Severe cyanide poisoning from an alternative medicine treatment with amygdalin and apricot kernels in a 4-year-old child.

BACKGROUND: The use of complementary and alternative medicine (CAM) is widespread in children with cancer and is poorly regulated. PATIENTS AND METHODS: Case report. RESULTS: We describe a case of severe cyanide poisoning arising from CAM use. A severely agitated, encephalopathic, unresponsive 4-year-old boy (initial Glasgow Coma Scale of 3) with a history of metastatic ependymoma was brought to our emergency department by ambulance services. Initial blood gas analysis demonstrated severe metabolic/lactic acidosis. On detailed questioning of the parents, the use of CAM including intravenous and oral "vitamin B 17" (amygdalin) and oral apricot kernel was reported. After administering sodium thiosulfate, rapid improvement in his medical condition with complete recovery without need for further intensive care treatment was seen. Serum cyanide level was markedly elevated. CONCLUSIONS: Cyanide poisoning can be the cause of severe encephalopathy in children receiving CAM treatment with substances containing cyanogenic glycosides.

EGFR tyrosine kinase inhibition radiosensitizes and induces apoptosis in malignant glioma and childhood ependymoma xenografts.

Malignant gliomas and childhood ependymomas have a high rate of treatment failure. Epidermal growth factor receptor (EGFR) activation has been implicated in the tumorigenesis and radioresistance of many cancers, including brain tumors. Therefore, combining EGFR targeting with irradiation is a potentially attractive therapeutic option. We evaluated the tyrosine kinase inhibitor gefitinib for its antitumor activity and potential to radio-sensitize in vivo in two xenograft models: an EGFR amplified glioma and an EGFR expressing ependymoma, both derived from primary tumors. When administered at 100 mg/kg for 5 consecutive days, gefitinib-induced partial tumor regression in all treated EGFR amplified IGRG88 glioma xenografts. The addition of 1 Gy of irradiation prior to gefitinib administration resulted in 5 complete and 4 partial regressions for the 9 treated tumors as well as a significant tumor growth delay of 33 days for the combined treatment compared to 19 days for each therapy alone, suggesting additive antitumor activity. Tumor regression was associated with inhibition of AKT and MAPK pathways by gefitinib. In contrast, the ependymoma IGREP83 was sensitive to irradiation, but remained resistant to gefitinib. Combined treatment was associated with inhibition of radiation-induced MAPK phosphorylation and significant induction of apoptotic cell death though radiation-induced AKT phosphorylation was maintained. Depending on the scheduling of both therapies, a trend towards superior antitumor activity was observed with combined treatment. Thus, EGFR targeting through tyrosine kinase inhibition appears to be a promising new approach in the treatment of EGFR-driven glioma, particularly in combination with radiation therapy.

Evaluation of the effects of swainsonine, captopril, tangeretin and nobiletin on the biological behaviour of brain tumour cells in vitro.

Although intrinsic tumours of the brain seldom metastasize to distant sites, their diffuse, infiltrative-invasive growth within the brain generally precludes successful surgical and adjuvant therapy. Hence, attention has now focused on novel therapeutic approaches to combat brain tumours that include the use of anti-invasive and anti-proliferative agents. The effect of four anti-invasive agents, swainsonine (a locoweed alkaloid), captopril (an anti-hypertensive drug), tangeretin and nobiletin (both citrus flavonoids), were investigated on various parameters of brain tumour invasion such as matrix metalloproteinase (MMP) secretion, migration, invasion and adhesion. A standard cytotoxicity assay was used to optimize working concentrations of the drugs on seven human brain tumour-derived cell lines of various histological type and grade of malignancy. A qualitative assessment by gelatin zymography revealed that the effect of these agents varied between the seven cell lines such that the low grade pilocytic astrocytoma was unaffected by three of the agents. In contrast, downregulation of the two gelatinases, MMP-2 and MMP-9 was seen in the grade 3 astrocytoma irrespective of which agent was used. Generally, swainsonine was the least effective whereas the citrus flavonoids, particularly nobiletin, showed the greatest downregulation of secretion of the MMPs. Furthermore, captopril and nobiletin were most efficient at inhibiting invasion, migration and adhesion in four representative cell lines (an ependymoma, a grade II oligoastrocytoma, an anaplastic astrocytoma and a glioblastoma multiforme). Yet again, the effects of the four agents varied between the four cell lines. Nobiletin was, nevertheless, the most effective agent used in these assays. In conclusion, the differential effects seen on the various parameters studied by these putative anti-invasive agents may be the result of interference with MMPs and other mechanisms underlying the invasive phenotype. From these pilot studies, it is possible that these agents, especially the citrus flavonoids, could be of future therapeutic value. However, further work is needed to validate this in a larger study.

1-Aryl-3,3-dimethyltriazenes: potential central nervous system active analogues of 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide (DTIC).

A series of 19 aryldimethyltriazenes were synthesized as potential central nervous system (CNS) active analogues of 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide (DTIC). The compounds were screened in mice against both intraperitoneally (ip) and intracerebrally (ic) implanted L1210 leukemia. Select compounds were further screened against ic implanted ependymoblastoma, and one compound was additionally screened against ic implanted B16 melanoma. Although several compounds were as effective as DTIC at prolonging the life span of mice bearing ip implanted L1210 leukemia, only 4-(3,3-dimethyl-1-triazeno)benzamide (DTB) and 4-(3,3-dimethyl-1-triazeno)benzoic acid (DTBA) were significantly active against the ic implanted tumor. DTB, unlike DTIC, was equally effective against both the ip and the ic implanted tumor, clearly indicating that it penetrated into the CNS in therapeutic concentration. DTB was also active against ic implanted ependymoblastoma and ic implanted B16 melanoma. Aryldimethyltriazenes, particularly DTB, may have a role in the treatment of tumors metastatic to the CNS. They may also be effective against primary brain tumors.

A statistical-heuristic methods for automated selection of drugs for screening.

A statistical-heuristic method for selecting drugs for animal screening is developed with molecular structure features as predictors of biological activity. The method is intended to work on large amounts of data over varied structures. A trial of this method on a small data set allows some comparison with more sophisticated pattern recognition methods. Problems connected with interdependence among structure predictors are critical in this method and schemes to eliminate redundancy are reviewed. Alternate sets of structure predictors are considered. The discussion here outlines directions to be taken in the near future.

Intraneoplastic injection of CCNU for experimental brain tumor chemotherapy.

Chemotherapy experiments were performed with 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) in an experimental mouse brain tumor model. Cell suspensions of a transplantable mouse ependymoblastoma were injected intracerebrally by means of a stereotactic frame. CCNU was given either intraperitoneally or by direct intraneoplastic injection beginning the fifth day after tumor cell implantation. Intraneoplastic injection beginning the fifth day after tumor cell implantation. Intraneoplastic injections of drugs were made with the stereotactic frame. A single intraneoplastic injection of CCNU was found to be highly effective in increasing the median day of death and in yielding large numbers of long-term survivors. In some experiments CCNU injected into the neoplasm produced increased numbers of long-term survivors and less systemic toxicity than when injected intraperitoneally.