Michael Wade

Pharmacokinetics and steady-state bioequivalence of treprostinil sodium (Remodulin®) administered by the intravenous and subcutaneous route to normal volunteers

Treprostinil sodium is a chemically stable analogue of prostacyclin administered as a chronic, continuous subcutaneous infusion for the treatment of pulmonary arterial hypertension (PAH). There has been significant clinical interest in determining the feasibility of delivering treprostinil by intravenous infusion. Therefore, a bioequivalence and comparative pharmacokinetics study of the two routes of administration was conducted in normal volunteers. A randomized, two-period, crossover study design was employed. Each subject was dosed at 10 ng/kg/min for 72 hours by each route, with the infusions separated by a 4-day wash-out period. In the 51 subjects who received at least 24 hours of treprostinil administered subcutaneously and intravenously, the steady-state ratios of the geometric means (IV/SC) and 90% confidence intervals for AUCss and Cmaxss were 92.9% (89.8–96.1%) and 106% (99.4–113%), respectively. Secondary pharmacokinetic assessments confirmed the comparability of the two routes of administration at steady state, and also demonstrated that the elimination half-life of treprostinil was 4.4 and 4.6 hours following intravenous and subcutaneous administration, respectively. Based on these findings it was concluded that intravenously and subcutaneously administered treprostinil are bioequivalent at steady state.

Revisiting the culprit lesion in non–Q-wave myocardial infarction ☆: Results from the VANQWISH trial angiographic core laboratory

OBJECTIVEnWe sought to determine the underlying coronary anatomy and characterize the culprit lesion after non-Q-wave myocardial infarction (NQWMI).nnnBACKGROUNDnAlthough the culprit lesion and infarct-related artery often are easily identified with coronary angiography after Q-wave MI, the culprit lesion after NQWMI has not been well characterized. Small retrospective studies have suggested that the absence of Q-waves on an electrocardiogram is due to incomplete occlusion of the infarct-related artery.nnnMETHODSnCoronary angiograms from 350 patients randomized to the early invasive strategy in the Veterans Affairs Non-Q-Wave Infarction Strategies in-Hospital (VANQWISH) trial were systematically analyzed in an angiographic core laboratory. A consensus panel identified the culprit lesion and the infarct-related artery using prespecified criteria for complex lesion morphology and acute versus chronic occlusions. Severity of angiographic disease and left ventricular function also were analyzed. Patients with a single identified culprit lesion were compared with those who had multiple apparent culprits and those without an identifiable culprit lesion.nnnRESULTSnA single culprit lesion was identified in only 49% of patients undergoing early angiography after NQWMI. The majority of patients either had no identifiable culprit (37%) or multiple apparent culprit lesions (14%). A single incomplete occlusion of the infarct-related artery was found in only 36% of patients, and an isolated acute occlusion of the infarct-related artery occurred in 13%. Patients without an identifiable culprit lesion had severe coronary disease (obstructive coronary artery disease [CAD] in 84%) but no complex lesion morphology. There was no difference in angiographic severity of disease comparing patients with and without identifiable culprit lesions. Patients with a single incomplete occlusion of the infarct-related artery were more likely to undergo percutaneous transluminal coronary angioplasty than other patients, whereas patients with multiple culprit lesions were more frequently treated with coronary artery bypass grafting.nnnCONCLUSIONSnCoronary angiography early after NQWMI frequently identifies severe obstructive CAD, but a single identifiable culprit lesion was identified in <50% of patients. Multiple culprit lesions were seen in 14% of patients. An angiographic culprit lesion could not be identified in more than one-third of patients undergoing coronary angiography as part of an invasive strategy.

Modeling associations between posttraumatic stress symptoms and substance use.

Comorbid substance use and posttraumatic stress disorders (SUD-PTSD) predict poorer treatment outcomes. Self-medication has been forwarded as a symptom-level explanatory model. However, research has yet to be conducted that can provide detailed examination of SUD and PTSD symptom fluctuations over time as posited by such a process. This pilot study examined associations between PTSD and substance dependence (SD) symptoms/substance use using two established methodologies that assess week-by-week symptom and substance use/dependence status. Outpatients (N=35) in SUD treatment completed the Longitudinal Follow-Up Evaluation and the Time Lime Follow-Back Interview, retrospectively reporting weekly PTSD and SD symptoms, and substance use over the previous 6-months. Results indicated that weekly PTSD symptom fluctuations were concurrently associated with the presence of alcohol and cocaine dependence symptoms and were associated with the presence of opiate dependence symptoms in the following week. These findings support a self-medication conceptualization, underscore the utility of using a more detailed process analysis of PTSD and SD symptoms, and suggest that PTSD fluctuations are associated with substance problems, rather than with substance use per se.

Post-traumatic Stress Disorder and Diabetes: Co-Morbidity and Outcomes in a Male Veterans Sample

The purpose of this study was to assess the prevalence and correlates of comorbid diabetes and Post-Traumatic Stress disorder(PTSD)and potential relationships between PTSD and diabetes outcomes. Male patients enrolled in a VA primary care database (N = 73,270) were classified as having diabetes from pharmacy records (N = 14,438) and grouped into those with diagnoses of PTSD with depression (N = 649), PTSD-only (N = 480), Depression-only (N = 1696), Other psychiatric diagnosis (N = 736), or No psychiatric diagnosis (N = 10,877) based on the Purpose of Visit diagnoses in the medical record. Outcomes included glycemic control (HbA1c), cholesterol and tryglycerides. Correlates were age, substance use disorder, other psychiatric diagnosis, number of primary care encounters, and medications. The prevalence of comorbid diabetes and PTSD was 8% (n = 1129). Of these, 57% (n = 649) had comorbid depression. Patients with PTSD and depression had higher rates of substance use disorder and higher cholesterol and LDL. Patients with depression had poorer glycemic control. Patients with PTSD and depression weighed more and had higher BMI than patients with neither diagnosis. Thus, male diabetes patients with PTSD and depression may be vulnerable to substance use disorders and to weight/lipid problems that can affect health. Depression is a likely contributor to poor glycemic control. Careful screening for mental health comorbidities is needed for diabetes patients.

Clinical researchTreatment of intermittent claudication with beraprost sodium, an orally active prostaglandin I2analogue: A double-blinded, randomized, controlled trial☆

OBJECTIVESnIn the current study, we hypothesized that beraprost would: 1) improve treadmill exercise performance and quality of life; and 2) decrease rates of ischemic events in patients with intermittent claudication.nnnBACKGROUNDnPrevious trials with beraprost sodium, an orally active prostaglandin I(2) analogue, in the treatment of claudication in patients with peripheral arterial disease (PAD) have been inconsistent.nnnMETHODSnPatients with intermittent claudication (n = 897) were randomized to receive either 40 microg three times a day of beraprost with meals (n = 385) or placebo (n = 377) in a double-blinded manner for one year. The primary efficacy parameter was treadmill-measured maximum walking distance, as assessed at three and six months after randomization. Secondary efficacy parameters included treadmill-measured pain-free walking distance and change in quality of life.nnnRESULTSnThere was no significant improvement in maximum walking distance in the beraprost group (16.7%) as compared with the placebo group (14.6%, p = NS). Administration of beraprost did not improve the pain-free walking distance (p = NS between treatment groups), and there was no improvement in the quality-of-life measures between the treatment groups. The incidence of critical cardiovascular events was 7.3% in the beraprost group and 11.4% in the placebo group (p = NS). There was a significant reduction in the combination of cardiovascular death and myocardial infarction in the beraprost group (p = 0.01).nnnCONCLUSIONSnDespite previous investigations suggesting efficacy, these results indicate that beraprost is not an effective treatment to improve symptoms of intermittent claudication in patients with PAD. The potential benefit of beraprost on critical cardiovascular events would require confirmation in a larger prospective investigation.

Association Between Posttraumatic Stress Disorder and Primary Care Provider-Diagnosed Disease Among Iraq and Afghanistan Veterans

Objective: To determine if a diagnosis of posttraumatic stress disorder (PTSD) was associated with primary care provider-diagnosed physical disease in the first 5 years post deployment. Methods: An examination of medical records of 4416 veterans of Operations Enduring Freedom and Iraqi Freedom (OEF/OIF) was conducted. Participants were veterans who served between September 11, 2001 and December 31, 2007, without prior combat exposure, and who utilized primary care services within the VA Healthcare Network of Upstate New York. Primary care provider-diagnosed International Statistical Classification of Diseases and Related Health Problems, Revision 9 (ICD-9) physical diseases were examined. Results: Adjusting for demographic characteristics and clinical factors (e.g., age, gender, depression, and substance use), PTSD was significantly associated with an almost two-fold increase of developing nervous system (odds ratio [OR], 1.98), musculoskeletal disease (OR, 1.84), and signs and ill-defined conditions of disease (OR, 1.78). A diagnosis of PTSD was significantly associated with increased odds of developing circulatory (OR, 1.29), hypertensive (OR, 1.38), and digestive system disease (OR, 1.34). Survival analyses showed that veterans with PTSD experienced early onset disease compared with veterans without PTSD; hypertensive (hazard ratio [HR], 1.56; 95% confidence interval [CI], 1.19-2.04), circulatory, (HR, 1.36; 95% CI, 1.11-1.67), digestive (HR, 1.24; 95% CI, 1.08-1.43), nervous (HR, 1.81; 95% CI, 1.59-2.06), musculoskeletal disease (HR, 1.49; 95% CI, 1.32-1.67), and signs and ill-defined disease (HR, 1.70; 95% CI, 1.51-1.92). Conclusions: PTSD is associated with increased prevalence and onset of physical disease among OEF/OIF veterans within the early years post military service. Rising rates of PTSD may foreshadow an increase in lifespan morbidity and healthcare utilization in the coming years among OEF/OIF veterans. CI = confidence interval; OEF/OIF = veterans of Operations Enduring Freedom and Iraqi Freedom; OR = odds ratio; PCPs = primary care providers; PTSD = posttraumatic stress disorder; HR = hazard ratio.

Diabetes prevention and control in the workplace: a pilot project for county employees.

OBJECTIVESnTo improve nutrition and physical activity of county employees and promote weight loss.nnnDESIGNnRandom assignment to begin the program when first offered or after 3 months (wait control group).nnnSETTINGnWorksite.nnnPARTICIPANTSnOnondaga County employees (n = 45) at risk for diabetes (n = 35) or with diabetes (n = 10). Mean (±SD) age = 51.2 (± 8.0) years and body mass index (BMI) = 37.3 ± (6.8 kg/m).nnnINTERVENTIONnTwelve weekly healthy lifestyle sessions based on the Diabetes Prevention Program curriculum, followed by monthly sessions for up to 12 months.nnnOUTCOMESnMedical: Weight, BMI, waist circumference, blood pressure, fasting glucose, lipid, and hemoglobin A1c levels. Psychosocial/behavioral: Health-related quality of life Short Form-12, Impact of Weight on Quality of Life Scale), physical activity (International Physical Activity Questionnaire), eating behavior (3-Factor Eating Questionnaire, National Cancer Institute Fat Screener), job satisfaction.nnnRESULTSnThe intervention group lost significant weight compared to the wait control group over the first 3 months (mean [95% CI], -2.23 kg [-3.5 to 0.97]) vs [+ 0.73 kg (+0.17 to +1.28)], with a decrease in BMI (P < .001) and waist circumference (P = .004), an increase in physical activity (International Physical Activity Questionnaire, P = .011) and lower dietary fat intake (P = .018). Over 12 months, 22.5% (9/40) lost more than 5% body weight and 12.5% (5/40) lost more than 7% body weight. After the first 3 months, there was gradual partial weight regain but reduction in waist circumference was maintained. The intervention group demonstrated significant improvement in Impact of Weight on Quality of Life Scale (P < .001), 3-Factor Eating (cognitive restraint P < .001, uncontrolled eating P = .003, and emotional eating P = .001), International Physical Activity Questionnaire (P = .011), and Short Form-12 Physical Component Summary (P = .048). No improvements were observed in blood pressure, lipid, hemoglobin A1c, or glucose levels. Job satisfaction was inversely related to BMI at baseline (P = .001) with a trend for improvement with the modest weight loss.nnnCONCLUSIONSnA worksite intervention program can help government employees adopt healthier lifestyles and achieve modest weight loss.

Usefulness of the TIMI risk score in predicting both short- and long-term outcomes in the Veterans Affairs Non–Q-Wave Myocardial Infarction Strategies In-Hospital (VANQWISH) Trial

We sought to test the validity and clinical utility of the Thrombolysis In Myocardial Infarction (TIMI) risk score for patients who have non-Q-wave myocardial infarction. A post hoc analysis of the Veterans Affairs Non-Q-Wave Infarction Strategies In-Hospital (VANQWISH) Trial was performed, wherein patients were assigned a TIMI risk score from which both 30-day and 12-month outcomes (death, nonfatal myocardial infarction, or urgent revascularization) were assessed. At 30 days, the TIMI risk score showed a close match between observed and predicted probabilities of events after adjustment for overall event rates. The event rate at 30 days was 6% for a score of 0 to 2, 10% for a score of 3, 13% for a score of 4, and 14% for a score of 5 to 7 (p = 0.003 and c statistic 0.59). Discriminative ability of the score was greater in the conservative group at 30 days (p = 0.0004, c statistic 0.67). The score remained modestly predictive of events at 1 year (c statistic 0.60). Conservative strategy patients had better 30-day outcomes than the invasive strategy patients if their score was 0 to 2 (odds ratio 0.24, 95% confidence interval 0.08 to 0.76). No significant difference in outcomes between strategies was detected for a score > or =3. The TIMI risk score provides moderate incremental prognostic information in high-risk patients, during both short- and long-term follow-up.

Trial of a novel prostacyclin analog, UT-15, in patients with severe intermittent claudication

Prostacyclin is an endothelially derived vasodilator and inhibitor of platelet aggregation. Despite its therapeutic potential for peripheral arterial disease, the short half-life and chemical instability are barriers to routine therapy. Accordingly, prostacyclin analogs are being evaluated in patients with peripheral arterial disease. State-of-the-art non-invasive ultrasonography allows for serial testing of the hemodynamic effects of vasoactive drugs. The safety, efficacy and hemodynamic effects of UT-15, a novel, long-acting prostacyclin analog, were studied in patients with severe intermittent claudication. A total of eight patients with stable severe intermittent claudication, Fontaine classes IIb-III, were admitted to the hospital for intravenous infusion of UT-15. A symptom-limited, dose-escalation protocol was instituted, beginning with placebo and then with increasing dosage at 60-min intervals, followed by a 2-h period of maintenance dose at the maximum well-tolerated infusion rate. The hemodynamic response in the lower limbs was assessed with serial ultrasonography, segmental arterial pressures and pulse volumes. Blood flow in the common femoral artery increased 29% (p = 0.003) by the end of the maintenance period and remained above baseline throughout the washout period (p = 0.044). Blood velocity in the lower limb increased in most of the peripheral arteries. These increases achieved statistical significance in the common femoral artery (p = 0.025) and anterior tibial artery (p = 0.019), and approached significance in the popliteal artery (p=0.062). In two of four patients in whom blood flow was undetectable before the infusion, arterial blood flow at the ankle level became apparent on ultrasonography during maintenance infusion. UT-15 infusion improved the pulse volume recording (p = 0.016) but the ankle/brachial index did not change significantly. Common side effects at peak dose included headache and nausea. There were no serious adverse events attributable to UT-15 treatment. In most patients, the optimal infusion rate was 10-20 ng/kg per min. In conclusion, ultrasonography is a novel approach for assessing the hemodynamic response to vasoactive agents. UT-15 is well tolerated when given for up to 2 h and increases arterial blood flow and velocity in patients with severe intermittent claudication.

Assessing daily fluctuations in posttraumatic stress disorder symptoms and substance use with interactive voice response technology: Protocol compliance and reactions.

PTSD symptoms and substance use commonly co-occur, but information is limited regarding their interplay. We used ecological momentary assessment (EMA) to capture fluctuations in PTSD symptoms and drinking within and across days. Fifty Iraq and Afghanistan War veterans completed four daily Interactive Voice Response (IVR) assessments of PTSD and substance use with cell phones for 28 days. The aims of this study were to (1) describe participant compliance and reactions to the protocol and (2) identify participant characteristics and protocol reactions that predict compliance. Protocol compliance was high, with participants completing an average of 96 out of a total of 112 IVR assessments (86%). While some participants perceived that the IVR assessments increased their drinking (21%) and PTSD symptoms (60%), self-report measures showed significant decreases in PTSD symptoms and nonsignificant decreases in drinking over the assessment period. Analyses revealed demographic (e.g., older than 24, full-time employment, more education), clinical (e.g., less binge drinking, less avoidance symptoms), and perceived benefit from participation predicted better protocol compliance. Results can guide future research on participant predictors of compliance with intensive EMA methods.