The Specific Endothelin A Receptor Antagonist ZD4054: Preclinical and Clinical Results

ContextZD4054 is a specific endothelin A (ET_A) receptor antagonist being investigated for the treatment of hormone-resistant prostate cancer (HRPC). ZD4054 binds specifically to the ET_A receptor, with no detectable activity at the ET_B receptor. In preclinical studies, ZD4054 inhibited endothelin (ET-1)-mediated changes in cellular invasiveness in vitro, and inhibited angiogenesis and growth of tumour xenografts in vivo. Consistent with its specific binding profile, ZD4054 inhibited ET_A-receptor-mediated antiapoptotic events while allowing ET_B-receptor-mediated proapoptotic signalling.Evidence acquisitionThe preclinical and clinical activity of ZD4054 is reviewed.Evidence synthesisIn the clinical setting, stable levels of circulating ET-1 following single ZD4054 doses up to 240 mg demonstrated the absence of ZD4054 activity at the ET_B receptor. ZD4054 is cleared principally via the urine, with a terminal elimination half-life of approximately 8–12 hours and with little accumulation after once-daily oral dosing.In a Phase 2 trial, patients with metastatic HRPC who were pain free or mildly symptomatic for pain were randomized to once-daily oral tablets of ZD4054 10 mg (n = 107), or 15 mg (n = 98), or matched placebo (n = 107). ZD4054 was generally well tolerated in this population, with an adverse effect profile consistent with its known pharmacological activity. The most common adverse effects were headache, peripheral oedema and nasal congestion. At the primary analysis there was no statistically significant difference in time to progression between the ZD4054-treated groups and placebo (hazard ratio [HR]: ZD4054 10 mg, 0.88 [80% CI 0.71, 1.09]; ZD4054 15 mg, 0.83 [0.66, 1.03]). However, a promising signal for prolonged overall survival was observed, which was sustained at a subsequent analysis (HR versus placebo: ZD4054 10 mg, 0.55 [80% CI 0.41, 0.73]; ZD4054 15 mg, 0.65 [0.49, 0.86]).ConclusionsThese results support the strategy of targeting the ET_A receptor in prostate cancer, and mandate further investigation of ZD4054 in Phase 3 clinical trials.     

The association between overactive bladder and diuretic use in the elderly

Several recent population-based studies have provided insight into the clinical importance and impact of overactive bladder (OAB). Although OAB can affect anyone at any age, the prevalence tends to increase with advancing age. Diuretic use is also common among older adults, as the prevalence of clinical conditions such as hypertension and heart failure requiring its use increases markedly with age. By causing increased formation of urine by the kidneys, diuretics increase urinary frequency and may cause urinary urgency and incontinence. This review provides a summary of available data, focusing on the association between OAB and diuretic use in the elderly. Although there is very little research work in this area, available studies have provided insight into the possible contribution of diuretic use to OAB in the elderly. Based on a recent report, OAB symptoms are common among older adults using diuretics, particularly the loop-type, and are associated with poor quality of life. More studies are required to fully understand the association between diuretic use and OAB, particularly its impact on health-related quality of life.