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.     

Gabapentin Activates Spinal Noradrenergic Activity in Rats and Humans and Reduces Hypersensitivity after Surgery

Background: Gabapentin has been reported to inhibit various acute and chronic pain conditions in animals and humans. Although the efficacy of gabapentin depends on the [alpha]2[delta] subunit of voltage-gated calcium channels, its analgesic mechanisms in vivo are still unknown. Here, the authors tested the role of spinal noradrenergic inhibition in gabapentin's analgesia for postoperative pain.

Methods: Gabapentin was administered orally and intracerebroventricularly to rats on the day after paw incision, and withdrawal threshold to paw pressure was measured. The authors also measured cerebrospinal fluid concentration of norepinephrine and postoperative morphine use after surgery in patients who received oral placebo or gabapentin.

Results: Both oral and intracerebroventricular gabapentin attenuated postoperative hypersensitivity in rats in a dose-dependent manner. This effect of gabapentin was blocked by intrathecal administration of the [alpha]2-adrenergic receptor antagonist idazoxan and the G protein-coupled inwardly rectifying potassium channel antagonist tertiapin-Q, but not by atropine. In humans, preoperative gabapentin, 1,200 mg, significantly increased norepinephrine concentration in cerebrospinal fluid and decreased morphine requirements.     

Burkholderia gladioli: five year experience in a cystic fibrosis and lung transplantation center.

BACKGROUND: The impact of infection with Burkholderia gladioli in cystic fibrosis, other chronic airway diseases and immunosuppressed patients is unknown. METHODS: A six-year retrospective review of all patients with B. gladioli infection was performed in a tertiary referral center with cystic fibrosis and lung transplantation programs. In addition, a targeted survey of all 251 lung transplant recipients was performed. Available B. gladioli isolates were analyzed via pulsed field gel electrophoresis. RESULTS: Thirty-five patients were culture positive for B. gladioli, including 33 CF patients. No bacteremia was identified. Isolates were available in 18 patients and all were genetically distinct. Two-thirds of these isolates were susceptible to usual anti-pseudomonal antibiotics. After acquisition, only 40% of CF patients were chronically infected (> or =2 positive cultures separated by at least 6 months). Chronic infection was associated with resistance to > or =2 antibiotic groups on initial culture and failure of eradication after antibiotic therapy. The impact of acquisition of B. gladioli infection in chronic infection was variable. Three CF patients with chronic infection underwent lung transplantation. One post-transplant patient developed a B. gladioli mediastinal abscess, which was treated successfully. CONCLUSIONS: The majority of patients' culture positive for B. gladioli at our center have CF. B. gladioli infection is often transient and is compatible with satisfactory post-lung transplantation outcomes.     

Biphasic Dose Response in Low Level Light Therapy

The use of low levels of visible or near infrared light for reducing pain, inflammation and edema, promoting healing of wounds, deeper tissues and nerves, and preventing cell death and tissue damage has been known for over forty years since the invention of lasers. Despite many reports of positive findings from experiments conducted in vitro, in animal models and in randomized controlled clinical trials, LLLT remains controversial in mainstream medicine. The biochemical mechanisms underlying the positive effects are incompletely understood, and the complexity of rationally choosing amongst a large number of illumination parameters such as wavelength, fluence, power density, pulse structure and treatment timing has led to the publication of a number of negative studies as well as many positive ones. A biphasic dose response has been frequently observed where low levels of light have a much better effect on stimulating and repairing tissues than higher levels of light. The so-called Arndt-Schulz curve is frequently used to describe this biphasic dose response. This review will cover the molecular and cellular mechanisms in LLLT, and describe some of our recent results in vitro and in vivo that provide scientific explanations for this biphasic dose response.