Faculty Bibliography

PURPOSE/OBJECTIVE:These studies were undertaken to determine if fexapotide triflutate 2.5 mg transrectal injectable (FT) has significant long-term (LT) safety and efficacy for the treatment of benign prostatic hyperplasia (BPH). METHODS:Two placebo controlled double-blind randomized parallel group trials with 995 BPH patients at 72 sites treated 3:2 FT:placebo, with open-label FT crossover (CO) re-injection in 2 trials n = 344 and long-term follow-up (LF) 2-6.75 years (mean 3.58 years, median 3.67 years; FT re-injection CO mean 4.27 years, median 4.42 years) were evaluated. 12 months post-treatment patients elected no further treatment, approved oral medications, FT, or interventional treatment. Primary endpoint variable was change in Symptom Score (IPSS) at 12 months and at LF. CO primary co-endpoints were 3-year incidence of (1) surgery for BPH in FT treated CO patients versus patients crossed over to oral BPH medications and (2) surgery or acute urinary retention in FT-treated CO placebo patients versus placebo patients crossed over to oral BPH medications. 28 CO secondary endpoints assessed surgical and symptomatic outcomes in FT reinjected patients versus conventional BPH medication CO and control subgroups at 2 and 3 years. RESULTS:FT injection had no significant safety differences from placebo. LF IPSS change from baseline was higher in FT treated patients compared to placebo (median FT group improvement - 5.2 versus placebo - 3.0, p < 0.0001). LF incidence of AUR (1.08% p = 0.0058) and prostate cancer (PCa) (1.1% p = 0.0116) were both reduced in FT treated patients. LF incidence of intervention for BPH was reduced in the FT group versus oral BPH medications (8.08% versus 27.85% at 3 years, p < 0.0001). LF incidence of intervention or AUR in placebo CO group with FT versus placebo CO group with oral medications was reduced (6.07% versus 33.3% at 3 years, p < 0.0001). 28/28 secondary efficacy endpoints were reached in LF CO re-injection studies. CONCLUSIONS:FT 2.5 mg is a safe and effective transrectal injectable for LT treatment of BPH. FT treated patients also had reduced need for BPH intervention, and reduced incidence of PCa and AUR.

Recently, we had the opportunity to review the progress that has been made in the field of cardiovascular disease over the past century in The FASEB Journal and, based on those thoughts, in this article we predict what may transpire inthis 'century of biology'. Although it is true that 'the best way to predict the future is to invent it', we gaze through the prism of modern biomolecular science for a vision of a possible future and see cardiology practice that is transformed. In the second half of the 20th century, we developed a more fundamental understanding of atherosclerotic vascular disorders and invented life-saving therapeutics. We saw a similar development of mechanism-based pharmacotherapy to address heart failure, primarily through agents that antagonize the excessive concentration of circulating neurohumoral agents. Now we are in the midst of the device era, from stents to cardiac resynchronization therapy to transcatheter valves.The next wave of treatments will build on an increasingly sophisticated understanding of the molecular determinants of cardiovascular disorders and engineering feats that are barely perceptible now. Genomic profiling, molecular prescriptions for prevention and personalized therapeutics, regenerative medicine and the new field of cardiovascular tissue bioengineering will transform cardiovascular medicine. If the human species can survive threats of our own doing, such as the related epidemics of obesity and diabetes, by the turn of the next century, treatment of cardiovascular disease will not resemble the present in almost any way. Touch Medical Media 2012

During the life span of The FASEB Journal, the decline in cardiovascular mortality was astonishing as the fundamental bases of the complex syndromes of cardiovascular disease were illuminated. In this Silver Anniversary Review, we highlight a few pivotal advances in the field and relate them to research in Pasteur's quadrant, the region of investigation driven by both a desire for fundamental understanding and the consideration of its use. In the second half of the 20th century, we advanced from little pathophysiologic understanding to a near-complete understanding and effective, evidence-based therapeutics for vascular disorders and a similar development of pharmacotherapy to address heart failure, primarily through agents that antagonize the excessive concentration of circulating neurohumoral agents. In the current era, we have witnessed 'the rise of the machines,' from stents to cardiac resynchronization therapy. The next wave of treatments will build on an increasingly sophisticated understanding of the molecular determinants of cardiovascular disorders. We briefly consider the promise of regenerative medicine and are intrigued by the possibility for the direct reprogramming of resident cardiac fibroblasts into cardiomyocytes. As for the future, genomic profiling should help physicians recommend individualized risk factor modification targeted to prevent specific manifestations of cardiovascular disease. Transcriptional and biomarker analyses will almost surely be used individually to tailor therapy for those at risk of or experiencing cardiovascular disease. Given the ongoing exponential expansion of scientific knowledge, all of human ingenuity will be needed to fully utilize the power of Pasteur's quadrant and to unleash another quarter century in cardiology as scientifically fruitful and effective on human health as the last.-Levin, R. I., Fishman, G. I. The power of Pasteur's quadrant: cardiovascular disease at the turn of the century

Over the past 20 years, we have observed a paucity of morbidity and mortality due to cardiovascular disease among drug users in a methadone maintenance clinic. The present study investigated whether long-term exposure to opiates or opioids is associated with decreased severity of coronary artery disease (CAD) by comparing 98 decedents with methadone or opiates (M/O) in their blood at autopsy with 97 frequency-matched decedents without M/O. Severe CAD was found significantly less often in M/O-positive decedents (5 of 98) than in M/O-negative decedents (16 of 97). Multiple logistic regression analysis contrasting those with moderate or severe CAD to those with no or mild CAD yielded an odds ratio of 0.43 (95% confidence interval 0.20 to 0.94) for M/O positivity after adjustment for potential confounding. Long-term opiate exposure thus may mitigate CAD severity and its often fatal consequences

Patients with chronic renal failure (CRF) who undergo hemodialysis experience accelerated atherosclerosis and premature death. While the cause of uremic atherogenesis is unknown, we reported that uremic levels of oxalate, an excretory metabolite, severely inhibit proliferation and migration of human endothelial cells (EC) without affecting other cell types. Since the physical, cellular and molecular events of endothelial injury are clearly established as key factors in the development of plaque, and since inhibition of proliferation and migration would enhance endothelial injury, we have proposed that oxalate is an atherogenic toxin of uremia. In the current study, we used in situ cell counting and total DNA measurement to show that the inhibitory effect of oxalate on proliferation is exclusive to endothelial cells among human cell lines tested (endothelial cells, fibroblasts, aortic smooth muscle cells (SMC), glioblastoma and embryonic kidney cells). Using the fluorescent calcium indicators fura-2 and fluo-3, we correlated the inhibition of proliferation with a prolonged elevation in intracellular free calcium levels. We also demonstrated that all cells tested internalize 14C-oxalic acid. We conclude that plasma oxalate exerts its atherogenic effects by elevating intracellular calcium exclusively in endothelial cells and preventing re-endothelialization