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Divergent proarrhythmic potential of macrolide antibiotics despite similar QT prolongation: fast phase 3 repolarization prevents early afterdepolarizations and torsade de pointes.

Macrolide antibiotics are known to have a different proarrhythmic potential in the presence of comparable QT prolongation in the surface ECG. Because the extent of QT prolongation has been used as a surrogate marker for cardiotoxicity, we aimed to study the different electrophysiological effects of the macrolide antibiotics erythromycin, clarithromycin, and azithromycin in a previously developed experimental model of proarrhythmia. In 37 Langendorff-perfused rabbit hearts, erythromycin (150-300 microM, n = 13) clarithromycin (150-300 microM, n = 13), and azithromycin (150-300 microM, n = 11) led to similar increases in QT interval and monophasic action potential (MAP) duration. In bradycardic (atrioventricular-blocked) hearts, eight simultaneously recorded epi- and endocardial MAPs demonstrated increased dispersion of repolarization in the presence of all three antibiotics. Erythromycin and clarithromycin led to early afterdepolarizations (EADs) and torsade de pointes (TdP) after lowering of potassium concentration. In the presence of azithromycin, no EAD or TdP occurred. Erythromycin and clarithromycin changed the MAP configuration to a triangular pattern, whereas azithromycin caused a rectangular pattern of MAP prolongation. In 13 additional hearts, 150 microM azithromycin was administered after previous treatment with 300 microM erythromycin and suppressed TdP provoked by erythromycin. In conclusion, macrolide antibiotics lead to similar prolongation of repolarization but show a different proarrhythmic potential (erythromycin > clarithromycin > azithromycin). In the presence of azithromycin, neither EAD nor TdP occur. This effect may be related to a rectangular pattern of action potential prolongation, whereas erythromycin and clarithromycin cause triangular action potential prolongation and induce TdP.

Animals↗

Overall and event-free survival are not improved by the use of myeloablative therapy following intensified chemotherapy in previously untreated patients with multiple myeloma: a prospective randomized phase 3 study.

We compared the efficacy of intensified chemotherapy followed by myeloablative therapy and autologous stem cell rescue with intensified chemotherapy alone in patients newly diagnosed with multiple myeloma. There were 261 eligible patients younger than 66 years with stage II/III multiple myeloma who were randomized after remission induction therapy with vincristine, adriamycin, dexamethasone (VAD) to receive intensified chemotherapy, that is, melphalan 140 mg/m(2) administered intravenously in 2 doses of 70 mg/m(2) (intermediate-dose melphalan [IDM]) without stem cell rescue (n = 129) or the same regimen followed by myeloablative therapy consisting of cyclophosphamide, total body irradiation, and autologous stem cell reinfusion (n = 132). Interferon-alpha-2a was given as maintenance. Of the eligible patients, 79% received both cycles of IDM and 79% of allocated patients actually received myeloablative treatment. The response rate (complete remission [CR] plus partial remission [PR]) was 88% in the intensified chemotherapy group versus 95% in the myeloablative treatment group. CR was significantly higher after myeloablative therapy (13% versus 29%; P =.002). With a median follow-up of 33 months (range, 8-65 months), the event-free survival (EFS) was not different between the treatments (median 21 months versus 22 months; P =.28). Time to progression (TTP) was significantly longer after myeloablative treatment (25 months versus 31 months; P =.04). The overall survival (OS) was not different (50 months versus 47 months; P =.41). Intensified chemotherapy followed by myeloablative therapy as first-line treatment for multiple myeloma resulted in a higher CR and a longer TTP when compared with intensified chemotherapy alone. However, it did not result in a better EFS and OS.

Adult↗

Prevalence of symptoms of asthma, rhinitis, and atopic eczema among Brazilian children and adolescents identified by the International Study of Asthma and Allergies in Childhood (ISAAC) - Phase 3.

OBJECTIVES: To determine the prevalence of symptoms of asthma, rhinitis, and atopic eczema among schoolchildren aged 6 to 7 years and adolescents aged 13 to 14 years in 20 Brazilian cities by using the standardized ISAAC written questionnaire, and to assess the association of this prevalence with latitude, altitude and average annual temperature of collaborating centers. METHODS: Schoolchildren and adolescents from five Brazilian regions participated in the study, totaling 23,422 ISAAC questionnaires answered by schoolchildren's parents and 58,144 questionnaires answered by adolescents. The values for latitude, altitude and average annual temperature were obtained from the Brazilian Institute of Geography and Statistics. RESULTS: The mean prevalence rates among schoolchildren and adolescents were respectively 24.3 and 19.0% for active asthma; 12.6 and 14.6% for rhinoconjunctivitis; and 8.2 and 5.0% for atopic eczema. A significant negative association was observed between latitude and physician-diagnosed asthma among schoolchildren, severe asthma, physician-diagnosed asthma, eczema and atopic eczema among adolescents. No association with altitude was found. CONCLUSIONS: The prevalence of asthma, rhinitis and atopic eczema in Brazil varies considerably. Higher prevalence rates, especially of asthma and eczema, were found at centers located closer to the equator.

Adolescent↗

Texas Medication Algorithm Project, phase 3 (TMAP-3): rationale and study design.

BACKGROUND: Medication treatment algorithms may improve clinical outcomes, uniformity of treatment, quality of care, and efficiency. However, such benefits have never been evaluated for patients with severe, persistent mental illnesses. This study compared clinical and economic outcomes of an algorithm-driven disease management program (ALGO) with treatment-as-usual (TAU) for adults with DSM-IV schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD) treated in public mental health outpatient clinics in Texas. DISCUSSION: The disorder-specific intervention ALGO included a consensually derived and feasibility-tested medication algorithm, a patient/family educational program, ongoing physician training and consultation, a uniform medical documentation system with routine assessment of symptoms and side effects at each clinic visit to guide ALGO implementation, and prompting by on-site clinical coordinators. A total of 19 clinics from 7 local authorities were matched by authority and urban status, such that 4 clinics each offered ALGO for only 1 disorder (SCZ, BD, or MDD). The remaining 7 TAU clinics offered no ALGO and thus served as controls (TAUnonALGO). To determine if ALGO for one disorder impacted care for another disorder within the same clinic ("culture effect"), additional TAU subjects were selected from 4 of the ALGO clinics offering ALGO for another disorder (TAUinALGO). Patient entry occurred over 13 months, beginning March 1998 and concluding with the final active patient visit in April 2000. Research outcomes assessed at baseline and periodically for at least 1 year included (1) symptoms, (2) functioning, (3) cognitive functioning (for SCZ), (4) medication side effects, (5) patient satisfaction, (6) physician satisfaction, (7) quality of life, (8) frequency of contacts with criminal justice and state welfare system, (9) mental health and medical service utilization and cost, and (10) alcohol and substance abuse and supplemental substance use information. Analyses were based on hierarchical linear models designed to test for initial changes and growth in differences between ALGO and TAU patients over time in this matched clinic design.

Adolescent↗

Texas Medication Algorithm Project, phase 3 (TMAP-3): clinical results for patients with a history of mania.

BACKGROUND: The Texas Medication Algorithm Project (TMAP) assessed the clinical and economic impact of algorithm-driven treatment (ALGO) as compared with treatment-as-usual (TAU) in patients served in public mental health centers. This report presents clinical outcomes in patients with a history of mania (BD), including bipolar I and schizoaffective disorder, bipolar type, during 12 months of treatment beginning March 1998 and ending with the final active patient visit in April 2000. METHOD: Patients were diagnosed with bipolar I disorder or schizoaffective disorder, bipolar type, according to DSM-IV criteria. ALGO was comprised of a medication algorithm and manual to guide treatment decisions. Physicians and clinical coordinators received training and expert consultation throughout the project. ALGO also provided a disorder-specific patient and family education package. TAU clinics had no exposure to the medication algorithms. Quarterly outcome evaluations were obtained by independent raters. Hierarchical linear modeling, based on a declining effects model, was used to assess clinical outcome of ALGO versus TAU. RESULTS: ALGO and TAU patients showed significant initial decreases in symptoms (p =.03 and p <.001, respectively) measured by the 24-item Brief Psychiatric Rating Scale (BPRS-24) at the 3-month assessment interval, with significantly greater effects for the ALGO group. Limited catch-up by TAU was observed over the remaining 3 quarters. Differences were also observed in measures of mania and psychosis but not in depression, side-effect burden, or functioning. CONCLUSION: For patients with a history of mania, relative to TAU, the ALGO intervention package was associated with greater initial and sustained improvement on the primary clinical outcome measure, the BPRS-24, and the secondary outcome measure, the Clinician-Administered Rating Scale for Mania (CARS-M). Further research is planned to clarify which elements of the ALGO package contributed to this between-group difference.

Adolescent↗