Myocardial injury in a 41-year-old male treated with methylphenidate: a case report.

BACKGROUND: Elevated cardiac troponin levels are consistent with the diagnosis of an acute coronary syndrome, but may also represent adverse drug reactions. Psychostimulating drugs raise both blood pressure and heart rate, and case reports of sudden death, stroke, and myocardial infarction have led to regulatory and public concern about the cardiovascular safety of these drugs. CASE PRESENTATION: We present a case where a 41-year-old Norwegian male with radiating chest pain, elevated troponins, and supraventricular tachycardia was hospitalized. Tentative diagnosis was acute coronary syndrome. Percutaneous coronary angiography, but not cardiac magnetic resonance imaging, was performed and medical antiplatelet treatment started. Because of an attention deficit/hyperactivity disorder the patient had recently increased his dose of methylphenidate, but still within the therapeutic dose range. Apart from venlafaxine, also in a therapeutic dose, the patient took no other drugs. An acute coronary syndrome was excluded during hospitalization, and a drug effect was suspected. CONCLUSIONS: When interpreting troponin results it is important to take into account the context of the patient's clinical presentation, including the possibility of adverse drug reactions. The adverse drug reaction could include a combination of vasospasm and/or increased oxygen demand due to tachycardia. This case should be borne in mind before a diagnosis of myocardial infarction is given, or a decision to perform invasive coronary angiography is made in patients that use methylphenidate or related substances. Cardiac magnetic resonance imaging could be of diagnostic value in such cases.

Diazoxide protects against doxorubicin-induced cardiotoxicity in the rat.

AIM: Chemotherapy with doxorubicin is limited by cardiotoxicity. Free radical generation and mitochondrial dysfunction are thought to contribute to doxorubicin-induced cardiac failure. In this study we wanted to investigate if opening of mitochondrial KATP-channels by diazoxide is protective against doxorubicin cardiotoxicity, and if 5-hydroxydecanoate (5-HD), a selective mitochondrial KATP-channel antagonist, abolished any protection by this intervention. METHODS: Wistar rats were divided into 7 groups (n = 6) and followed for 10 days with 5 intervention groups including the following treatments: (1) Diazoxide and doxorubicin, (2) diazoxide and 5-hydroxydecanoate (5-HD), (3) 5-HD and doxorubicin, (4) diazoxide and saline and (5) 5-HD and saline. On day 1, 3, 5 and 7 the animals received intraperitoneal (i.p.) injections with 10 mg/kg diazoxide and/or 40 mg/kg 5-HD, 30 minutes before i.p. injections with 3.0 mg/kg doxorubicin. One control group received only saline injections and the other control group received saline 30 minutes prior to 3.0 mg/kg doxorubicin. On day 10 the hearts were excised and Langendorff-perfused. Cardiac function was assessed by an intraventricular balloon and biochemical effects by release of hydrogen peroxide (H2O2) and troponin-T (TnT) in effluate from the isolated hearts, and by myocardial content of doxorubicin. RESULTS: Doxorubicin treatment produced a significant loss in left ventricular developed pressure (LVDP) (p < 0.05) and an increase in both H2O2 and TnT release in effluate (p < 0.05). Diazoxide significantly attenuated the decrease in LVDP (p < 0.05) and abolished the increased release of H2O2 and TnT (p < 0.05). 5-HD abolished the effects of pretreatment with diazoxide, and these effects were not associated with reduced myocardial accumulation of doxorubicin. CONCLUSIONS: Pretreatment with diazoxide attenuates doxorubicin-induced cardiac dysfunction in the rat, measured by physiological indices and TnT and H2O2 in effluate from isolated hearts. The effect could be mediated by opening of mitochondrial KATP-channels, reduced doxorubicin-associated free radical generation and decreased cardiomyocyte damage. Diazoxide represents a promising protective intervention against doxorubicin-induced acute cardiotoxicity.

Morphine enhances doxorubicin-induced cardiotoxicity in the rat.

Interventions to reduce the cardiotoxicity of doxorubicin are clinically relevant. Pharmacological preconditioning mimicking ischemic preconditioning has been demonstrated with morphine and represents an acceptable clinical intervention. The purpose of this study was to examine if pretreatment in vivo with morphine could reduce doxorubicin-induced cardiotoxicity ex vivo in a rat model. Wistar rats were divided into six groups and pretreated with an intraperitoneal (i.p.) injection of 3 or 10 mg/kg morphine, 1 mg/kg naloxone and saline, 1 mg/kg naloxone and 3 mg/kg morphine or saline, 60 min before excision of the heart. Biochemical indices such as troponin T (TnT) and hydrogen peroxide (H2O2) in effluate were measured together with physiological parameters in Langendorff hearts before and after doxorubicin infusion (2 mg/mL 0.05 mL/min for 45 min). Myocardial content of doxorubicin was measured at the end of infusion. Pretreatment with morphine, irrespective of dosage, produced a significant loss in left ventricular-developed pressure and an increase of TnT and H2O2 in effluate before doxorubicin infusion (p < 0.05). Morphine also produced a significant increase in left ventricular end-diastolic pressure and an increase of TnT and H2O2 in effluate (p < 0.05) at the end of doxorubicin infusion. Naloxone, a non-selective opioid receptor antagonist, abolished the effects of morphine both before and after doxorubicin infusion. Morphine, irrespective of dosage, increased myocardial content of doxorubicin compared to pretreatment with saline (p < 0.05). Pretreatment with morphine is associated with a cardiodepressive effect and enhances cardiotoxicity of doxorubicin measured by increased myocardial accumulation of doxorubicin and physiological and biochemical indices. The negative effects observed in our rat model are abolished by naloxone.

A short-time model to study relevant indices of cardiotoxicity of doxorubicin in the rat.

AIM: Short-time models (STM) to study the cardiotoxicity (acute or chronic) of doxorubicin in rats are of interest to assess protective interventions and pathways. STM promotes more ethical animal treatment with less stress, and at a lower cost compared to established long-time models (LTM). We wanted to investigate if an STM of 9 d yields the same information regarding cardiotoxicity as an LTM of 9 weeks. METHODS: Male Wistar rats received identical drug administration protocols in STM and LTM. The two intervention groups (n = 6) received intraperitoneal (i.p.) injections of 2 mg/kg doxorubicin every day for five consecutive days, with a total cumulative dose of 10 mg/kg. The two control groups (n = 6), received an equivalent volume of saline injected every day for five consecutive days. Hearts from STM and LTM were excised and Langendorff-perfused after 9 d or 9 weeks, respectively, after the first drug injection. Cardiotoxicity was assessed in paced Langendorff hearts by a release of hydrogenperoxide (H2O2) and troponin T (TnT) in effluent, by myocardial accumulation of doxorubicin and its metabolite doxorubicinol, and by physiological parameters recorded during pressure, or volume-regulated perfusion. RESULTS: In STM, hearts exposed to doxorubicin demonstrated a 15% reduction in left ventricular developed pressure (LVDP) irrespective of flow mode, and a 13% increase in aortic pressure (AoP), during volume-regulated perfusion, an index of coronary resistance, compared to controls. Left ventricular end-diastolic pressure (LVEDP) was increased by 72% during pressure-regulated perfusion and 100% during volume-regulated perfusion in STM. In LTM, hearts exposed to doxorubicin demonstrated a 40% reduction in LVDP during pressure-regulated perfusion and a 20% reduction during volume-regulated perfusion. LVEDP was 70% higher in doxorubicin-treated hearts during pressure-regulated perfusion and 80% higher during volume-regulated perfusion. In addition, aortic pressure was increased by 30% during volume-regulated perfusion. In both STM and LTM, hearts exposed to doxorubicin demonstrated a higher H2O2 and TnT release, compared to respective controls. The difference was most pronounced in STM. Myocardial content of doxorubicin was detectable in both STM and LTM. However, doxorubicinol was only detectable in STM. CONCLUSION: STM is comparable to LTM to study relevant indices of cardiotoxicity of doxorubicin in rat hearts. Biochemical differences are more pronounced in STM, while contractile differences are more pronounced in LTM. STM could be a preferred model for preliminary studies of protective interventions.