David Albert Fryburg

Increased Food Intake and Energy Expenditure Following Administration of Olanzapine to Healthy Men

Atypical antipsychotic medications like olanzapine (OLZ) induce weight gain and increase the risk of diabetes in patients with schizophrenia. The goal of this study was to assess potential mechanisms of OLZ‐induced weight gain and accompanying metabolic effects. Healthy, lean, male volunteers received OLZ and placebo (PBO) in a randomized, double‐blind, crossover study. In periods 1 and 2, subjects received OLZ (5 mg for 3 days then OLZ 10 mg for 12 days) or matching PBO separated by a minimum 12‐day washout. Twenty‐four hour food intake (FI), resting energy expenditure (REE), activity level, metabolic markers, and insulin sensitivity (IS) were assessed. In total, 30 subjects were enrolled and 21 completed both periods. Mean age and BMI were 27 years (range: 18–49 years) and 22.6 ± 2.2 kg/m2, respectively. Relative to PBO, OLZ resulted in a 2.62 vs. 0.08 kg increase in body weight (P < 0.001) and 18% (P = 0.052 or 345 kcal) increase in FI. Excluding one subject with nausea and dizziness on the day of OLZ FI measurement, the increase in FI was 547 kcal, (P < 0.05). OLZ increased REE relative to PBO (113 kcal/day, P = 0.003). Significant increases in triglycerides, plasminogen activator inhibitor‐I (PAI‐I), leptin, and tumor necrosis factor‐α (TNF‐α) were observed. No significant differences in activity level or IS were observed. This study provides evidence that OLZ pharmacology drives the early increase in weight through increased FI, without evidence of decreased energy expenditure (EE), activity level, or short‐term perturbations in IS.

Potential implications of matrix metalloproteinase-9 in assessment and treatment of coronary artery disease

Background: Matrix metalloproteinase (MMP)-9, a member of the MMP superfamily is consistently implicated in the pathophysiology of atherosclerosis and plaque rupture, the most common mechanism responsible for acute coronary syndrome (ACS). Aim: To summarize the role of MMP-9 in atherosclerosis and its potential implications in assessment and treatment of coronary artery disease (CAD). Methods: We reviewed the PubMed database for relevant data regarding the role of MMP-9 in the pathophysiology of atherosclerosis. In the light of these data, we postulate potential implications of MMP-9 in the management and treatment of CAD. Results and conclusions: Existing data strongly support the role of MMP-9 in plaque destabilization and rupture. Based on the current knowledge, MMP-9 can potentially serve as a diagnostic biomarker in ACS and a prognostic biomarker in ACS and chronic CAD patients. MMP-9 is reduced by therapies that are associated with favourable outcome in atherosclerosis and thus may serve as a surrogate biomarker of treatment efficacy. However, large morbidity and mortality trials are still required to confirm that MMP-9 reduction is associated with improved outcome independent of the traditional risk factors (i.e. low-density lipoprotein cholesterol). Given its role in plaque rupture, inhibition of MMP-9 may promote plaque stabilization and consequently reduce cardiovascular events. Yet, the efficacy and safety of MMPs inhibitors should be first studied in preclinical models of atherosclerosis.

Non-traditional biomarkers of atherosclerosis in stable and unstable coronary artery disease, do they differ?

Background: Biomarkers of atherosclerosis are emerging as a potential tool for assessment of coronary artery disease (CAD) patients. As acute coronary syndrome (ACS), and stable CAD are distinguished in their pathophysiology it is conceivable that they are also characterized by different biomarkers of atherosclerosis. Methods: We systematically reviewed the literature for clinical studies of several non‐traditional biomarkers of atherosclerosis reflecting various pathophysiological processes, namely macrophage‐activity, oxidative‐stress, tissue remodeling, and thrombosis in ACS and stable CAD to determine whether circulating biomarkers are differently expressed/predict outcome in these two clinical conditions. Results: Macrophage‐activity (monocyte chemoattractant protein‐1, neopterin), tissue‐remodeling (matrix metalloproteinase‐9) and thrombosis (tissue‐factor) related biomarkers were consistently elevated in ACS compared to stable CAD, in accordance with the pathophysiological role of these mediators in plaque rupture, characterizing ACS. Thus, these biomarkers may be applicable for diagnosis of ACS. Additionally, neopterin was consistently shown to predict outcome in both stable and ACS patients and myeloperoxidase was strongly shown to predict outcome in ACS, implying for their potential role in risk stratification of these patients. Conclusions: As ACS and stable CAD are characterized by different pathophysiological processes, it appears that the biomarkers that are associated with them are differently expressed in these two clinical conditions.

Acute passive cigarette smoke exposure and inhaled human insulin (Exubera) pharmacokinetics.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Active cigarette smoking is associated with increased permeability of the pulmonary alveolar epithelium, resulting in faster absorption of inhaled drugs such as Exubera (EXU). Absorption of EXU is increased approximately twice to four times as much in chronic smokers compared with nonsmokers. The rate of clearance of radioaerosols such as technetium-labelled diethylenetriamine penta-acetic acid is decreased in response to passive smoke exposure. WHAT THIS STUDY ADDS Passive smoke exposure causes a decrease in lung permeability, an effect opposite to that of active smoking. Acute passive smoke exposure results in a decrease in EXU bioavailability and does not create a risk of hypoglycaemia. These results are consistent with previous studies of radioaerosol lung clearance. AIMS Relative to nonsmokers, the bioavailability of inhaled human insulin (Exubera(R); EXU) is markedly increased in chronic smokers. The pharmacokinetics of EXU following passive cigarette smoke exposure is unknown. METHODS In an open-label, crossover study, healthy nonsmoking volunteers received two treatments in randomized sequence separated by a 2-week wash-out: (i) EXU 3 mg with no passive smoke exposure and (ii) EXU 3 mg after passive smoke exposure (atmospheric nicotine levels 75-125 mug m(-3)) for 2 h. Blood samples were obtained at prespecified times up to 6 h after EXU administration. RESULTS Twenty-seven subjects completed both study periods. Mean plasma insulin AUC(0-360) decreased by 17% [ratio 83%, 95% confidence interval (CI) 68.8, 99.5] and mean C(max) by 29% (ratio 71%, 95% CI 59.8, 83.1) after passive cigarette smoke exposure. The median (range) t(max) was 60 min (20-120 min) and 75 min (20-360 min) in the EXU with no exposure and EXU passive exposure groups, respectively. EXU was well tolerated. CONCLUSIONS Unlike active chronic smoking, acute passive cigarette smoke exposure modestly decreases EXU bioavailability and thus should not increase hypoglycaemia risk. These results are consistent with those from published literature involving technetium-labelled diethylenetriamine penta-acetic acid and suggest that passive cigarette smoke exposure causes an acute decrease in lung permeability vs. active smoking, which causes an increase in permeability.