amphotericin-b and Arrhythmias--Cardiac

Amphotericin B (AmB) is a crucial agent in the management of serious systemic fungal infections. In spite of its proven track record, its well-known side effects and toxicity will sometimes require discontinuation of therapy despite a life-threatening systemic fungal infection. The mechanism of action of AmB is based on the binding of the AmB molecule to the fungal cell membrane ergosterol, producing an aggregate that creates a transmembrane channel, allowing the cytoplasmic contents to leak out, leading to cell death. Most of the efforts at improving AmB have been focused on the preparation of AmB with a lipid conjugate. AmB administration is limited by infusion-related toxicity, an effect postulated to result from proinflammatory cytokine production. The principal acute toxicity of AmB deoxycholate includes nausea, vomiting, rigors, fever, hypertension or hypotension, and hypoxia. Its principal chronic adverse effect is nephrotoxicity. AmB probably produces renal injury by a variety of mechanisms. Risk factors for AmB nephrotoxicity include male gender, higher average daily dose of AmB (> or = 35 mg/day), diuretic use, body weight > or = 90 kg, concomitant use of nephrotoxic drugs, and abnormal baseline renal function. Clinical manifestations of AmB nephrotoxicity include renal insufficiency, hypokalemia, hypomagnesemia, metabolic academia, and polyuria due to nephrogenic diabetes insipidus. Human studies show convincingly that sodium loading in excess of the usual dietary intake notably reduces the incidence and severity of AmB-induced nephrotoxicity.

Topics: Amphotericin B; Anemia; Animals; Arrhythmias, Cardiac; Calcium Channel Blockers; Cytokines; Fever; Gastrointestinal Diseases; Humans; Hyperkalemia; Kidney Diseases; Liposomes; Mycoses; Rats; Sodium Chloride

Topics: Amphotericin B; Antimony Sodium Gluconate; Antiprotozoal Agents; Arrhythmias, Cardiac; Electrocardiography; Female; Humans; Leishmaniasis, Visceral; Male

In order to assess the safety of 1-h infusions of amphotericin B (AMB), we prospectively monitored 213 1-h infusions of AMB (dose range, 0.27 to 0.89 mg/kg of body weight) in 27 patients with creatinine clearances of > 25 ml/min. Holter monitor tracings during 1-h infusions were compared with those during a 4-h baseline period of monitoring. There were no ventricular dysrhythmias during 1-h infusions of AMB that were not present during baseline monitoring. Nausea and/or rigors were noted for 32 (15%) infusions in six (22%) patients. No patient exhibited a temperature rise of > 1 degree C. We conclude that, in doses of up to 0.9 mg/kg, AMB does not appear to induce asymptomatic ventricular dysrhythmias when administered over 1 h to patients with creatinine clearances of > 25 ml/min.

Topics: Adolescent; Adult; Aged; Amphotericin B; Arrhythmias, Cardiac; Drug Administration Schedule; Electrocardiography, Ambulatory; Female; Heart Ventricles; Humans; Infusions, Intravenous; Kidney; Male; Middle Aged; Prospective Studies; Ventricular Fibrillation; Ventricular Function

Ventricular arrhythmias are a common cause of death in patients with heart failure (HF). Structural and electrical abnormalities in the heart provide a substrate for such arrhythmias. Canine tachypacing-induced HF models of 4-6 weeks duration are often used to study pathophysiology and therapies for HF. We hypothesized that a chronic canine model of HF would result in greater electrical and structural remodeling than a short term model, leading to a more arrhythmogenic substrate.. HF was induced by ventricular tachypacing for one (short-term) or four (chronic) months to study remodeling.. Left ventricular contractility was progressively reduced, while ventricular hypertrophy and interstitial fibrosis were evident at 4 month but not 1 month of HF. Left ventricular myocyte action potentials were prolonged after 4 (p<0.05) but not 1 month of HF. Repolarization instability and early afterdepolarizations were evident only after 4 months of HF (p<0.05), coinciding with a prolonged QTc interval (p<0.05). The transient outward potassium current was reduced in both HF groups (p<0.05). The outward component of the inward rectifier potassium current was reduced only in the 4 month HF group (p<0.05). The delayed rectifier potassium currents were reduced in 4 (p<0.05) but not 1 month of HF. Reactive oxygen species were increased at both 1 and 4 months of HF (p<0.05).. Reduced Ito, outward IK1, IKs, and IKr in HF contribute to EAD formation. Chronic, but not short term canine HF, results in the altered electrophysiology and repolarization instability characteristic of end-stage human HF.

Topics: Action Potentials; Amphotericin B; Analysis of Variance; Animals; Arrhythmias, Cardiac; Delayed Rectifier Potassium Channels; DNA Primers; Dogs; Electrocardiography; Electron Spin Resonance Spectroscopy; Heart Failure; Immunoblotting; Myocardial Contraction; Patch-Clamp Techniques; Potassium Channels, Inwardly Rectifying; Reactive Oxygen Species; Real-Time Polymerase Chain Reaction; Time Factors; Ventricular Remodeling

Kala-azar or visceral leishmaniasis is a disseminated protozoal infection caused by parasites of the genus Leishmania (Leishmania donovani in India). Conventional therapy for visceral leishmaniasis continues to be pentavalent antimony (sodium antimony gluconate [SAG]). Amphotericin B is widely used for SAG-unresponsive cases and sometimes even as a first-line drug, especially in endemic areas. With the conventional regimen of SAG, cardiac toxicity has been reported in 8% to 17% of cases with 5% to 7% of them having fatal toxicity. Cardiac toxicity is uncommon with amphotericin B with only few isolated reports. We report some patients with kala-azar in whom coadministration of SAG and amphotericin B led to arrhythmia and sudden death.

Topics: Amphotericin B; Antimony Sodium Gluconate; Antiprotozoal Agents; Arrhythmias, Cardiac; Child; Child, Preschool; Drug Therapy, Combination; Fatal Outcome; Humans; India; Leishmania donovani; Leishmaniasis, Visceral; Male

To report the clinical course of a woman with cryptococcal meningitis and no previous cardiac disease who developed a fatal cardiac arrhythmia after an acute overdose of amphotericin B and to review its toxicity.. A 41-year-old woman with a history of proliferative glomerulonephritis from systemic lupus erythematosus was admitted with a diagnosis of cryptococcal meningitis. Liposomal amphotericin B was prescribed at the standard dose of 5 mg/kg/day; however, amphotericin B deoxycholate 5 mg/kg was inadvertently administered (usual dose of the deoxycholate formulation is 0.5-0.8 mg/kg/day). The patient developed cardiac arrhythmias, acute renal failure, and anemia. The medication error was noticed after she had received 2 doses of amphotericin B deoxycholate, and it was then discontinued. Despite treatment in the intensive care unit, the woman died on the sixth day after admission.. Amphotericin B deoxycholate has been reported to produce significant cardiac toxicity, with ventricular arrhythmias and bradycardia reported in overdoses in children and in adults with preexisting cardiac disease, even when administered in conventional dosages and infusion rates. Use of the Naranjo probability scale indicated a highly probable relationship between the observed cardiac toxicity and amphotericin B deoxycholate therapy in this patient.. Given the fulminant course of amphotericin B deoxycholate overdosage and lack of effective therapy, stringent safeguards against its improper administration should be in place.

Topics: Acute Disease; Adult; Amphotericin B; Arrhythmias, Cardiac; Chemistry, Pharmaceutical; Deoxycholic Acid; Drug Combinations; Drug Overdose; Fatal Outcome; Female; Humans; Medication Errors; Meningitis, Cryptococcal

: In sinoatrial (SA) node cells, nitric oxide (NO) exerts a dual effect on the hyperpolarization-activated current, I(f), i.e. in basal conditions NO enhances I(f) whereas in the presence of beta-adrenergic stimulation it decreases it. Recent studies have shown that I(f) is present in ventricular myocytes from hypertrophied or failing hearts where it may promote abnormal automaticity. Since these pathological conditions are associated with increased sympathetic tone and upregulation of myocardial NO production, we set out to investigate whether I(f) is similarly modulated by NO in hypertrophied ventricular myocytes.. Left ventricular myocytes were isolated from 18-20-month-old spontaneously hypertensive rats (SHRs). Membrane current was measured under whole-cell or amphotericin-perforated patch-clamp conditions, at 35 degrees C.. Application of diethylamine-NO (DEA-NO, 1-100 microM) did not alter the amplitude or voltage dependence of activation of I(f) under basal conditions (half-activation voltage, V(h): control -82.9+/-2.6, DEA-NO -84.0+/-2.6 mV). Similarly, I(f) was not affected by the inhibition of endogenous NO production (L-NMMA, 500 microM) or guanylate cyclase (ODQ, 10 microM). Forskolin (10 microM) or isoprenaline (100 nM) elicited a positive shift in V(h) but subsequent application of DEA-NO did not further affect the properties of I(f).. Our results show that, unlike in SA node cells, in SHR ventricular myocytes basal and adrenergically stimulated I(f) is not modulated by exogenous NO or by constitutive NO or cGMP production.

Topics: Adenylyl Cyclases; Adrenergic beta-Agonists; Amphotericin B; Analysis of Variance; Animals; Arrhythmias, Cardiac; Cardiomegaly; Colforsin; Enzyme Inhibitors; Guanylate Cyclase; Hydrazines; Isoproterenol; Male; Membrane Potentials; Nitric Oxide Donors; Nitric Oxide Synthase; Nitrogen Oxides; omega-N-Methylarginine; Oxadiazoles; Patch-Clamp Techniques; Penicillamine; Pyridines; Rats; Rats, Inbred SHR; Sinoatrial Node

To report the first five cases of amphotericin B overdose with secondary cardiac complications in a pediatric population. Treatment is also presented.. Hospital.. Two infants and three children inpatients receiving amphotericin B.. Cardiac complications were observed in five pediatric patients who received between 4.6 and 40.8 mg/kg/d of amphotericin B. Cardiac arrest occurred in all patients, and four patients died. A detailed description of the cardiac event is provided for one patient who was on a cardiac monitor during the adverse reaction. Hydrocortisone prophylaxis and verapamil therapy were the primary therapies used in patient 1 (the only survivor). Evaluation of the literature provides substantial evidence for the use of hydrocortisone in prevention of cardiac arrhythmias.. Amphotericin B overdose can be fatal in children and infants. The presentation in humans appears similar to that in dogs where cardiac arrhythmias occurred at doses of 5-15 mg/kg. Hydrocortisone may decrease the incidence of mortality associated with cardiac arrhythmias in children receiving amphotericin B overdoses. Animal studies are necessary to evaluate this observation and potential disadvantages of hydrocortisone usage.

Topics: Amphotericin B; Arrhythmias, Cardiac; Candidiasis; Child; Child, Preschool; Drug Overdose; Female; Heart Arrest; Humans; Hydrocortisone; Infant; Male; Premedication; Verapamil

Topics: Administration, Oral; Amphotericin B; Arrhythmias, Cardiac; Brain Diseases; Cytosine; Flucytosine; Gastrointestinal Diseases; Humans; Hypokalemia; Injections, Intravenous; Injections, Spinal; Intestinal Perforation; Kidney Diseases; Meningitis; Mycoses; Paralysis; Radiculopathy; Vision Disorders