Minocycline Synergizes with N-Acetylcysteine and Improves Cognition and Memory Following Traumatic Brain Injury in Rats

Background: There are no drugs presently available to treat traumatic brain injury (TBI). A variety of single drugs have failed clinical trials suggesting a role for drug combinations. Drug combinations acting synergistically often provide the greatest combination of potency and safety. The drugs examined (minocycline (MINO), N-acetylcysteine (NAC), simvastatin, cyclosporine A, and progesterone) had FDA-approval for uses other than TBI and limited brain injury in experimental TBI models. Methodology/Principal Findings: Drugs were dosed one hour after injury using the controlled cortical impact (CCI) TBI model in adult rats. One week later, drugs were tested for efficacy and drug combinations tested for synergy on a hierarchy of behavioral tests that included active place avoidance testing. As monotherapy, only MINO improved acquisition of the massed version of active place avoidance that required memory lasting less than two hours. MINO-treated animals, however, were impaired during the spaced version of the same avoidance task that required 24-hour memory retention. Coadministration of NAC with MINO synergistically improved spaced learning. Examination of brain histology 2 weeks after injury suggested that MINO plus NAC preserved white, but not grey matter, since lesion volume was unaffected, yet myelin loss was attenuated. When dosed 3 hours before injury, MINO plus NAC as single drugs had no effect on interleukin-1 formation; together they synergistically lowered interleukin-1 levels. This effect on interleukin-1 was not observed when th

Cost-effectiveness of Screening for Coronary Artery Disease in Asymptomatic Patients with Type 2 Diabetes and Additional Atherogenic Risk Factors

OBJECTIVE: Screening for coronary artery disease (CAD) in asymptomatic diabetic patients with two additional atherogenic risk factors has been recommended by the American College of Cardiology/American Diabetes Association, but its cost-effectiveness is yet to be determined. The present study aims to evaluate the cost-effectiveness of screening and determine acceptable strategies. DESIGN: Cost-effectiveness analysis using a Markov model was performed from a societal perspective to measure the clinical benefit and economic consequences of CAD screening in asymptomatic men with diabetes and two additional atherogenic risk factors. We evaluated cohorts of patients stratified by different age groups, and 10 possible combination pairs of atherogenic risks. Incremental cost-effectiveness of no screening, exercise electrocardiography, exercise echocardiography, or exercise single-photon emission-tomography (SPECT) was calculated. Input data were obtained from the published literature. Outcomes were expressed as U.S. dollars per quality-adjusted life-year (QALY). MEASUREMENTS AND MAIN RESULTS: Compared with no screening, incremental cost-effectiveness ratio of exercise electrocardiography was $41,600/QALY in 60-year-old asymptomatic diabetic men with hypertension and smoking, but was weakly dominated by exercise echocardiography. Exercise echocardiography was most cost-effective, with an incremental cost-effectiveness ratio of$40,800/QALY. Exercise SPECT was dominated by other strategies. Sensitivity analyses found that results varied depending on age, combination of additional atherogenic risk factors, and diagnostic test performance. CONCLUSIONS: Incremental cost-effectiveness ratio of CAD screening in asymptomatic patients with diabetes and two or more additional atherogenic risk factors is shown to be acceptable from a societal perspective. Exercise echocardiography was the most cost-effective strategy, followed by exercise electrocardiography