A phase I open-label trial evaluating the cardiovascular safety of regorafenib in patients with advanced cancer.

PURPOSE: To characterize the cardiovascular safety profile of regorafenib in patients with advanced cancer. METHODS: Patients received regorafenib 160 mg/day for 21 days followed by a 7-day break. The primary endpoint was the change from baseline in QTcF at the regorafenib t(max) (Day 21, Cycle 1 or 2) and changes in left ventricular ejection fraction (LVEF) from baseline on Cycle 2, Day 21. Secondary objectives were pharmacokinetics, safety, anti-tumor activity and effects on electrocardiogram intervals. QT intervals were corrected using the methods of Fridericia (QTcF) and Bazett (QTcB). LVEF was assessed by multigated acquisition scanning. RESULTS: Fifty-three patients were enrolled, and all received at least one dose of regorafenib 160 mg. Twenty-five patients received regorafenib for 21 days without dose reduction. The mean change from baseline in QTcF at t(max) was (-)2 ms (90 % CI -8, 3). No patient experienced a change from baseline in QTcF > 60 ms, and two had QTcF changes between 30 and 60 ms. No patient had a QTcF or QTcB > 480 ms. In 27 patients who received at least 80 mg of regorafenib, the mean change from baseline in LVEF% ± SD was 1.7 ± 7.8. In 14 patients without a dose reduction, the mean change from baseline in LVEF% was (-)0.1 ± 8.6 at Cycle 2, Day 21. Four patients experienced a LVEF decrease between 10 and 20 %. CONCLUSION: The effects of regorafenib on the QT/QTc interval and LVEF were modest and unlikely to be of clinical significance in the setting of advanced cancer therapy.

Delayed bupropion cardiotoxicity associated with elevated serum concentrations of bupropion but not hydroxybupropion.

CONTEXT: Bupropion overdose commonly causes generalized seizures and central nervous system depression. Less commonly, cardiotoxicity has been reported. The toxicity of the parent drug compared to its active metabolite hydroxybupropion is uncertain. CASE DETAILS: A 31-year-old man presented to the emergency department with altered mental status after an intentional overdose of bupropion. Three hours after admission he developed status epilepticus requiring intubation, and 13 h after admission he developed marked widening of the QRS complex and prolongation of the QTc interval. Serial serum bupropion levels peaked with the onset of cardiotoxicity (334 ng/mL) and fell into the therapeutic range within 24 h, which coincided with normalization of his ECG intervals. Levels of the metabolite hydroxybupropion peaked later (4302 ng/mL) and remained elevated even after neurological and cardiotoxic symptoms resolved. DISCUSSION: Cardiotoxicity appears to be caused primarily by bupropion rather than its active metabolite hydroxybupropion.

Perflurooctanoic acid induces developmental cardiotoxicity in chicken embryos and hatchlings.

Perfluorooctanoic acid (PFOA) is a widespread environmental contaminant that is detectable in serum of the general U.S. population. PFOA is a known developmental toxicant that induces mortality in mammalian embryos and is thought to induce toxicity via interaction with the peroxisome proliferator activated receptor alpha (PPARα). As the cardiovascular system is crucial for embryonic survival, PFOA-induced effects on the heart may partially explain embryonic mortality. To assess impacts of PFOA exposure on the developing heart in an avian model, we used histopathology and immunohistochemical staining for myosin to assess morphological alterations in 19-day-old chicken embryo hearts after PFOA exposure. Additionally, echocardiography and cardiac myofibril ATPase activity assays were used to assess functional alterations in 1-day-old hatchling chickens following developmental PFOA exposure. Overall thinning and thinning of a dense layer of myosin in the right ventricular wall were observed in PFOA-exposed chicken embryo hearts. Alteration of multiple cardiac structural and functional parameters, including left ventricular wall thickness, left ventricular volume, heart rate, stroke volume, and ejection fraction were detected with echocardiography in the exposed hatchling chickens. Assessment of ATPase activity indicated that the ratio of cardiac myofibril calcium-independent ATPase activity to calcium-dependent ATPase activity was not affected, which suggests that developmental PFOA exposure may not affect cardiac energetics. In summary, structural and functional characteristics of the heart appear to be developmental targets of PFOA, possibly at the level of cardiomyocytes. Additional studies will investigate mechanisms of PFOA-induced developmental cardiotoxicity.

Prediction of anthracycline cardiotoxicity after chemotherapy by biomarkers kinetic analysis.

Anthracyclines are active drugs against breast cancer, but can exert cardiotoxic effects. We analyzed the association between the kinetics of various biomarkers during chemotherapy, and the risk of subsequent cardiac toxicity. 50 patients (49 women) with early breast cancer surgically treated and eligible to anthracycline-based adjuvant chemotherapy were analyzed. The left ventricular ejection fraction (LVEF) together with the plasma concentration of several blood markers was measured at the beginning of anthracycline chemotherapy (t (0)), 5 months (t (1)), 16 months (t (2)), 28 months (t (3)), and 40 months later (t (4)). A single measured LVEF value less than 50% or a clinically overt congestive heart failure (CHF) was considered cardiotoxic effects. We tested whether the kinetics of LVEF and blood biomarkers measured during chemotherapy was predictive of subsequent cardiotoxicity and overall cardiac fitness. The left ventricular ejection fraction measured at the end of treatment as well as the rate of change of hemoglobin concentration during anthracycline-based chemotherapy predicted cardiotoxicity in a 3-year follow-up period. When LVEF at the end of chemotherapy was lower than 53% or hemoglobin blood concentration declined more than 0.33 g/dL/month during chemotherapy, the odds ratio of subsequent cardiotoxicity was 37.3 and 18, respectively. The specificity of these two tests was 93.3% and 80%, whereas the sensitivity was 90.9 and 81.2%, respectively. Testing the rate of change of hemoglobin concentration during anthracycline-based chemotherapy, as well as the left ventricular ejection fraction at the end of treatment, seems a powerful method to assess the effects of anthracyclines on cardiac fitness and identify patients at high risk of CHF. Further validation of these tests on a large cohort of patients and cost-benefit analysis should be encouraged.

Carnitine deficiency increases susceptibility to bupivacaine-induced cardiotoxicity in rats.

BACKGROUND: Anecdotal reports suggest that carnitine deficiency increases susceptibility to bupivacaine-induced cardiotoxicity. Bupivacaine inhibits lipid-based respiration in myocardial mitochondria via inhibition of acylcarnitine exchange in rats. The authors hypothesized that carnitine deficiency increases susceptibility to bupivacaine-induced asystole in rats and that acute repletion with L-carnitine reverses this effect. METHODS: Thirty male Sprague-Dawley rats were assigned to three groups. Rats assigned to the L-carnitine-deficient and L-carnitine-replete groups received subcutaneous D-carnitine on the 10 d before the experiment to induce L-carnitine deficiency. Control rats received an equal volume of subcutaneous normal saline. The rats were anesthetized and mechanically ventilated. Bupivacaine was infused intravenously at a rate of 2.0 mg · kg⁻¹ · min⁻¹ until asystole occurred. The L-carnitine-replete group received intravenous L-carnitine 100 mg · kg⁻¹ immediately before bupivacaine infusion. At asystole, blood was sampled to measure bupivacaine concentration. The primary outcome was time to asystole. RESULTS: L-carnitine deficiency significantly decreased survival duration (P < 0.0001). Time to bupivacaine-induced asystole decreased by 22% (P < 0.05) in the L-carnitine-deficient group (847 s [787-898]) (median [interquartile range]) compared with controls (1,082 s [969-1,427]). Intravenous administration of L-carnitine completely reversed the reduction in time to asystole. At asystole, the median plasma bupivacaine concentration in the L-carnitine-deficient group was 38% (P < 0.05) less than that in control animals. Plasma bupivacaine concentration was similar in L-carnitine-replete and control animals. CONCLUSIONS: Carnitine deficiency increased sensitivity to bupivacaine-induced asystole, an effect that was reversed completely by L-carnitine repletion. This study suggests that carnitine deficiency may predispose to bupivacaine-induced cardiotoxicity. L-carnitine may have a protective role against bupivacaine cardiotoxicity.