Long-term efficacy and toxicity of high-dose amiodarone therapy for ventricular tachycardia or ventricular fibrillation

Amiodarone was administered to 154 patients who had sustained, symptomatic ventricular tachycardia (VT) (n = 118) or a cardiac arrest (n = 36) and who were refractory to conventional antiarrhythmic drugs. The loading dose was 800 mg/day for 6 weeks and the maintenance dose was 600 mg/day. Sixty-nine percent of patients continued treatment with amiodarone and had no recurrence of symptomatic VT or ventricular fibrillation (VF) over a follow-up of 6 to 52 months (mean ± standard deviation 14.2 ± 8.2). Six percent of the patients had a nonfatal recurrence of VT and were successfully managed by continuing amiodarone at a higher dose or by the addition of a conventional antiarrhythmic drug. One or more adverse drug reactions occurred in 51% of patients. Adverse effects forced a reduction in the dose of amiodarone in 41 % and discontinuation of amiodarone in 10% of patients. The most common symptomatic adverse reactions were tremor or ataxia (35 %), nausea and anorexia (8%), visual halos or blurring (6%), thyroid function abnormalities (6%) and pulmonary interstitial infiltrates (5%).Although large-dose amiodarone is highly effective in the long-term treatment of VT or VF refractory to conventional antiarrhythmic drugs, it causes significant toxicity in approximately 50% of patients. However, when the dose is adjusted based on clinical response or the development of adverse effects, 75 % of patients with VT or VF can be successfully managed with amiodarone.     

Dexamethasone-based regimens versus melphalan-prednisone for elderly multiple myeloma patients ineligible for high-dose therapy

Dexamethasone alone increases life expectancy in patients with relapsed multiple myeloma (MM); however, no large randomized study has compared dexamethasone and dexamethasone-based regimens with standard melphalan-prednisone in newly diagnosed MM patients ineligible for high-dose therapy. In the Intergroupe Francophone du Myélome (IFM) 95-01 trial, 488 patients aged 65 to 75 years were randomized between 4 regimens of treatment: melphalan-prednisone, dexamethasone alone, melphalan-dexamethasone, and dexamethasone-interferon alpha. Response rates at 6 months (except for complete response) were significantly higher among patients receiving melphalan-dexamethasone, and progression-free survival was significantly better among patients receiving melphalan (P < .001, for both comparisons), but there was no difference in overall survival between the 4 treatment groups. Moreover, the morbidity associated with dexamethasone-based regimens was significantly higher than with melphalan-prednisone, especially for severe pyogenic infections in the melphalan-dexamethasone arm and hemorrhage, severe diabetes, and gastrointestinal and psychiatric complications in the dexamethasone arms. Overall, these results indicated that dexamethasone should not be routinely recommended as first-line treatment in elderly patients with MM. In the context of the IFM 95-01 trial, the standard melphalan-prednisone remained the best treatment choice when efficacy and patient comfort were both considered. These results might be useful in the context of future combinations with innovative drugs.      

Electropharmacology of amiodarone therapy initiation. Time courses of onset of electrophysiologic and antiarrhythmic effects

The time courses of onset of the electrophysiologic and antiarrhythmic effects of amiodarone were determined with serial electrophysiologic studies in 34 patients with inducible ventricular tachycardia. A standardized oral loading dosage was used for all patients (1,200 mg/day for 14 days; 800 mg/day for 7 days; and 400 mg/day thereafter). Eleven patients had the studies performed at baseline and after 2, 6, 10, and 20 weeks. Subsequently, 23 patients had studies at baseline and after 2 and 10 weeks. Changes in atrial, sinus, and atrioventricular nodal properties and in conduction intervals were maximal within 2 weeks (early effects). For example, atrioventricular nodal Wenckebach cycle length increased between baseline (369 +/- 80 msec) and 2 weeks (498 +/- 78 msec) (p less than 0.001) but did not change further after 10 weeks (500 +/- 89 msec). However, ventricular Class III effects required 10 weeks to become maximal (late effects). For example, the QT interval during atrial pacing increased between baseline (355 +/- 36 msec) and 2 weeks (406 +/- 37 msec) (p less than 0.001) and increased further after 10 weeks (436 +/- 45 msec) (p less than 0.001). Antiarrhythmic effects also followed different time courses of onset. Suppression of ventricular premature beats was maximal within 2 weeks. However, suppression of ventricular tachycardia inducibility and slowing of ventricular tachycardia rate was not maximal for 10 weeks. Correlations between serum desethylamiodarone concentrations and some late effects suggest that the mechanism of the time delay to maximal ventricular Class III effects may involve desethylamiodarone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Ketoconazole therapy for systemic fungal infections: inadequacy of standard dosage regimens

We treated 29 patients with ketoconazole for systemic mycoses. Twenty-two had coccidioidomycosis, 5 had histoplasmosis, and 2 had sporotrichosis. Of the 25 patients who received 200 mg/day, 16% improved on that dose. Of 17 patients who did not improve on 200 mg/day, 71% responded after the dose was increased to 400 or 800 mg/day. Treatment periods ranged from 21 days to more than 600 days. Five patients relapsed. In 2, ketoconazole had been reduced in dose or discontinued. In 3, the drug was still being given. Ketoconazole is effective in suppressing disease in various mycoses. However, patients may require high doses for prolonged periods to achieve maximal benefit.     

Once-daily therapy for H. pylori infection: a randomized comparison of four regimens

OBJECTIVE: We sought to determine the efficacy and tolerability of novel, once-daily therapies in the treatment of Helicobacter pylori infection. METHODS: One hundred sixty subjects with H. pylori infection documented by endoscopic biopsy or serology plus 13C-urea breath test were randomly assigned to omeprazole 80 mg q.d. and metronidazole extended-release formulation 750 mg q.d. for 10 days (OM); OM plus amoxicillin 1.5 g q.d. for 10 days (OMAm); OM plus azithromycin 500 mg q.d. for 7 days (OMAz); or OM plus clarithromycin 1 g q.d. for 10 days (OMCI). A repeat breath test was done 6 wk after the completion of therapy. Subjects were considered compliant if they took > or = 80% of each study medication as prescribed. RESULTS: Intent-to-treat eradication rates were OM = 8% (95% confidence interval [CI], 2-20%), OMAm = 35% (95% CI, 21-52%), OMAz = 65% (95% CI, 48-79%), and OMCI = 78% (95% CI, 62-89%). Lack of compliance was seen in 5% of subjects given OM, 8% given OMAm, 3% given OMAz, and 15% given OMCI. CONCLUSIONS: This pilot study demonstrated that once-daily triple therapy with high-dose omeprazole, metronidazole extended-release formulation, and clarithromycin achieved an eradication rate approaching 80%. Further study may permit development of optimal once-daily dosing and enhance eradication rates.     

Antiadrenergic cardiovascular adverse effects of high-dose amiodarone loading regimen.

A 55-year-old patient with inferior wall infarction was treated effectively for ventricular tachycardia with high-dose oral amiodarone loading regimen (5 g within 16 hours). Serial pharmacokinetic studies demonstrated a rapid temporary increase in amiodarone plasma concentration to a maximum of 3.40 micrograms/ml 17 hours after initiation of therapy followed by a return to normal plasma concentration within 8 hours. During fast drug evasion the patient developed acute low-output syndrome with syncope successfully controlled with intravenous catecholamine administration. Our findings suggest that the cardiovascular collapse was caused by the non-competitive adrenoceptor antagonism of amiodarone resulting in secondary autonomic insufficiency.     

Hematopoietic stem cell depletion by restorative growth factor regimens during repeated high-dose cyclophosphamide therapy.

We studied the effects of six cycles of repeated cyclophosphamide (CTX) therapy followed by restorative therapy with either granulocyte-macrophage colony-stimulating factor (GM-CSF) or G-CSF on the hematopoietic stem cell compartment. Stem cell function was assessed by serially transferring bone marrow cells from CTX-CSF-treated mice into lethally irradiated recipient mice. Bone marrow cells from mice that initially received either G-CSF or GM-CSF after CTX therapy more rapidly lost the ability to repopulate the recipient lymphoid organs, showed a dramatic loss of hematopoietic progenitors, a more rapid loss of CFU-S capacity, and a 40% to 50% reduction in marrow repopulating ability (MRA). Interleukin-1 (IL-1) appeared to have little effect on the CTX-treated mice when used alone. However, when administered before the CTX-CSF regimen, IL-1 prevented the stem cell depletion as determined by CFU-C, CFU-S, and MRA through the serial transplantation procedures. These results support the hypothesis that repeated treatments with myelosuppressive drugs followed by stimulation with the CSFs may induce damage to the host stem cell compartment, and further suggest that pretreatment with IL-1 before CTX therapy may prevent this stem cell damage.     

A comparison of cardioversion of atrial fibrillation using oral amiodarone, intravenous amiodarone and DC cardioversion.

Fifty-two consecutive patients with atrial fibrillation underwent 86 episodes of attempted cardioversion with oral amiodarone, intravenous amiodarone or DC cardioversion. The presence of chronic obstructive pulmonary disease or a presenting heart rate of less than 110 beats per minute were associated with a favourable outcome. Conversion to sinus rhythm was achieved in 29% of the group treated with oral amiodarone, 42% of the group treated with DC cardioversion and 64% of the group given intravenous amiodarone. The overall statistical significance of this distribution on chi square testing was p < 0.032. However when only first attempts at cardioversion were analyzed there was no difference between intravenous amiodarone and DC cardioversion.     

Cost-effectiveness of the implantable cardioverter-defibrillator: effect of improved battery life and comparison with amiodarone therapy.

The implantable cardioverter-defibrillator (ICD) greatly reduces the incidence of sudden cardiac death among patients with recurrent sustained ventricular tachycardia and fibrillation who do not respond to conventional antiarrhythmic therapy. A cost-effectiveness analysis was performed, comparing the ICD, amiodarone and conventional agents. Actual variable costs of hospitalization and follow-up care were used for 21 ICD- and 43 amiodarone-treated patients. Life expectancy and total variable costs were predicted with use of a Markov decision analytic model. Clinical event rates and probabilities were based on published reports or expert opinion. Life expectancy with an ICD (6.1 years) was 50% greater than that associated with treatment with amiodarone (3.9 years) and 2.5 times that associated with conventional treatment (2.5 years). Assuming replacement every 24 months, ICD lifetime treatment costs (in 1989 dollars) for a 55-year old patient are expected to be $89,600 compared with $24,800 for amiodarone and $16,100 for conventional therapy, yielding a marginal cost/effectiveness ratio for ICD versus amiodarone therapy of 1f429,200/year of life saved, which is comparable to that of other accepted medical treatments. If technologic improvements extend average battery life to 36 months, the marginal cost/effectiveness ratio would be $21,800/year of life saved, and at 96 months it would be $13,800/year of life saved. Patient age at implantation did not significantly affect these results. If quality of life on amiodarone therapy is 30% lower than that with the ICD, the marginal cost/effectiveness ratio decreases by 35%. If the quality of life for patients receiving drugs is 40% lower than that of patients treated with an ICD, use of the defibrillator becomes the dominant strategy.     

A standard heparin nomogram for the management of heparin therapy.

A nomogram for the adjustment of heparin dosage was developed to standardize heparin therapy and to reduce delays in achieving and maintaining a therapeutic activated partial thromboplastin time (APTT) result. Fifty consecutive patients with acute venous thromboembolism had their continuous intravenous heparin therapy adjusted according to this heparin nomogram. The effect of the nomogram on heparin therapy in these patients was compared with data from 53 historical control patients. The proportion of patients in the nomogram group who reached a therapeutic APTT at 24 hours after the start of heparin therapy was 66%, which increased to 81% at 48 hours. In contrast, 37% and 58% of the control patients reached a therapeutic APTT at 24 and 48 hours, respectively. The percentage of therapeutic APTT results of the total number of APTT determinations was greater in the nomogram patients than controls. The use of this heparin nomogram resulted in (1) achieving a therapeutic APTT at 24 and 48 hours in a large proportion of patients and (2) reduced periods of inadequate anticoagulation and overanticoagulation during heparin therapy.     

Allo-HSCT for acute leukemia of ambiguous lineage in adults: the comparison between standard conditioning and intensified conditioning regimens

Knowledge concerning the clinical and biological characteristics of acute leukemia of ambiguous lineage (ALAL) is limited so that there has been a lack of uniformity in treatment. In this report, we retrospectively investigated the effect of intensified conditioning on adult ALAL undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). A total of 59 patients with ALAL (male in 37 cases and female in 22 cases) were consecutively enrolled in the data analyses. Twenty-four patients received the standard conditioning (total body irradiation (TBI)?+?cyclophosphamide (CY) or busulfan?+?CY protocol) and 35 received the intensified conditioning (TBI?+?CY?+?etoposide or fludarabine?+?cytarabine plus TBI?+?CY?+?etoposide protocol). Five-year transplant-related mortality was 17.6?±?9.6 % and 25.5?±?8.0 %, the 5-year overall survival (OS) post-transplantation was 23.8?±?8.9 % and 64.0?±?8.4 %, disease-free survival was 16.7?±?7.6 % and 55.8?±?9.4 %, the 5-year cumulative incidence of relapse was 80.8?±?8.5 % and 28.8?±?9.9 %, respectively, in the standard and the intensified group (P?=?0.380, P?=?0.029, P?=?0.005, and P?<?0.001). Both univariate and multivariate analysis indicated that the intensified conditioning regimen and acute graft-versus-host disease were favorable factors to reduce the relapse. The younger patients, patients with CR at the time of transplantation, and the intensified conditioning regimen were favorable factors to elevate the survival. In conclusion, intensified conditioning regimens followed by allo-HSCT might improve long-term survival and decrease relapse of leukemia in adult ALAL compared to the standard conditioning regimens.     

Efficacy and tolerance of high-dose intravenous amiodarone for recurrent, refractory ventricular tachycardia

High-dose intravenous amiodarone was given to 35 patients with recurrent life-threatening ventricular tachycardia (VT) refractory to conventional antiarrhythmic agents. Intravenous amiodarone was given as a 5 mg/kg dose over 30 minutes followed by 20 to 30 mg/kg/day as a constant infusion for 5 days. Twenty-two (63%) patients responded to intravenous amiodarone. All 22 responders received oral amiodarone. Thirteen (59%) continue to receive oral amiodarone after an average follow-up of 19 months, 4 (18%) had sudden cardiac death on oral amiodarone, 2 (9%) died while receiving amiodarone, secondary to left ventricular failure, and 3 (14%) discontinued amiodarone because of side effects. Of the 13 (37%) nonresponders, 10 died in the hospital while receiving intravenous amiodarone, secondary to lethal arrhythmia. Three nonresponders were discharged from the hospital; 2 with automatic cardioverter/defibrillators and 1 receiving a combination of antiarrhythmic agents. Serious adverse events occurred in 13 (37%) patients during intravenous amiodarone therapy. These included hypotension in 8 patients, symptomatic bradycardia in 4 patients and sinus arrest with bradycardia and hypotension in 1 patient. Minor side effects occurred in 23 (66%) patients. In conclusion, high dose intravenous amiodarone is effective in most patients with recurrent, sustained VT but is associated with an unacceptably high incidence of serious adverse events. The optimal dose and duration of intravenous amiodarone for patients with recurrent, refractory sustained VT remain unknown.     

A comparison of bepridil with amiodarone in the treatment of established atrial fibrillation.

Fourteen patients with established atrial fibrillation (longer than three months) that was refractory to treatment were studied to compare the clinical and electrophysiological effects of amiodarone and bepridil. All patients initially received bepridil for three weeks (200-600 mg/day), followed by amiodarone for two to three months (100-400 mg/day). Bepridil seemed to be slightly more effective than amiodarone in converting the fibrillation to sinus rhythm (nine of fourteen compared with four of ten). The ventricular response in atrial fibrillation was equally well controlled by bepridil and amiodarone, both at rest and during exercise. Bepridil was associated with the development of ventricular arrhythmias in eight of fourteen patients; two had torsade de pointes, which in one degenerated into fatal ventricular fibrillation. These arrhythmias seemed to be associated with bepridil induced prolongation of the QTc interval. No ventricular arrhythmias were seen during amiodarone treatment. Although bepridil seems to be an effective antiarrhythmic agent for the management of atrial fibrillation, its arrhythmogenic actions make it unsuitable for this purpose.     

Nausea and vomiting with high-dose chemotherapy and stem cell rescue therapy: a review of antiemetic regimens

Stem cell transplantation, using high-dose chemotherapy with or without TBI, is usually associated with significant nausea and vomiting. A variety of antiemetic regimens have been studied to control nausea and vomiting associated with the preparative therapy phase of SCT. We review the most significant studies and highlight the limitations of many of these studies. In addition, we review the few studies with the use of aprepitant as an antiemetic in combination with a 5HT(3) antagonist and a steroid. The American Society of Clinical Oncology guideline for antiemetic use for treatment regimens that are highly emetogenic is reviewed regarding recommendations for SCT preparative regimens. On the basis of this review of published data, we recommend the basic outline for an effective antiemetic investigational approach to the study and to the control of nausea and vomiting during the preparative phase of treatment for SCT.     

A randomised controlled trial of high-dose isoniazid adjuvant therapy for multidrug-resistant tuberculosis.

SETTING: Tertiary care hospital in Kanpur, India. BACKGROUND: The need for a standardised treatment protocol for multidrug-resistant tuberculosis (MDR-TB) in resource-limited countries is being increasingly recognised. OBJECTIVE: To assess the effectiveness of high-dose isoniazid (INH) (16-18 mg/kg) adjuvant to second-line therapy in documented cases of MDR-TB. DESIGN: The present study is a double blind, randomised controlled trial with three treatment arms, high-dose INH, normal-dose INH and placebo, in addition to second-line drugs. Primary outcomes of the study were time to sputum culture conversion and proportion with sputum culture negative 6 months after treatment initiation. Secondary outcomes were radiological improvement at 1 year post treatment and development of toxicity. RESULTS: After adjustment for potential confounders, subjects who received high-dose INH became sputum-negative 2.38 times (95%CI 1.45-3.91, P = 0.001) more rapidly than those who did not receive it, and had a 2.37 times (95%CI 1.46-3.84, P < 0.001) higher likelihood of being sputum-negative at 6 months. These subjects showed significantly better radiological improvement without an increased risk of INH toxicity. CONCLUSION: In low-resource scenarios where a standardised therapeutic protocol is used for MDR-TB, the protocol can be significantly improved by including high-dose INH as an adjuvant.     

Outpatient parenteral antimicrobial therapy for surgery patients: A comparison with previous standard of care

BACKGROUND:

Current literature reports that outpatient parenteral antimicrobial therapy (OPAT) programs improve cure rates, and reduce length of hospitalization and costs. OPAT programs are still relatively new in Canada.

OBJECTIVE:

To evaluate the benefits of an OPAT program initiated at a multispecialty tertiary care facility in Toronto, Ontario, compared with the previous standard of care.

METHODS:

The present retrospective observational study was conducted using data from a group of surgical patients who were treated for active infections. Between February 1, 2010 and November 30, 2010, a total of 108 surgical patients were enrolled in the OPAT program. Patients were matched 1:1 with historical controls discharged between January 1, 2001 and January 1, 2010 according to age, sex, type of surgery, infection and comorbidities (Charlson Comorbidity Index). Cure rate, 30-day rehospitalization and length of stay were evaluated as primary end points.

RESULTS:

Of 108 eligible OPAT patients, 21 were matched to the control group using the prespecified criteria. For this cohort, the OPAT program was associated with improved cure rates (OPAT 61.7% versus control 57.1%; P>0.10), reduction in rehospitalization rate (14.3% versus 28.6%; P>0.10) and reduced length of stay (10.7 versus 13.9 days, P>0.10) compared with the control group.

CONCLUSIONS:

For this cohort of surgery patients, the OPAT program demonstrated a trend toward improved outcomes but did not achieve statistical significance. Due to the lack of statistical power, further evaluation is required to determine the full benefit of OPAT to patients and the health care system.     

Use of amiodarone for short-term and adjuvant therapy in young patients.

Limited data are available defining the safety of amiodarone for short-term use or as part of combination antiarrhythmic therapy in pediatric patients. Results of amiodarone in 47 young patients for an average treatment duration of 12 months were examined. There were 21 male and 26 female patients (age range of 23 weeks gestation to 29 years). Patients were divided into 4 groups: group 1--electrocardiographic documented ventricular tachycardia (n = 7); group 2--syncope of unknown cause (n = 16); group 3--primary atrial tachycardia (n = 11); and group 4--supraventricular tachycardia (n = 13). Amiodarone was clinically useful in 32 (68%) patients. Amiodarone was considered effective as a sole antiarrhythmic agent in 21 (45%) patients. Treatment was ineffective but was continued in 11 (23%) patients; in 10 of these 11 patients amiodarone was adjuvant to other antiarrhythmic drugs. Amiodarone was considered ineffective and was withdrawn in 15 (32%) patients. No patient required cardiac pacemaker implant during therapy. Torsades de pointes and cardiac arrest occurred in 1 patient each after 9 and 14 days of therapy, respectively. Two patients underwent successful cardiac transplant after 2 and 14 months of amiodarone administration, respectively. Amiodarone was used as short-term treatment (less than 18 months) in 7 infants (age less than 18 months), and after cessation of treatment there was no recurrence of tachycardia for 4 to 24 months. Results of this study confirm reports of successful amiodarone use in pediatric patients with a variety of rhythm disturbances.(ABSTRACT TRUNCATED AT 250 WORDS)