Case series discussion of cardiac and vascular events following carfilzomib treatment: possible mechanism, screening, and monitoring.

BACKGROUND: Carfilzomib is a selective proteasome inhibitor approved in the United States in 2012 for the treatment of relapsed and refractory multiple myeloma. Although cardiopulmonary and vascular events have been reported infrequently, they can be potentially serious complications, and their incidence and pathophysiology following carfilzomib treatment remain poorly characterized in a real-world patient population. METHODS: We retrospectively reviewed the records of 67 patients with relapsed and/or refractory multiple myeloma treated at our institution. RESULTS: We describe 12 patients who experienced cardiac or vascular-related adverse events subsequent to carfilzomib-based treatment (median age, 59 years [range, 49-77]). Nine patients had prior autologous stem cell transplant, and three had prior anthracycline exposure. Detailed case reports are provided for five representative patients: (1) systemic hypertension in a 65-year-old Caucasian female with a history of hypertension, hypothyroidism, and stage III chronic kidney disease; (2) pulmonary hypertension in a 72-year-old Caucasian male with a history of recurrent respiratory infections and chronic right lower extremity deep venous thrombosis; (3) acute renal insufficiency with increased blood pressure in a 50-year-old Caucasian male with a history of hypertension and stage IV chronic kidney disease; (4) heart failure in a 64-year-old African American female with a history of hypertension; and (5) dyspnea and lung disease in a 58-year-old Asian American male with a history significant for hepatitis B virus infection. CONCLUSIONS: While cardiac and vascular-related adverse events were reported in patients with relapsed and/or refractory multiple myeloma who were treated with carfilzomib, most patients had a history of the specific cardiac or vascular adverse event they exhibited and demonstrated an improvement or resolution in symptoms after the discontinuation of therapy. Appropriate screening and monitoring could potentially allow at-risk patients to benefit fully from treatment with carfilzomib.

FDA-approved drugs that protect mammalian neurons from glucose toxicity slow aging dependent on cbp and protect against proteotoxicity.

Screening a library of drugs with known safety profiles in humans yielded 30 drugs that reliably protected mammalian neurons against glucose toxicity. Subsequent screening demonstrated that 6 of these 30 drugs increase lifespan in C. elegans: caffeine, ciclopirox olamine, tannic acid, acetaminophen, bacitracin, and baicalein. Every drug significantly reduced the age-dependent acceleration of mortality rate. These protective effects were blocked by RNAi inhibition of cbp-1 in adults only, which also blocks protective effects of dietary restriction. Only 2 drugs, caffeine and tannic acid, exhibited a similar dependency on DAF-16. Caffeine, tannic acid, and bacitracin also reduced pathology in a transgenic model of proteotoxicity associated with Alzheimer's disease. These results further support a key role for glucose toxicity in driving age-related pathologies and for CBP-1 in protection against age-related pathologies. These results also provide novel lead compounds with known safety profiles in human for treatment of age-related diseases, including Alzheimer's disease and diabetic complications.