Phase I/II study of pemetrexed with or without ABT-751 in advanced or metastatic non-small-cell lung cancer.

PURPOSE: ABT-751 is an antimitotic and vascular disrupting agent with potent preclinical anticancer activity. We conducted a phase I and randomized double-blind phase II study of pemetrexed with ABT-751 or placebo in patients with recurrent advanced or metastatic non-small-cell lung cancer (NSCLC). METHODS: One hundred seventy-one patients received intravenous pemetrexed 500 mg/m(2) day 1 and oral ABT-751 or placebo days 1 to 14 of 21-day cycles. The primary end point was progression-free survival (PFS). Secondary end point included overall survival (OS); pharmacokinetic and pharmacodynamic parameters were also analyzed. RESULTS: The recommended phase II dose of ABT-751 with pemetrexed is 200 mg. Fatigue, constipation, anemia, nausea, and diarrhea were the most common toxicities in both study arms. No pharmacokinetic interactions were observed. Median PFS in the ABT-751 arm was 2.3 months versus 1.9 for placebo (P = .819, log-rank) for the intention-to-treat population. However, differences in PFS (P = .112, log-rank) and OS (P = .034, log-rank; median 3.3 v 8.1 months) favoring ABT-751 were seen in the squamous NSCLC subgroup. Baseline circulating tumor cell concentrations were predictive of improved OS (P = .013). Changes from baseline of greater than 20% in plasma levels of placenta growth factor (P = .056), squamous cell carcinoma antigen (P = .03), and cytokeratin 19 fragment antigen 21-1 (P = .01) were markers best associated with improved OS. CONCLUSION: Addition of ABT-751 to pemetrexed is well-tolerated, but does not improve outcome in unselected patients with recurrent NSCLC. ABT-751 may have therapeutic potential in squamous NSCLC. Exploratory cellular and molecular analyses in this study identified biomarkers that may correlate with survival.

Wireless capsule endoscopy in enteropathy induced by nonsteroidal anti-inflammatory drugs in pigs.

AIM: The aim of this study is to evaluate the diagnostic yield of capsule endoscopy in nonsteroidal anti-inflammatory drug (NSAID)-induced enteropathy in pigs. MATERIALS AND METHODS: Indomethacin (400 mg/day) was administrated orally for 10 days to eight female pigs weighing 36.3+/-2.4 kg. Afterwards, capsule endoscopy was performed, using the EndoCapsule system (Olympus Optical Co., Tokyo, Japan). The following morning, pharmacological euthanasia and immediate autopsy were performed. RESULTS: Small bowel injury compatible with NSAID-induced enteropathy was observed in 7/8 animals. The most common lesions were red spots and erosions. Ulcers and small intestinal bleeding were identified sporadically. Sensitivity and specificity of capsule endoscopy were 83.3% and 95.8%, respectively. CONCLUSION: Our results indicate that wireless capsule endoscopy is a highly accurate noninvasive method for evaluation of experimental NSAID-induced enteropathy.

Wireless video capsule enteroscopy in preclinical studies: methodical design of its applicability in experimental pigs.

The aim of this project was to develop a methodology to introduce wireless video capsule endoscopy in preclinical research. Five mature female pigs (Sus scrofa domestica) were selected for the study. Capsule endoscopes (the EndoCapsule system; Olympus) were introduced into the duodenum endoscopically in each of the animals. The life span of batteries (i.e., total time of endoscopy recording) was 487-540 min (median 492 min). The capsule endoscope reached the cecum during enteroscopy once (after 7 h 57 min), in the remaining cases, endoscopy recordings terminated in the distal or terminal ileum. All capsule enteroscopies found a normal pattern of the small intestine. The intestinal lumen is narrower, transverse folds are sparse or even absent, villi are wider but less prominent in pigs compared to humans. Capsule endoscopy in experimental pigs will be helpful for future trials on injury of different drugs and xenobiotics to the small bowel.

Different solutions used for submucosal injection influenced early healing of gastric endoscopic mucosal resection in a preclinical study in experimental pigs.

BACKGROUND: We hypothesised that different solutions for submucosal injection may influence early healing of endoscopic mucosal resection (EMR). The aim of this study was to evaluate histological and immunological changes after EMR in experimental pigs. MATERIALS AND METHODS: Two parallel EMRs on the anterior and posterior wall of the gastric body were performed by means of the cap technique in 21 female pigs. A glycerol-based solution (anterior EMR) and hydroxypropyl methylcellulose solution (posterior EMR) were applied for submucosal injection. The animals were sacrificed 7 days later, and tissue sections of all EMRs were stained using combined trichrome. Computer image analysis was used for objective evaluation of elastic and collagen fibres content. Two-colour indirect immunophenotyping of blood and gastric samples were performed using mouse anti-pig monoclonal antibodies. RESULTS: The values of collagen fibre content 7 days after EMR were significantly higher in lesions after the use of solution A in comparison with solution B (2.10 +/- 0.25% versus 1.57 +/- 0.25%, p = 0.009). Concordant results were found in elastic fibres (3.23 +/- 0.49% versus 2.93 +/- 0.61%, p = 0.018). No systemic changes in major leukocyte subpopulations were found. In gastric tissue, lymphocyte subsets exhibited only minor changes. CD4(+) T-lymphocytes were increased in the healing tissue after EMR using solution A (17.08 +/- 9.24% versus 9.76 +/- 7.97%, p = 0.011). Significant increase of SWC3(+) leukocytes was observed after EMR using solution B (47.70 +/- 25.41% versus 18.70 +/- 12.16%, p = 0.001). CONCLUSIONS: The use of glycerol-based solution for submucosal injection was associated with more pronounced histological signs of early healing of EMRs compared with hydroxypropyl methylcellulose.

The use of wireless capsule enteroscopy in a preclinical study: a novel diagnostic tool for indomethacin-induced gastrointestinal injury in experimental pigs.

OBJECTIVES: The aim was the utilization of capsule microscopy and other diagnostic techniques for prospective pre-clinical research of absorption and biotransformation mechanisms of xenobiotics in the intestinal wall after induction of gastrointestinal dysfunction. Consequently, there is a demonstration of the extrems of gastrointestinal lesions development induced with indomethacin as a representative of non-steroidal anti-inflammatory drug. METHODS: The experimental animal species were small adult pigs (n=10; body weight 30-35 kg; 4-5 months old) used for their relative physiological and metabolic resemblance to man. The following experimental methods were used for diagnostic verification of gastrointestinal lesions (damage scale: 1 - erosions, red spots, inflammatory infiltration, 2 - single ulcers, 3 - strings of ulcers): endoscopic image for the diagnostics of gastro-duodenal segment (in vivo conditions), confocal laser microscopy (ex vivo imaging) and optical light microscopy (in vitro), small intestinal imaging by means of wireless capsule enteroscopy (in vivo), macroscopic findings and optical light microscopy (after animal sacrifice). RESULTS: The mutual confrontation of used methodological approaches proved the conformity in the frequency and extent of damage in the gastric wall and caecum, partly in the duodenal wall and terminal ileum. The signs of first-degree damage were discovered in the jejunal-ileal segment. CONCLUSIONS: The scale of lesions in particular gastrointestinal segments was verified using the combination of five diagnostic techniques for prospective utilisation of non-invasive capsule enteroscopy for the through-control of mucosal state.

Radioprotective effects of amifostine (WR-2721) or cystamine on radiation damage and its repair in rats whole body exposed to fission neutrons.

Sulphur containing radioprotective drugs amifostine (gammaphos, WR-2721) or cystamine (disulfide of meracaptoethylamine) of Czechoslovak production were examined in whole body fission neutrons irradiated rats in the thermal column of reactor VVR-S. Using the split-dose technic the first sublethal neutron dose in the range 1-2 Gy was followed by second lethal exposures in the two time intervals (3 or 6 days) using whole body fission neutrons irradiations (3 days interval) or whole body gamma-irradiations (6 days interval) for LD50/30 evaluation within next 30 days survival observation. In other experiments the mean survival time (MST) in days was estimated in different rats group, when animals were whole body fission neutrons irradiated twice with 3-days interval using the total lethal doses of 4 or 5 Gy. Protected rats received amifostine (160 mg.kg(-1) i.p. and 200 mg.kg(-1) i.m.) or cystamine (40 mg.kg(-1) i.p. and 50 mg.kg(-1) i.m.), control rats obtained saline 20 min before beginning of irradiation in the amount of 0.5 ml.100 g(-1) of the rat's body weight. Non-significant DRF value 1.13 for WR-2721 i.p. was calculated in survival studies in rats twice neutron irradiated with 3 days interval (DRF 1.04 for cystamine). Chemical protectors were administered before each neutron exposure. MST of twice neutron lethal iradiated rats was prolonged not regularly by radioprotectors tested. WR-2721 and cystamine i.m. were not able to increase 6 days reparation processes after sublethal 2 Gy fission neutrons whole body irradiated rats.