Pre-clinical evaluation of a new orally-active CCK-2R antagonist, Z-360, in gastrointestinal cancer models.

BACKGROUND: Gastrin has a role in gastrointestinal (GI) malignancy. This study provides pre-clinical evaluation of a novel, orally-active gastrin/cholecystokinin-2 receptor (CCK-2R) antagonist, Z-360. METHODS: (125)I gastrin-17 (G17) displacement and G17-stimulated calcium assays were used in classical CCK-2R-transfected cell lines. Akt phosphorylation was assessed by Western blotting. Z-360 efficacy in vivo was evaluated in three human xenograft models, and microvessel density and apoptosis in these models were investigated by immunohistochemistry. RESULTS: Z-360 inhibited (125)I G17 binding to cells expressing CCK-2R, and G17-stimulated signalling. Reduced Akt phosphorylation in an oesophageal cell-line treated with Z-360 was reversed by co-treatment with G17. Z-360 increased survival in a gastric ascites model (p=0.011) and decreased tumour growth in a hepatic metastasis model (81%, p=0.02). In an orthotopic pancreatic model, Z-360 combined with gemcitabine decreased final tumour weight compared to single agents (84%, p=0.002) and there was increased apoptosis and decreased microvessel density in ex vivo tumour tissue. CONCLUSIONS: These results show that the orally-active CCK-2R antagonist, Z-360 has high sub-nM affinity for classical CCK-2R, is well tolerated in vivo and exerts an anti-tumour effect.

A phase II study of G17DT in gastric carcinoma.

PURPOSE: G17DT is a gastrin immunogen, raising antibodies that blockade gastrin-stimulated growth. The aim of the study was to characterise antibody response and assess safety and tolerability of G17DT given to patients with gastric cancer. EXPERIMENTAL DESIGN: G17DT was administered to 52 patients with gastric adenocarcinoma at weeks 0, 2 and 6 by intramuscular injection at doses of 10, 100 and 250 microg. Antibody levels were measured by an ELISA assay. A radioligand displacement assay determined the ability of G17DT-immunised patients' sera to inhibit binding of 125IG17 to cholecystokinin (CCK)-2 receptors. RESULTS: By week 12 of the study, 6/12 evaluable stage I-III patients achieved an antibody response in the 10 microg group, 7/11 in the 100 microg group, and 11/12 in the 250 microg group. Stage IV patients dosed at 250 microg achieved a similar response rate to stage I-III patients dosed at 10 or 100 microg. G17DT was well tolerated in 47/52 patients. Two patients suffered significant adverse reactions including injection site pain and abscess. G17DT antibodies displaced iodinated gastrin from CCK-2 receptors, with the level of displacement correlating with antibody titre. CONCLUSIONS: G17DT immunisation is a well-tolerated method of raising functional antibodies to 17 amino acid gastrin forms in patients with gastric carcinomas.

Perioperative hypoxaemia detected by intermittent pulse oximetry.

Perioperative pulse oximetry was performed on one hundred consecutive abdominal surgical patients to audit our management of perioperative oxygenation. Oximetry was performed preoperatively, in the recovery room, and daily in the ward until discharge or the sixth postoperative day, with prescribed oxygen therapy continuing during measurement. Twenty-nine patients had saturations of 90% or less on a total of fifty-one occasions. Twenty-nine patients were prescribed prophylactic oxygen therapy, but seven had oxygen therapy stopped prematurely and were found to have saturations of 90% or less. In this group of patients, clinical assessment of oxygenation and the need for oxygen therapy was inadequate. Intermittent oximetry is rapidly and simply performed, and by detecting patients with arterial haemoglobin desaturation, could improve oxygen prescribing in the perioperative period.

Reinforcing a "low flow" anaesthesia policy with feedback can produce a sustained reduction in isoflurane consumption.

A three-month audit of isoflurane consumption at Palmerston North Hospital in 1994 showed an averaged vapour flow rate of approx 85 ml per minute of anaesthesia, equivalent to 1.4% isoflurane at six litres per minute. After purchasing volatile agent analysers, a program encouraging low flow anaesthesia and providing a report of the previous month's consumption rate was started in July 1996. The isoflurane averaged vapour flow rate was tracked over the following twenty-month period and fell by a sustained 65% to range around 30 +/- 5 ml/min, producing savings of approximately NZ$104,000 over this period.

Possible interaction between SPPS and enalapril.

A patient undergoing groin lymph node dissection with spinal and general anaesthesia was receiving enalapril to control hypertension. Infusion of stable plasma protein solution (Commonwealth Serum Laboratories, Australia) was associated with significant hypotension and flushing. A brief review of stable plasma protein solution and angiotensin converting enzyme inhibitor pharmacology is presented to provide a possible mechanism for these events. This mechanism implies that angiotensin converting enzyme inhibitor therapy is a relative contraindication to rapid SPPS infusion.

Propofol is a 'safe' anaesthetic agent in malignant hyperthermia susceptible patients.

In this study we investigated in vitro and in vivo effects of propofol in malignant hyperthermia susceptible (MHS) patients in order to assess the safety of propofol infusion as a non-triggering anaesthetic technique for diagnostic and therapeutic procedures. In vitro, human MHS muscle samples were exposed to propofol and changes in (a) baseline tension and (b) contracture tension on exposure to halothane and caffeine were measured. In vivo, (a) anaesthesia was induced in ten muscle biopsy positive MHS patients with propofol 2.5 mg/kg and (b) anaesthesia was produced in five muscle biopsy positive MHS patients with infusions of propofol up to 10 mg/kg/hr. In vitro, human MHS muscle did not develop contractures with propofol alone. Propofol had no significant effect on contracture development in response to halothane and caffeine. In vivo, no evidence of an MH response was detected following induction or maintenance of anaesthesia with propofol. Our results and literature review are in agreement that propofol is a 'safe' induction and maintenance agent in MHS patients. Propofol can be used for muscle biopsy anaesthesia because it does not alter the sensitivity of diagnostic muscle biopsy testing.