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.     

Rapid Immunofluorescence Microscopy for Diagnosis of Melioidosis

An immunofluorescent (IF) method that detects Burkholderia pseudomallei in clinical specimens within 10 min was devised. The results of this rapid method and those of an existing IF method were prospectively compared with the culture results for 776 specimens from patients with suspected melioidosis. The sensitivities of both IF tests were 66%, and the specificities were 99.5 and 99.4%, respectively.     

Die Verwendung eines Nervenstimulators zur sicheren Platzierung von Ilisarov-Drähten

OBJECTIVE: Avoidance of potential iatrogenic nerve injury during insertion of Ilizarov fine wires into areas of high anatomic risk by using a modified nerve stimulation technique. INDICATIONS: Application of the Ilizarov ring fixator to areas of high anatomic hazard, in situations where anatomic topography may be distorted by previous surgery, trauma, or congenital anomalies. CONTRAINDICATIONS: Use of systemic muscle relaxants. Caution in patient with cardiac pacemaker. SURGICAL TECHNIQUE: Preliminary experiments showed that a standard nerve-stimulating device can deliver a negatively charged, monophasic square pulse of current through Ilizarov wires. During the application of an Ilizarov frame to potentially hazardous anatomic regions, providing no systemic muscle relaxants are used, a voltage field sufficient to cause nerves in close proximity to the Ilizarov wire to depolarize is produced. Identification of a distal muscle twitch provoked by the stimulation may indicate a potential for iatrogenic nerve injury. RESULTS: Results show that with the nerve stimulator set at 2.5 mA (pulsed at a frequency of 2 Hz), peripheral nerves are stimulated if they lie within 5 mm of the wires. Should a distal muscle twitch occur, wires should be repositioned so that equivalent stimulation produces no twitch. The technique was used during Ilizarov frame application in ten patients, with only a single occurrence of distal muscle twitches in a lower-leg frame. Following repositioning of the Ilizarov wire in this case, no further twitches were observed, indicating that no Ilizarov wire was inserted close to peripheral nerves. No neurologic impairment was present postoperatively.     

The Effects of Zero Magnesium Dialysate and Magnesium Supplements on Ionised Calcium Concentration in Patients on Regular Dialysis Treatment

The effect of oral magnesium carbonate aluminium hydroxide onserum ionised calcium, total calcium, aluminium and magnesium,was assessed in 31 patients with chronic renal failure, duringand after one haemodialysis. The behaviour of ionised calcium and total calcium was the samein both groups. Each showed a slight fall during dialysis, whichwas not significant. Serum total calcium was 0.2–0.3 mmol/l(0.8–1.2 mg/dl) greater throughout the period of dialysisin the group taking aluminium hydroxide. Serum magnesium andaluminium were both lower in the group treated with magnesiumcarbonate. In the group taking magnesium carbonate, serum magnesium concentrationsfell markedly during dialysis, but otherwise were maintainedwithin the reference range by the use of a magnesium-free dialysate.These results show the effectiveness of magnesium carbonateoral phosphate-binding agents and zero magnesium dialysate inreducing serum aluminium without affecting the behaviour ofserum calcium fractions during dialysis.     

The influence of growth hormone on the reversibility of articular cartilage degeneration in rabbits

Growth hormone has chondrogenic affects on normal as well as on damaged articular cartilage. In this study, the influence of growth hormone is investigated on early degenerative changes in the articular cartilage in 72 New Zealand white rabbits. Cartilage lesions were created in femoral condyles using an immobilization model. Cartilage damage was assessed using biochemical, histologic, and biomechanical criteria. Growth hormone had no influence on prevention of immobilization abnormalities but had a significant affect on healing of established lesions.     

A model for the function of glycosaminoglycans in the urinary tract

Summary Investigations into the antibacterial defense mechanisms of the urinary tract revealed an important function for cell surface glycosaminoglycans (GAG), that of a generalized antiadherent activity. This activity was found to prevent bacterial, protein, and ionic adherence to the cell membrane. A model was developed to explain mechanically the activity of sulfated polysaccharides at the bladder surface. The model predicted injurious effects of quaternary amines and also that the mucus would be the so-called blood-urine barrier. It also led to the hypothesis that exogenous polysaccharides may be important in treating bladder disease such as infection and interstitial cystitis. For the first clinical test of these concepts, a polysaccharide was employed in several double-blind studies and was shown to ameliorate significantly the symptoms of interstitial cystitis. These discoveries suggest new methods to manipulate the microenvironment between the transitional cell surface and the urine, leading to novel therapies in regulating disease of the genitourinary tract. They also stress the importance of understanding the mechanisms by which GAGs exert their effect in the urinary tract and how they are produced, maintained, and even inactivated (e.g., by urinary substances such as protamine).Supported by the Medical Research Service of the Veterans Administration, Urological Research and Education Foundation, and by National Institutes of Health grant R01DK39239.     

Lipoprotein (a) levels in those with high molecular weight apo (a) isoforms may remain low in a significant proportion of patients with end-stage renal disease.

BACKGROUND: Studies have reported an increase in median Lipoprotein (Lp) (a) in patients with high molecular weight (HMW) apolipoprotein (apo) (a) isoforms and renal impairment. Some studies identify Lp (a) levels as a risk factor for vascular disease in renal failure whilst others have demonstrated an association with apo (a) isoform type and vascular disease. METHODS: A total of 239 patients at end-stage renal failure (ESRF) were studied prior to the initiation of dialysis. Blood was taken for Lp (a) levels and apo (a) isoforms. Clinical vascular disease (CVD) was assessed on the basis of clinical history and Rose questionnaire. The control group for Lp (a) levels consisted of 228 healthy volunteers. RESULTS: Despite a higher median Lp (a) level in those with HMW isoforms, 30% of patients had Lp (a) levels <10 mg/dl. Overall, 49% patients were identified as having CVD. Diabetes, smoking history and Lp (a) levels were significantly associated with CVD in logistic regression analysis, although when patients with low molecular weight (LMW) and HMW isoforms were analysed separately, Lp (a) levels were not significantly associated with CVD in those with LMW isoforms. The rates of CVD in those with HMW isoform and low Lp (a) levels were significantly lower than those with HMW isoforms and elevated Lp (a) levels, 34 vs 57% (P < 0.01). CONCLUSIONS: Although median Lp (a) levels in those patients at ESRF with HMW isoforms are higher than controls, in a third of such patients Lp (a) levels remain relatively low. These patients have lower rates of CVD than those with high levels of Lp (a).