Hypothermia is ineffective in 45% of neonates with hypoxic-ischemic encephalopathy. Xenon has additive neuroprotective properties, but is expensive, and its application complicated. Argon gas is cheaper, easier to apply, and also has neuroprotective properties in experimental settings. The aim was to explore the safety of argon ventilation in newborn piglets.MethodsEight newborn piglets (weight 1.4–3.0 kg) were used. Heart rate, blood pressure, regional cerebral saturation, and electrocortical brain activity were measured continuously. All experiments had a 30 min. baseline period, followed by three 60 min. periods of argon ventilation alternated with 30 min argon washout periods. Two animals were ventilated with increasing concentrations of argon (1h 30%, 1 h 50%, and 1 h 80%), two were subjected to 60 min. hypoxia (FiO2 0.08) before commencing 50% argon ventilation, and two animals received hypothermia following hypoxia as well as 50% argon ventilation. Two animals served as home cage controls and were terminated immediately.ResultsArgon ventilation did not result in a significant change of heart rate (mean ± s.d. −3.5±3.6 bpm), blood pressure (−0.60±1.11 mmHg), cerebral oxygen saturation (0.3±0.9%), electrocortical brain activity (−0.4±0.7 µV), or blood gas values. Argon ventilation resulted in elevated argon concentrations compared to the home cage controls (34.5, 25.4, and 22.4 vs. 7.3 µl/ml).ConclusionVentilation with up to 80% argon during normoxia, and 50% argon after hypoxia did not affect heart rate, blood pressure, cerebral saturation and electrocortical brain activity. Clinical safety studies of argon ventilation in humans seem justified.

PurposeTo investigate the use of liposomal irinotecan (Irinophore C™) plus or minus 5-fluorouracil (5-FU) for the treatment of colorectal cancer.Experimental DesignThe effect of irinotecan (IRI) and/or 5-FU exposure times on cytotoxicity was assessed in vitro against HT-29 or LS174T human colon carcinoma cells. The pharmacokinetics and biodistribution of Irinophore C™ (IrC™) and 5-FU, administered alone or in combination, were compared in vivo. A subcutaneous model of HT-29 human colorectal cancer in Rag2-M mice was utilized to assess the efficacy of IrC™ alone, and in combination with 5-FU.ResultsThe cytotoxicity of IRI and 5-FU were strongly dependent on exposure time. Synergistic interactions were observed following prolonged exposure to IRI/5-FU combinations. Pharmacokinetics/biodistribution studies demonstrated that the 5-FU elimination rate was decreased significantly when 5-FU was co-administered intravenously with IrC™, versus alone. Significant decreases in 5-FU elimination were also observed in plasma, with an associated increase of 5-FU in some tissues when 5-FU was given by intraperitoneal injection and IrC™ was given intravenously. The elimination of IrC™ was not significantly different when administered alone or in combination with 5-FU. Therapeutic studies demonstrated that single agent IrC™ was significantly more effective than the combination of IRI/5-FU; surprisingly, IrC™/5-FU combinations were no more effective than IrC™ alone. The administration of combinations of 5-FU (16 mg/kg) and IrC™ (60 mg IRI/kg) showed increased toxicity when compared to IrC™ alone. Treatment with IrC™ alone (60 mg IRI/kg) delayed the time required for a 5-fold increase in initial tumor volume to day 49, compared to day 23 for controls. When IrC™ (40 mg IRI/kg) was used in combination with 5-FU (16 mg/kg), the time to increase tumor volume 5-fold was 43 days, which was comparable to that achieved when using IrC™ alone (40 mg IRI/kg).ConclusionsSingle agent IrC™ was well tolerated and has significant therapeutic potential. IrC™ may be a suitable replacement for IRI treatment, but its use with free 5-FU is complicated by IrC™-engendered changes in 5-FU pharmacokinetics/biodistribution which are associated with increased toxicity when using the combination.

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Case description To evaluate whether continuous intravenous (i.v.) administration of enfuvirtide (T20) could be a suitable alternative to subcutaneous (s.c.) administration of T20 in a patient with extensively drug-resistant HIV experiencing difficulties administering T20 subcutaneously. T20 was administered to a patient through 100 mL cassettes once daily via a CADD. Plasma samples were drawn and the pharmacokinetic profile compared to that of s.c. twice daily administration of T20. Also, viral replication and CD4+ count were monitored over a period of 9 months for this study. Continuous i.v. administration of T20 resulted in significantly higher T20 plasma levels compared to s.c. administration, continued viral suppression, a rise in CD4+ count and strong patient preference over s.c. administration. Conclusion This method of T20 administration may be a suitable alternative for selected patients who are not able to tolerate it when given subcutaneously. It may even be considered a priori in selected patients with extensive viral resistance who are unable or unwilling to inject T20 subcutaneously.

Introduction: Colorectal cancer is the third most common cancer in the world. The predominant chemotherapeutic treatment in CRC is a combination of 5-fluorouracil (5-FU) and irinotecan (CPT-11). However, the combination is limited by toxicity and resistance. We now report on the effects of 5-FU in combination with a liposomal formulation of CPT-11, Irinophore C, that is more efficacious and less toxic than free CPT-11. Materials and Methods: 5-FU was used singly and in combination with Irinophore C in a subcutaneous model of colorectal cancer, HT-29, to assess therapeutic efficacy and toxic effects. 5-FU and Irinophore C (40mg/kg) were injected intravenously on a Q7Dx3 schedule, and tumor growth delay was measured. In a subsequent study, a single bolus injection of 14C-spiked 5-FU was delivered at different timepoints during Irinophore C (tritium-labeled) or saline treatment (Q7Dx3), and the accumulation of 5-FU in tumor tissue measured with scintigraphy. Tumors were also harvested and snap-frozen at early (days 1 - 7) and late (days 14 and 21) time points following Irinophore C treatment. Cryosections were subsequently examined for perfusion using the fluorescent dye Hoechst 33342, stained for apoptosis (TUNEL), CD31, CD105, Collagen IV and with H&E to examine changes in vascular function and tissue morphology. Results: Irinophore C significantly reduced tumour growth (p<0.001) with little or no toxicity compared to saline controls, 5-FU alone and free CPT-11 plus 5-FU. In some cases, tumour growth was completely abolished. When used in combination with 5-FU, there was a slight increase in growth delay. Treatment of the tumours with Irinophore C increased the accumulation of the active lactone form of the drug in the tumour, and also significantly increased the tissue accumulation of a single bolus injection of 5-FU after two (∼50% increase, p<0.001) and three weeks (∼66% increase, p<0.001). Following treatment with Irinophore C, the density of tumor tissue was decreased, and the vascular coverage was increased, leading to increased total perfusion. In addition, apoptotic activity was increased following 1 to 2 weeks of treatment with Irinophore C, compared to controls. Conclusions: Irinophore C is more efficacious, and less toxic, than free CPT-11. This novel formulation of CPT-11 appears to have a bimodal mechanism of action wherein both endothelial and cancer cells are targeted, and which may improve the delivery of a second drug. We further believe that the dose of Irinophore C used in the combination studies is with 5-FU is overly efficacious and masks the effects of 5-FU. Clinically, Irinophore C with its low toxicity and high efficacy could have advantages over the use of free CPT-11. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3661.