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.     

Toxocariasis: a serological survey of blood donors in the Australian Capital Territory together with observations on the risks of infection

The sera from 660 healthy blood donors from Canberra were tested for antibodies to Toxocara canis by the ELISA test. The results were compared with those from patients with suspected or confirmed visceral larva migrans or ocular toxocariasis. Over 7% of Canberra sera showed elevated levels of antibody reacting with T. canis antigen. Sera from patients resident in Australia with other helminth parasites did not cross-react with T. canis antigen in our tests. However, studies of sera collected in several tropical countries with other parasitic infection, show that cross-reactions with other parasites are possible. The use of purified glycoprotein antigen does not alter the possibility of cross-reaction. Observations and experiments show that people in Canberra may be exposed to the infective eggs of T. canis.     

Glycine transporter I inhibitor, N-methylglycine (sarcosine), added to antipsychotics for the treatment of schizophrenia.

BACKGROUND: Hypofunction of N-methyl-D-aspartate glutamate receptor had been implicated in the pathophysiology of schizophrenia. Treatment with D-serine or glycine, endogenous full agonists of the glycine site of N-methyl-D-aspartate receptor, or D-cycloserine, a partial agonist, improve the symptoms of schizophrenia. N-methylglycine (sarcosine) is an endogenous antagonist of glycine transporter-1, which potentiates glycine's action on N-methyl-D-aspartate glycine site and can have beneficial effects on schizophrenia. METHODS: Thirty-eight schizophrenic patients were enrolled in a 6-week double-blind, placebo-controlled trial of sarcosine (2 g/d), which was added to their stable antipsychotic regimens. Twenty of them received risperidone. Measures of clinical efficacy and side effects were determined every other week. RESULTS: Patient who received sarcosine treatment revealed significant improvements in their positive, negative, cognitive, and general psychiatric symptoms. Similar therapeutic effects were observed when only risperidone-treated patients were analyzed. Sarcosine was well-tolerated, and no significant side effect was noted. CONCLUSIONS: Sarcosine treatment can benefit schizophrenic patients treated by antipsychotics including risperidone. The significant improvement with the sarcosine further supports the hypothesis of N-methyl-D-aspartate receptor hypofunction in schizophrenia. Glycine transporter-1 is a novel target for the pharmacotherapy to enhance N-methyl-D-aspartate function.     

Hot beverages and oesophageal cancer in southern Brazil: a case-control study

There is a cluster of high-incidence areas of oesophageal cancer in south-eastern South America, including Southern Brazil, Uruguay and parts of Argentina. The present case-control study investigated the hypothesis that this may be due to the drinking of maté, a traditional beverage drunk at a very high temperature, and also studied the role of other known risk factors such as alcohol and tobacco. Cases (171) and age- and sex-matched controls (342) were recruited from hospitals in the State of Rio Grande do Sul in Southern Brazil. The crude odds ratio for daily maté drinkers was 1.92 relative to those drinking less frequently than daily (p = 0.006). Other risk factors included the drinking of cachaça (a sugar cane spirit), smoking, rural residence, low fruit consumption and high intake of meats. After adjustment for these variables through conditional logistic regression, the odds ratio associated with daily maté drinking was reduced to 1.47 (90% CI = 0.87 - 2.50). Although the study failed to provide evidence of a strong association between maté and oesophageal cancer, the cluster of high rates could be explained by relative risks of the magnitude observed. This is due to the fact that approximately 70% of adult males and 50% of females are daily drinkers. In addition, this study revealed that alcohol, tobacco smoking and rural residence are the main risk factors for oesophageal cancer in this population and the fruit consumption confers some degree of protection.     

Management of Constipation in Patients with Cancer

In patients with cancer, constipation is a common complication. However, unlike in the general population, the impact of the symptoms of constipation on the quality of life in cancer patients is often greater. More importantly, in patients who are in the more advanced stages of the disease, constipation may also be suggestive of disease progression. Constipation as a symptom in this population is of significant importance as it may lead to life-threatening complications, i.e. bowel perforation due to fecal impaction. Therefore, in this regard, this problem deserves particular attention, as early recognition and management of complications may prevent further physical deterioration. This review aims to provide an overview of the management of constipation in patients with cancer. A symptom-based criteria definition for chronic constipation and prevalence of the problem in cancer patients provides a brief introduction. For the initial assessment and evaluation of constipation in cancer patients, an algorithm is described. The different possible etiologies of constipation in cancer patients are also discussed. Regarding therapeutic management, guidelines and recommendations for the use of different types of laxatives, stool softeners, suppositories and rectal enemas, prokinetic agents, antidepressant medications, and miscellaneous agents are succinctly discussed. Management of fecal impaction and opioid-induced bowel dysfunction are also described. Lastly, a brief overview of the management of acute colonic pseudo-obstruction and surgical or endoscopic options for large bowel obstruction are described.