three specific areas that have been the focus of current asthma research: the role of nitric oxide in the control of airway tone and inflammation, mechanisms of exercise-induced asthma, and current studies in the genetics of asthma. Recent advances in each of these areas have contributed to a better understanding of the pathophysiologic mechanisms in asthma and are important in the diagnosis and therapy of this disease.

Asthma training in third-year medical students.

To assess the educational experiences of physicians-in-training with asthma patients, we had medical students complete asthma surveys at the beginning and end of their internal medicine clerkship (IMC). At the beginning of the IMC, all students received a 1-hr asthma lecture and half of the students received a compilation of pocket cards containing many of the algorithms from the National Heart, Lung, and Blood Institute asthma guidelines. We found that students had relatively few encounters with asthmatic patients during the IMC. Students were good judges of asthma severity but performed poorly on survey questions pertaining to asthma treatment. Confidence in treating and assessing patients improved by the end of the IMC, but remained low. We conclude that the usual 1-hr lecture and limited contact with asthma patients during the IMC may be in adequate to train students to care for patients with asthma.

Prospective, randomized, controlled clinical trial comparing traditional versus reduced tidal volume ventilation in acute respiratory distress syndrome patients.

OBJECTIVE: To assess the safety and potential efficacy of a mechanical ventilation strategy designed to reduce stretch-induced lung injury in acute respiratory distress syndrome. DESIGN: Prospective, randomized, controlled clinical trial. SETTING: Eight intensive care units in four teaching hospitals. PATIENTS: Fifty-two patients with acute respiratory distress syndrome. INTERVENTIONS: Traditional tidal volume patients: tidal volume 10-12 mL/kg ideal body weight, reduced if inspiratory plateau pressure was > 55 cm H2O (7.3 kPa). Small tidal volume patients: tidal volume 5-8 mL/kg ideal body weight, to keep plateau pressure < 30 cm H2O (4.0 kPa). MEASUREMENTS AND MAIN RESULTS: Mean tidal volumes during the first 5 days in traditional and small tidal volume patients were 10.2 and 7.3 mL/kg, respectively (p < .001), with mean plateau pressure = 30.6 and 24.9 cm H2O (3.3 kPa), respectively (p < .001). There were no significant differences in requirements for positive end-expiratory pressure or FIO2, fluid intakes/outputs, requirements for vasopressors, sedatives, or neuromuscular blocking agents, percentage of patients that achieved unassisted breathing, ventilator days, or mortality. CONCLUSIONS: The reduced tidal volume strategy used in this study was safe. Failure to observe beneficial effects of small tidal volume ventilation treatment in important clinical outcome variables may have occurred because a) the sample size was too small to discern small treatment effects; b) the differences in tidal volumes and plateau pressures were modest; or c) reduced tidal volume ventilation is not beneficial.