A phase I trial of ispinesib, a kinesin spindle protein inhibitor, with docetaxel in patients with advanced solid tumours.

The aim of this study is to define the maximum tolerated dose (MTD), safety, pharmacokinetics (PKs) and efficacy of ispinesib (SB-715992) in combination with docetaxel. Patients with advanced solid tumours were treated with ispinesib (6-12 mg m(-2)) and docetaxel (50-75 mg m(-2)). Docetaxel was administered over 1 h followed by a 1-h infusion of ispinesib on day 1 of a 21-day schedule. At least three patients were treated at each dose level. Blood samples were collected during cycle 1 for PK analysis. Clinical response assessments were performed every two cycles using RECIST guidelines. Twenty-four patients were treated at four dose levels. Prolonged neutropaenia and febrile neutropaenia were dose limiting in six and two patients, respectively. The MTD was ispinesib 10 mg m(-2) with docetaxel 60 mg m(-2). Pharmacokinetic assessment demonstrated concentrations of ispinesib and docetaxel, consistent with published data from single agent studies of the drugs. Seven patients (six hormone refractory prostate cancer (HRPC), one renal cancer) had a best response of stable disease (>or=18 weeks). One patient with HRPC had a confirmed >50% prostatic-specific antigen decrease. The MTD for ispinesib and docetaxel was defined and the combination demonstrated an acceptable toxicity profile. Preliminary PK data suggest no interaction between ispinesib and docetaxel.

Triple therapy with clarithromycin, omeprazole, and amoxicillin for eradication of Helicobacter pylori in duodenal ulcer patients in Asia and Africa.

BACKGROUND: Studies assessing the efficacy of triple therapy containing clarithromycin and amoxicillin for the eradication of Helicobacter pylori infection and healing of duodenal ulcers in Asian and African countries are limited. AIM: To determine the efficacy and safety of 1-week triple therapy with omeprazole, amoxicillin and clarithromycin for eradicating H. pylori infection in patients with active duodenal ulcer living in Asian and African regions. METHODS: This was an open-label, multicentre study in 11 centres in Asia and Africa. Patients with endoscopy-proven duodenal ulcer and who were H. pylori-positive were treated with clarithromycin 500 mg, omeprazole 20 mg, and amoxicillin 1000 mg, all given twice daily for 7 days. Upper endoscopy was repeated at week 6 to check for ulcer healing and H. pylori status. RESULTS: A total of 117 patients were recruited. H. pylori eradication rates were 85% by per protocol analysis and 80% by intention-to-treat analysis. Ulcer healing was found in 94% of subjects (per protocol analysis). Clinical success, measured by change of pre-treatment ulcer symptoms, was strongly supported by complete resolution or improvement in 100% of the evaluable patients (per protocol analysis). Since treatment-related adverse events, when present, were largely mild or moderate, the triple therapy regimen was considered safe. CONCLUSION: Seven-day triple therapy with omeprazole, amoxicillin, and clarithromycin was efficacious for treating Asian and African patients with duodenal ulcer disease associated with H. pylori infection, and the treatment regimen was well-tolerated.

TNF receptor 2-deficient CD8 T cells are resistant to Fas/Fas ligand-induced cell death.

Apoptotic cell death plays a fundamental role in the maintenance of tissue homeostasis in complex biological systems. It is also a major mechanism for keeping immune reactions in check. Members of the TNF family of receptors and cytokines are implicated in the regulation of apoptotic signals that shape the immune system. In this study, we have examined the role of three members of the TNFR family, Fas (CD95), TNFR1 (p55), and TNFR2 (p75), in inducing cell death in Con A-activated CD4 and CD8 T cells. It was found that Con A-activated p55(-/-) CD4 or CD8 T cells were highly resistant to TNF-induced cell death. By contrast, although activated p75(-/-) CD4 or CD8 T cells were killed by TNF, they were more resistant to TNF-induced killing when compared with p75(+/+) cells, particularly at higher concentrations of TNF. We also determined whether activated p55(-/-) and p75(-/-) T cells differ in their sensitivity to cell death induced by TCR cross-linking. We found that activated p55(-/-) CD4 or CD8 T cells were equally susceptible to TCR-induced cell death. More interestingly, the loss of the p75 receptor conferred resistance to TCR-induced death in activated CD8, but not CD4 T cells. This resistance to TCR-induced death in activated p75(-/-) CD8 T cells correlated with the resistance of these cells to Fas/Fas ligand-induced cell death.

Ulcerative colitis in the Indian population of Durban.

This study on ulcerative colitis in the Indian population of Durban between 1983 and 1987 revealed an incidence of 2,7/100,000 per year. Patients tended to have clinically mild-to-moderate disease, with macroscopic examination showing moderate severity and either extensive or total involvement. No relationship was found between clinical, macroscopic and laboratory indices of severity and extent of disease. The only relationship between laboratory tests and severity was that patients with low albumin values were more likely to have clinically severe disease. Extra-intestinal manifestations were rare, but many patients had liver involvement and colonic strictures. Ulcerative colitis was diagnosed more frequently than tuberculosis of the bowel during the study period, and amoebic dysentery was rarely diagnosed.

Sialidosis type I: first report in the Indian population. A clinical, biochemical and electrophysiological study.

Sialidosis type I has been described in several ethnic groups but to the best of our knowledge has not been reported in Indian families. We report on the clinical, biochemical and electrophysiological features in three siblings born to parents of South Indian origin. The diagnosis was missed for two years as they were labelled as cases of Ramsay-Hunt Syndrome.

Gastric carcinoma in Durban's Indian population.

Histologically proven gastric carcinoma was studied to establish the incidence and pattern of the disease in the Indian population of Durban. The incidence in this population was found to be low, 6.9/100,000/year. Over a 7-year period (1980-1986) 115 patients were treated for gastric carcinoma at R. K. Khan Hospital. There was a male preponderance, and the average age at presentation was 56 years. The commonest presenting symptoms were dyspepsia and vomiting, and the majority of patients presented with advanced disease. Only a third underwent resection, a third had no treatment, and a third underwent palliative bypass or laparotomy only. The majority of patients who had a palliative bypass or no treatment died within 9 months. The 5-year survival rate for patients undergoing curative resection was 38% and for palliative resection 9%. To improve survival, emphasis must be on early diagnosis and it is recommended that any patient with dyspepsia who is over the age of 30 years should have an endoscopic investigation.

Septicaemia caused by an imported strain of multiply antibiotic resistant Salmonella typhi successfully treated with ciprofloxacin.

A case of typhoid fever caused by a multiply antibiotic resistant strain of Salmonella typhi is reported. The S. typhi strain was resistant to ampicillin, chloramphenicol and sulphamethoxazole-trimethoprim. Treatment with cefotaxime, resulted in a clinical and bacteriological cure, but the infection relapsed within a month after completion of therapy. It resolved completely with oral ciprofloxacin with no relapse after a follow up period of one year. To our knowledge this represents the first such reported case in South Africa. The role of ciprofloxacin in treating infections caused by multiantibiotic resistant S. typhi is also discussed.

Hepatocellular carcinoma in South African Indians resident in Natal.

Hepatoma is a rare disease in Natal Indians. It occurs in male patients in the fifth decade. They have no history of alcohol intake. The main presenting feature is abdominal pain, weight loss and hepatomegaly. Blood tests reveal a raised alkaline phosphatase, hypoalbuminaemia, hypergammaglobulinaemia and markedly raised gamma glutamyl transferase. The tumour is a single large expanding mass in the right lobe. The patient usually presents in a late stage of the illness and shows a progressive downhill course. Hepatitis B virus infection is emerging as the likeliest carcinogen.

Typhoid fever in the adult and paediatric Indian population of Durban.

The features of typhoid fever in Indian South Africans are described. In children the illness was usually uncomplicated. However, anaemia, thrombocytopenia and hypo-albuminaemia were found in both adults and children. The initial symptoms on presentation of diarrhoea and vomiting frequently led to a misdiagnosis of gastro-enteritis. The previous administration of antibiotics also resulted in failure to isolate Salmonella typhi in 41% of patients studied. Typhoid acquired in the microbiology laboratory and that seen in visitors returning from India and the Far East is emphasised. The S. typhi isolates were uniformly sensitive to all antibiotics tested. The disproportionately high number of Indians of south Indian ancestry presenting to the R. K. Khan Hospital needs to be investigated.

Dystonia and choreo-athetosis in Wernicke's encephalopathy. A case report.

An Indian man with Wernicke's encephalopathy had nystagmus, pupillary changes and confusion, but the unusual and prominent features in his presentation were marked dystonia and choreo-athetosis, which responded rapidly to thiamine. The possible pathogenesis is discussed.

Patterns of cirrhosis in Natal Indians.

A retrospective study was designed to analyse the mode of presentation, clinical signs, haematological, biochemical and histological features in 46 Indian patients admitted with cirrhosis to R. K. Khan and King Edward VIII Hospitals, Durban, between 1977-1981. The commonest presenting feature was swelling of the body followed by pain in the right upper quadrant, most patients had hepatomegaly, jaundice and ascites, and splenomegaly was detected in one-third of cases. Biochemical investigations indicated that most patients had a high globulin and low albumin concentration. Liver function tests revealed raised bilirubin and gamma-glutamyltransferase values in most cases. On histological examination, micronodular cirrhosis predominated (95%) with a high incidence of fat and iron deposition. Changes consistent with alcoholic hepatitis were superimposed in one-third of cases while immunological and viral markers were absent. This study suggests that alcohol is the predominant cause of cirrhosis in Natal Indians.