Studies on the Efficacy, Potential Cardiotoxicity and Monkey Pharmacokinetics of GLP-26 as a Potent Hepatitis B Virus Capsid Assembly Modulator.

While treatment options are available for hepatitis B virus (HBV), there is currently no cure. Anti-HBV nucleoside analogs and interferon-alpha 2b rarely clear HBV covalently closed circular DNA (cccDNA), requiring lifelong treatment. Recently, we identified GLP-26, a glyoxamide derivative which modulates HBV capsid assembly. The impact of GLP-26 on viral replication and integrated DNA was assessed in an HBV nude mouse model bearing HBV transfected AD38 xenografts. At day 45 post-infection, GLP-26 reduced HBV titers by 2.3-3 log10 versus infected placebo-treated mice. Combination therapy with GLP-26 and entecavir reduced HBV log10 titers by 4.6-fold versus placebo. Next, we examined the pharmacokinetics (PK) in cynomolgus monkeys administered GLP-26 via IV (1 mg/kg) or PO (5 mg/kg). GLP-26 was found to have 34% oral bioavailability, with a mean input time of 3.17 h. The oral dose produced a mean peak plasma concentration of 380.7 ng/mL, observed 0.67 h after administration (~30-fold > in vitro EC90 corrected for protein binding), with a mean terminal elimination half-life of 2.4 h and a mean area under the plasma concentration versus time curve of 1660 ng·hr/mL. GLP-26 was 86.7% bound in monkey plasma. Lastly, GLP-26 demonstrated a favorable toxicity profile confirmed in primary human cardiomyocytes. Thus, GLP-26 warrants further preclinical development as an add on to treatment for HBV infection.

Cardiac and pulmonary toxicity of mesoporous silica nanoparticles is associated with excessive ROS production and redox imbalance in Wistar rats.

Mesoporous silica nanoparticles (MSNs) represent one of the most promising drug delivery systems. MSNs have attracted considerable attention in recent years both in industry and biomedicine due to their unique properties. Thus, evaluation of the toxic effects of MSNs is necessary before the biomedical and clinical applications. We investigated the in vivo effect of MSNs on the production of reactive oxygen species (ROS), antioxidant defenses and histology of the heart and lung. Rats received 25, 50, 100 and 200 mg/kg body weight of synthesized MSNs intraperitoneally for 30 days and samples were collected for analysis. MSNs induced significant increase in serum cardiac function markers, tumor necrosis factor alpha and lipids. MSNs-induced rats exhibited anemia, thrombocytopenia, leukocytosis, significantly increased ROS, malondialdehyde and nitric oxide, and declined antioxidant defenses in the heart and lung of rats. In addition, MSNs induced histological alterations in the heart and lung of rats. In conclusion, our results demonstrated that MSNs induce cardiotoxicity and pulmonary toxicity via excessive generation of ROS, suppressed antioxidants, inflammation and histological alterations. Further investigations are recommended to understand the molecular mechanism underlying the toxic effects of MSNs and to improve the performance of nanomedicine.

Thorough QT/QTc in a Dish: An In Vitro Human Model That Accurately Predicts Clinical Concentration-QTc Relationships.

"Thorough QT/corrected QT (QTc)" (TQT) studies are cornerstones of clinical cardiovascular safety assessment. However, TQT studies are resource intensive, and preclinical models predictive of the threshold of regulatory concern are lacking. We hypothesized that an in vitro model using induced pluripotent stem cell (iPSC)-derived cardiomyocytes from a diverse sample of human subjects can serve as a "TQT study in a dish." For 10 positive and 3 negative control drugs, in vitro concentration-QTc, computed using a population Bayesian model, accurately predicted known in vivo concentration-QTc. Moreover, predictions of the percent confidence that the regulatory threshold of 10 ms QTc prolongation would be breached were also consistent with in vivo evidence. This "TQT study in a dish," consisting of a population-based iPSC-derived cardiomyocyte model and Bayesian concentration-QTc modeling, has several advantages over existing in vitro platforms, including higher throughput, lower cost, and the ability to accurately predict the in vivo concentration range below the threshold of regulatory concern.

[Electrocardiographic aspects of morphogenesis of neuroleptic cardiopathy].

Neuroleptic cardiomyopathy (NCMP) is a consequence of cardiotoxic side effect of antipsychotic drugs. Changes of ECG associated with this condition are poorly known. Aim: To elucidate dynamics of ECG at different clinical stages of NCMP and evaluate its diagnostic value. Methods. We determined the frequency and informative values of 8 different ECG signs includingQTinterval corrected based at theBazettformula (QTc). Their informative value was estimated from the Kullback formula. The data obtained were analyzed by parametric and non-parametric statistics methods. Results: Pathological changes of ECG parameters associated with NCM Preflect processes of structural rearrangement in the heart at different levels of its organization. The analysis of the available information showed that almost all ECG parameters have high diagnostic value listed in the following rank order (frequency/informativeness): rhythm disorder - 1/8, prolongation of the QTc interval - 4/3, conduction disorder - 2/2, diffuse muscular changes - 3/1, right heart overload - 5/6, left ventricular hypertrophy - 7-8/5, impaired electrical activity of myocardium - 7-8/5, deviation of the electrical axis to the left - 6/4. It seems appropriate to distinguish the following three maximally informative (and therefore most important) ECG signs indicative of developing NCMP: diffuse muscular changes, conduction disorder, and prolongation of the QTc interval. Conclusion: The analysis of the available information provides a new insight into dynamics of ECG signs associated with NCMP and permits to estimate the diagnostic value of pathological changes for its earlier detection.

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.

Mechanisms of Fatal Cardiotoxicity following High-Dose Cyclophosphamide Therapy and a Method for Its Prevention.

Observed only after administration of high doses, cardiotoxicity is the dose-limiting effect of cyclophosphamide (CY). We investigated the poorly understood cardiotoxic mechanisms of high-dose CY. A rat cardiac myocardial cell line, H9c2, was exposed to CY metabolized by S9 fraction of rat liver homogenate mixed with co-factors (CYS9). Cytotoxicity was then evaluated by 3-(4,5-dimethyl-2-thiazolyl)¬2,5-diphenyl¬2H-tetrazolium bromide (MTT) assay, lactate dehydrogenase release, production of reactive oxygen species (ROS), and incidence of apoptosis. We also investigated how the myocardial cellular effects of CYS9 were modified by acrolein scavenger N-acetylcysteine (NAC), antioxidant isorhamnetin (ISO), and CYP inhibitor ß-ionone (BIO). Quantifying CY and CY metabolites by means of liquid chromatography coupled with electrospray tandem mass spectrometry, we assayed culture supernatants of CYS9 with and without candidate cardioprotectant agents. Assay results for MTT showed that treatment with CY (125-500 µM) did not induce cytotoxicity. CYS9, however, exhibited myocardial cytotoxicity when CY concentration was 250 µM or more. After 250 µM of CY was metabolized in S9 mix for 2 h, the concentration of CY was 73.6 ± 8.0 µM, 4-hydroxy-cyclophosphamide (HCY) 17.6 ± 4.3, o-carboxyethyl-phosphoramide (CEPM) 26.6 ± 5.3 µM, and acrolein 26.7 ± 2.5 µM. Inhibition of CYS9-induced cytotoxicity occurred with NAC, ISO, and BIO. When treated with ISO or BIO, metabolism of CY was significantly inhibited. Pre-treatment with NAC, however, did not inhibit the metabolism of CY: compared to control samples, we observed no difference in HCY, a significant increase of CEPM, and a significant decrease of acrolein. Furthermore, NAC pre-treatment did not affect intracellular amounts of ROS produced by CYS9. Since acrolein seems to be heavily implicated in the onset of cardiotoxicity, any competitive metabolic processing of CY that reduces its transformation to acrolein is likely to be an important mechanism for preventing cardiotoxicity.

Protective effects of berberine against doxorubicin-induced cardiotoxicity in rats by inhibiting metabolism of doxorubicin.

1. The clinical use of doxorubicin, an effective anticancer drug, is severely hampered by its cardiotoxicity. Berberine, a botanical alkaloid, has been reported to possess cardioprotective and antitumor effects. In this study, we investigated the cardioprotective effect of berberine on doxorubicin-induced cardiotoxicity and the effect of berberine on the metabolism of doxorubicin. 2. Adult male Sprague-Dawley rats were administered doxorubicin in the presence or absence of berberine for 2 weeks. Administration of berberine effectively prevented doxorubicin-induced body weight reduction and mortality in rats. 3. Berberine reduced the activity of myocardial enzymes, including aspartate aminotransferase (AST), creatine kinase (CK), CK isoenzyme (CK-MB) and lactate dehydrogenase (LDH). Echocardiographic examination further demonstrated that berberine effectively ameliorated cardiac dysfunction induced by doxorubicin. 4. Berberine inhibited the metabolism of doxorubicin in the cytoplasm of rat heart and reduced the accumulation of doxorubicinol (a secondary alcohol metabolite of doxorubicin) in heart. 5. These data showed that berberine alleviated the doxorubicin-induced cardiotoxicity in rats via inhibition of the metabolism of doxorubicin and reduced accumulation of doxorubicinol selectively in hearts.

Delivery as nanoparticles reduces imatinib mesylate-induced cardiotoxicity and improves anticancer activity.

Clinical effectiveness of imatinib mesylate in cancer treatment is compromised by its off-target cardiotoxicity. In the present study, we have developed physically stable imatinib mesylate-loaded poly(lactide-co-glycolide) nanoparticles (INPs) that could sustainably release the drug, and studied its efficacy by in vitro anticancer and in vivo cardiotoxicity assays. MTT (methylthiazolyldiphenyl-tetrazolium bromide) assay revealed that INPs are more cytotoxic to MCF-7 breast cancer cells compared to the equivalent concentration of free imatinib mesylate. Wistar rats orally administered with 50 mg/kg INPs for 28 days showed no significant cardiotoxicity or associated changes. Whereas, increased alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase levels, and reduced white blood cell, red blood cell, and hemoglobin content were observed in the animals administered with free drug. While the histological sections from hearts of animals that received INPs did not show any significant cardiotoxic symptoms, loss of normal architecture and increased cytoplasmic vacuolization were observed in the heart sections of animals administered with free imatinib mesylate. Based on these results, we conclude that nano-encapsulation of imatinib mesylate increases its efficacy against cancer cells, with almost no cardiotoxicity.

Multi-modal contributions to detoxification of acute pharmacotoxicity by a triglyceride micro-emulsion.

Triglyceride micro-emulsions such as Intralipid® have been used to reverse cardiac toxicity induced by a number of drugs but reservations about their broad-spectrum applicability remain because of the poorly understood mechanism of action. Herein we report an integrated mechanism of reversal of bupivacaine toxicity that includes both transient drug scavenging and a cardiotonic effect that couple to accelerate movement of the toxin away from sites of toxicity. We thus propose a multi-modal therapeutic paradigm for colloidal bio-detoxification whereby a micro-emulsion both improves cardiac output and rapidly ferries the drug away from organs subject to toxicity. In vivo and in silico models of toxicity were combined to test the contribution of individual mechanisms and reveal the multi-modal role played by the cardiotonic and scavenging actions of the triglyceride suspension. These results suggest a method to predict which drug toxicities are most amenable to treatment and inform the design of next-generation therapeutics for drug overdose.

Chemotherapy-induced changes in cardiac capillary permeability measured by fluorescent multiple indicator dilution.

Anthracyclines cause severe irreversible cardiac toxicity. The study of changes in cardiac permeability with chemotherapy could enhance the understanding of mechanisms behind cardiac damage, and provide useful information to evaluate anthracycline cardiotoxicity. Thirty-six rats (12 Sprague-Dawley, 12 Wistar, 12 Fischer-344) were randomly assigned to control (n = 21) or doxorubicin (n = 15), and injected i.p. with a cumulative dose of 18 mg/kg doxorubicin in saline (vehicle) or vehicle alone over 12 days. Echocardiography was performed at baseline and on day 11. An isolated heart experiment was done on day 12 to obtain perfused heart pressure values, and to measure cardiac capillary permeability using a Texas Red/sodium fluorescein multiple indicator dilution method. Control animals had significantly lower average permeability-surface-area-products (0.035 ± 0.013 cm(3)/s) than doxorubicin animals (0.066 ± 0.023 cm(3)/s), PSP ± SD, p < 0.001. These permeability changes correlated with significant functional changes. There was a significant decline in cardiac function with a deleterious effect of chemotherapy on fractional shortening (p < 0.001), left ventricular developed pressure (p < 0.001), contractility (p < 0.001), and relaxation (p = 0.02). Based on our results, cardiac capillary permeability changes can be detected after in vivo chemotherapy treatment using our fluorescent multiple indicator dilution technique, and may provide valuable information in evaluating cardiotoxicity of novel drugs.

Pharmacokinetics of Naja sumatrana (equatorial spitting cobra) venom and its major toxins in experimentally envenomed rabbits.

BACKGROUND: The optimization of snakebite management and the use of antivenom depend greatly on the knowledge of the venom's composition as well as its pharmacokinetics. To date, however, pharmacokinetic reports on cobra venoms and their toxins are still relatively limited. In the present study, we investigated the pharmacokinetics of Naja sumatrana (Equatorial spitting cobra) venom and its major toxins (phospholipase A2, neurotoxin and cardiotoxin), following intravenous and intramuscular administration into rabbits. PRINCIPAL FINDINGS: The serum antigen concentration-time profile of the N. sumatrana venom and its major toxins injected intravenously fitted a two-compartment model of pharmacokinetics. The systemic clearance (91.3 ml/h), terminal phase half-life (13.6 h) and systemic bioavailability (41.9%) of N. sumatrana venom injected intramuscularly were similar to those of N. sputatrix venom determined in an earlier study. The venom neurotoxin and cardiotoxin reached their peak concentrations within 30 min following intramuscular injection, relatively faster than the phospholipase A2 and whole venom (Tmax=2 h and 1 h, respectively). Rapid absorption of the neurotoxin and cardiotoxin from the injection site into systemic circulation indicates fast onsets of action of these principal toxins that are responsible for the early systemic manifestation of envenoming. The more prominent role of the neurotoxin in N. sumatrana systemic envenoming is further supported by its significantly higher intramuscular bioavailability (Fi.m.=81.5%) compared to that of the phospholipase A2 (Fi.m.=68.6%) or cardiotoxin (Fi.m.=45.6%). The incomplete absorption of the phospholipase A2 and cardiotoxin may infer the toxins' affinities for tissues at the injection site and their pathological roles in local tissue damages through synergistic interactions. CONCLUSION/SIGNIFICANCE: Our results suggest that the venom neurotoxin is absorbed very rapidly and has the highest bioavailability following intramuscular injection, supporting its role as the principal toxin in systemic envenoming.

Effects of endothelin-1 chronic stimulation on electrical restitution, beat-to-beat variability of repolarization, and ventricular arrhythmogenesis.

Chronically elevated levels of endothelin-1 (ET-1) have been detected in several cardiovascular diseases. In this study, we investigated the chronic effects of ET-1 on the electrophysiological characteristics expected to influence the genesis and maintenance of ventricular arrhythmia (VA). Rabbits were randomized to ET-1 (ET-1 group) or 0.9% saline (control group) for 2 weeks. The S1-S2 protocol and S1-S1 dynamic pacing were performed to assess the action potential duration restitution (APDR) and to induce APD alternans or VA in 4 sites of Langendorff-perfused rabbit hearts. The beat-to-beat variability of repolarization was quantified as short-term variability and long-term variability. Compared with the control group, chronic ET-1 administration significantly prolonged QT intervals, APD at 90% repolarization (APD90), and effective refractory period (ERP), steepened the maximum slopes of the APDR curve, decreased the ERP/APD90 ratio, and increased the spatial dispersions of APD90, ERP, and maximum slopes (P < 0.05 for all). Moreover, chronic ET-1 administration markedly increased the short-term variability and long-term variability (P < 0.01 for all). APD alternans occurred in both groups, but the threshold of APD alternans was decreased at all sites in the ET-1 group (P < 0.01 for all). We also observed that chronic ET-1 stimulation significantly increased the incidence and duration of the VA episodes. These results suggest that chronic stimulation with ET-1 facilitated VA by steepening the APDR curve and increasing the spatial dispersion of APDR and beat-to-beat variability of repolarization.

Exercise mitigates cardiac doxorubicin accumulation and preserves function in the rat.

PURPOSE: Doxorubicin (DOX) is an effective antineoplastic agent with well-characterized cardiotoxic effects. Although exercise has been shown to protect against DOX cardiotoxicity, a clear and concise mechanism to explain its cardioprotective effects is lacking. The purpose of this study was to determine if exercise training reduces cardiac DOX accumulation, thereby providing a possible mechanism to explain the cardioprotective effects of exercise against DOX toxicity. METHODS: Sprague-Dawley rats were randomly assigned to 1 of 3 primary experimental groups: sedentary (n = 77), wheel running (n = 65), or treadmill (n = 65). Animals in wheel running and treadmill groups completed 10 weeks of exercise before DOX treatment. DOX was administered 24 hours after the last training session as a bolus intraperitoneal injection at 10 mg/kg. Subgroups of rats from each primary group were killed at 1, 3, 5, 7, and 9 days after DOX exposure to assess cardiac function and DOX accumulation. RESULTS: Ten weeks of exercise preconditioning reduced myocardial DOX accumulation, and this reduction in accumulation was associated with preserved cardiac function. CONCLUSIONS: These data suggest that the cardioprotective effects of exercise against DOX-induced injury may be due, in part, to a reduction in myocardial DOX accumulation.

Cardiovascular safety of tyrosine kinase inhibitors: with a special focus on cardiac repolarisation (QT interval).

The development of tyrosine kinase inhibitors (TKI) represents a major milestone in oncology. However, their use has been found to be associated with serious toxicities that impinge on various vital organs including the heart. Sixteen TKIs have been approved for use in oncology as of 30 September 2012, and a large number of others are in development or under regulatory review. Cardiovascular safety of medicinal products is a major public health issue that has concerned all the stakeholders. This review focuses on three specific cardiovascular safety aspects of TKIs, namely their propensity to induce QT interval prolongation, left ventricular (LV) dysfunction and hypertension (both systemic and pulmonary). Analyses of information in drug labels, the data submitted to the regulatory authorities and the published literature show that a number of TKIs are associated with these undesirable effects. Whereas LV dysfunction and systemic hypertension are on-target effects related to the inhibition of ligand-related signalling pathways, QT interval prolongation appears to be an off-target class III electrophysiologic effect, possibly related to the presence of a fluorine-based pharmacophore. If not adequately managed, these cardiovascular effects significantly increase the morbidity and mortality in a population already at high risk. Hitherto, the QT effect of most QT-prolonging TKIs (except lapatinib, nilotinib, sunitinib and vandetanib) is relatively mild at clinical doses and has not led to appreciable morbidity clinically. In contrast, LV dysfunction and untreated hypertension have resulted in significant morbidity. Inevitably, dilemmas arise in determining the risk/benefit of a TKI therapy in an individual patient who develops any of these effects following the treatment of the TKI-sensitive cancer. QT interval prolongation, hypertension and LV dysfunction can be managed effectively by using reliable methods of measurement and careful monitoring of patients whose clinical management requires optimisation by a close collaboration between an oncologist and a cardiologist, an evolving subspecialty referred to as cardio-oncology. Despite their potential adverse clinical impact, the effects of TKIs on hypertension and LV function are generally inadequately characterised during their development. As has been the case with QT liability of drugs, there is now a persuasive case for a regulatory requirement to study TKIs systematically for these effects. Furthermore, since most of these novel drugs are studied in trials with relatively small sample sizes and approved on an expedited basis, there is also a compelling case for their effective pharmacovigilance and on-going reassessment of their risk/benefit after approval.

A novel self-assembly albumin nanocarrier for reducing doxorubicin-mediated cardiotoxicity.

Doxorubicin is an antitumor drug commonly used against a wide spectrum of tumors. However, the clinical application of DOX is restricted by its cardiotoxicity. To reduce the cardiotoxicity, we develop an albumin-based nanocarrier via a new molecular switch method for DOX delivery. Spherically shaped DOX-loaded HSA nanoparticles (NPs-DOX) are prepared with a drug-loading capacity and particle size of 4.3% and 120.1 ± 26 nm, respectively. In vivo studies demonstrate that NPs-DOX is able to preferentially accumulate in tumor and show great tumor inhibition on H22 hepatocellular-carcinoma-bearing mice. As for the toxicity, compared with free DOX, the maximum tolerated dose of NPs-DOX is increased from 10 to over 30 mg/kg, indicating the reduced systematic toxicity. More importantly, the cardiotoxicity induced by NPs-DOX is also significantly reduced because both left ventricular ejection fraction and left ventricular fractional shortening are almost not changed and other cardiotoxicity markers such as serum creatine kinase-MB, lactate dehydrogenase, superoxide dismutase, and malonaldehyde are kept constant. The reduced cardiotoxicity of NPs-DOX is also confirmed by nonhistological changes in the heart tissue. Therefore, such albumin-based nanocarrier can be one of the most promising strategies for the delivery of DOX.

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.

Mechanism of the cardioprotective effects of docetaxel pre-administration against adriamycin-induced cardiotoxicity.

We revealed that pre-treatment with docetaxel (DOC) 12 h before adriamycin (ADR) administration significantly reduced ADR-induced toxic death compared with the simultaneous dosing schedule that was commonly used in previous studies. We considered that pre-treatment with DOC relieves ADR-induced cardiotoxicity. In this study, we investigated the influence of DOC on the pharmacokinetics and pharmacodynamics of ADR in order to clarify the mechanism by which DOC pre-treatment relieves ADR-induced cardiotoxicity. When ADR and/or DOC was intravenously administered, the DOC pre-treatment (DOC-ADR) group showed significantly less toxic death than the ADR-alone group. We examined hepatopathy, nephropathy, leukopenia, and cardiotoxicity, all of which can cause toxic death. Of these toxicities, ADR-induced cardiotoxicity was significantly relieved in the DOC-ADR group. To elucidate the mechanism by which DOC pre-treatment relieved ADR-induced cardiotoxicity, lipid peroxidation as a proxy for the free radical level and the pharmacokinetics of ADR were measured. There was no difference in the pharmacokinetics of ADR between the ADR and DOC-ADR groups. On the other hand, the DOC-ADR group showed significantly inhibited lipid peroxidation in the heart compared with the ADR group. It was considered that DOC pre-administration inhibited ADR-induced free radicals and decreased cardiotoxicity.

Cardiotoxicity of kinase inhibitors: the prediction and translation of preclinical models to clinical outcomes.

Targeted therapeutics, particularly those that inhibit the activity of protein kinases that are mutated and/or overexpressed in cancer, have revolutionized the treatment of some cancers and improved survival rates in many others. Although these agents dominate drug development in cancer, significant toxicities, including cardiotoxicity, have emerged. In this Review, we examine the underlying mechanisms that result in on-target or off-target cardiotoxicities of small molecule kinase inhibitors. We also discuss how well the various preclinical safety models and strategies might predict clinical cardiotoxicity. It is hoped that a thorough understanding of the mechanisms underlying cardiotoxicity will lead to the development of safe, effective drugs and consequently, fewer costly surprises as agents progress through clinical trials.