Retrospective analysis of the tolerability and activity of lacosamide in patients with brain tumors: clinical article.

OBJECT: The object of this study was to determine the tolerability and activity of lacosamide in patients with brain tumors. METHODS: The authors reviewed the medical records at 5 US academic medical centers with tertiary brain tumor programs, seeking all patients in whom a primary brain tumor had been diagnosed and who were taking lacosamide. RESULTS: The authors identified 70 patients with primary brain tumors and reviewed seizure frequency and toxicities. The majority of the patients had gliomas (96%). Fifty-five (78%) had partial seizures only, and 12 (17%) had generalized seizures. Most of the patients (74%) were started on lacosamide because of recurrent seizures. Forty-six patients (66%) reported a decrease in seizure frequency, and 21 patients (30%) reported stable seizures. Most of the patients (54 [77%]) placed on lacosamide did not report any toxicities. CONCLUSIONS: This retrospective analysis demonstrated that lacosamide was both well tolerated and active as an add-on antiepileptic drug (AED) in patients with brain tumors. Lacosamide's novel mechanism of action will allow for concurrent use with other AEDs, as documented by its activity across many different types of AEDs used in this patient population. Larger prospective studies are warranted.

A new pharmacological agent (AKB-4924) stabilizes hypoxia inducible factor-1 (HIF-1) and increases skin innate defenses against bacterial infection.

Hypoxia inducible factor-1 (HIF-1) is a transcription factor that is a major regulator of energy homeostasis and cellular adaptation to low oxygen stress. HIF-1 is also activated in response to bacterial pathogens and supports the innate immune response of both phagocytes and keratinocytes. In this work, we show that a new pharmacological compound AKB-4924 increases HIF-1 levels and enhances the antibacterial activity of phagocytes and keratinocytes against both methicillin-sensitive and methicillin-resistant strains of Staphylococcus aureus in vitro. AKB-4924 is also effective in stimulating the killing capacity of keratinocytes against the important opportunistic skin pathogens Pseudomonas aeruginosa and Acinetobacter baumanii. The effect of AKB-4924 is mediated through the activity of host cells, as the compound exerts no direct antimicrobial activity. Administered locally as a single agent, AKB-4924 limits S. aureus proliferation and lesion formation in a mouse skin abscess model. This approach to pharmacologically boost the innate immune response via HIF-1 stabilization may serve as a useful adjunctive treatment for antibiotic-resistant bacterial infections.

Hypoxia-inducible factor-1alpha is a key regulator of metastasis in a transgenic model of cancer initiation and progression.

Adaptation to hypoxia is a critical step in tumor progression and is, in part, regulated by the transcription factor hypoxia-inducible factor-1alpha (HIF-1alpha). Xenograft models have been extensively used to characterize the role of HIF-1alpha in experimental cancers. Although these models provide an understanding of tumor growth at terminal stages of malignancy, they do not address tumor initiation or metastatic progression. To elucidate these roles, HIF-1alpha was conditionally deleted in the mammary epithelium of a transgenic mouse model for metastatic breast cancer. Conditional deletion of HIF-1alpha in the mammary epithelium resulted in delayed tumor onset and retarded tumor growth; this was correlated with decreased tumor cell proliferation. Tumors with conditional deletion of HIF-1alpha were also less vascular during early tumor progression. Perhaps most surprisingly, deletion of HIF-1alpha in the mammary epithelium resulted in decreased pulmonary metastasis. These results show that whereas HIF-1alpha is not required for the initiation of breast tumor growth or tumor cell metastasis, the transcriptional activity of HIF-1alpha is a significant positive regulator of tumor progression and metastatic potential.