Citations

Abstract Effective treatment with antidepressants is currently limited by factors that affect treatment compliance, including delay in onset of therapeutic effects and intolerable side-effects. Recent data suggest that use of antidepressant combinations with different mechanisms of action may be a better first-line strategy prior to augmentation with other drug classes. The rationale for this approach is that combining multiple pharmacological actions affecting multiple monoamine targets produces greater efficacy. Several new multi-modal compounds are in development and early results for the most advanced agents indicate shorter onset of therapeutic effects and improved tolerability. By modulating multiple receptors and transmitter systems, it is hoped that these new agents may also treat some of the associated symptoms of major depressive disorder, such as anxiety and cognitive dysfunction.

AbstractBackgroundFunctional GI syndromes are known to be very prevalent, but this may be linked to unrecognized medications use. We aimed to estimate the prevalence of PPI, antidepressant, and narcotic use in the general population, and to evaluate the association between each medication and functional GI syndromes adjusting for potential confounders.MethodsIn 2008 and 2009, newly revised versions of a validated bowel disease questionnaire were mailed to a community‐based cohort (total mailed = 8006) of Olmsted County, MN residents; 3831 returned the questionnaire (response rate = 48.0%). Medication usage, specifically PPIs, narcotics, and antidepressants in the last year, was elicited via three separate questions on the questionnaire. The association between each medication and GI symptom complexes was assessed using multiple variable logistic regression models.Key ResultsA total of 3515 of the respondents (92%) had complete data (mean age: 61 ± 15; 54% female). The overall proportion reporting PPI use was 20% (95% CI: 19, 22), narcotic use 12% (95% CI: 11, 13), and antidepressant use 15% (95% CI: 14, 16). PPI use was significantly associated with IBS status (OR = 1.4, 95% CI 1.1, 1.7) as well as with GERD (OR = 3.5, 95% CI 2.7, 4.4) and dyspepsia (OR = 2.0, 95% CI 1.5, 2.7). The association of PPI use with IBS was not explained by coexistent GERD or dyspepsia. Antidepressant use was significantly associated only with bloating (OR = 1.6, 1.1, 2.2).Conclusions & InferencesSome medications that may alter intestinal transit or bowel flora are commonly utilized by the general population, and PPI use appears to be linked to IBS.

OBJECTIVE: To describe a case of torsades de pointes (TdP) in a patient treated with aripiprazole. CASE SUMMARY: A 42-year-old white male with schizophrenia, diabetes, hypertension, and a history of stroke was admitted to the intensive care unit following 2 days of fever, diarrhea, and altered mental status. Following the resolution of his acute illness, previous therapy with quetiapine 400 mg orally at bedtime was resumed for schizophrenia and presumed delirium. Quetiapine was discontinued after 1 dose because of QTc interval prolongation. Twenty-three days later, with a baseline Q Tc interval of 414 milliseconds, aripiprazole 2.5 mg orally once daily was initiated. Following 5 days of aripiprazole therapy, the patient had a cardiac arrest due to TdP. Normal sinus rhythm was restored after 30 seconds of cardiopulmonary resuscitation, 1 shock of 200 Joules, and 4 g of intravenous magnesium sulfate. Serial electrocardiographs obtained after aripiprazole discontinuation revealed resolution of QTc interval prolongation. DISCUSSION: Aripiprazole is a second-generation antipsychotic that may be selected for patients with prolonged QTc intervals and at risk for TdP. Data from trials indicate that aripiprazole has minimal effects on the QTc interval. However, in this case, aripiprazole was associated with TdP in a patient with minimal risk factors. The Naranjo probability scale was used to determine a probable association between aripiprazole and the development of TdP. To our knowledge, this is the first reported case of TdP associated with the use of aripiprazole. CONCLUSIONS: Five days of low-dose aripiprazole therapy was associated with the development of TdP in a man with minimal risk factors. Clinicians should be aware of this potential adverse drug event with aripiprazole.

Object The presence of a “July effect,” where the influx of new residents and fellows at teaching hospitals every July may negatively affect patient care and outcomes, is widely debated. The authors used the Nationwide Inpatient Sample (NIS) to identify all cases of spinal surgery and examine outcomes among patients who underwent surgery in July compared with those who underwent surgery in other months. Methods Spinal surgery hospitalizations from 2001 to 2008 were identified in the NIS by extracting relevant ICD-9 codes. Rates of in-hospital mortality, discharge to a long-term care facility, and postoperative complications were compared between admission months and between teaching and nonteaching hospitals using the Wilcoxon rank-sum test, Fisher exact test, and multivariate regression analysis. Results Compared with patients admitted in other months, patients who were admitted to teaching hospitals in July for spinal surgery showed a similar likelihood of in-hospital mortality (OR 0.94 [95% CI 0.78–1.11], p = 0.46), reaction to implanted device/instrumentation (OR 0.88 [95% CI 0.77–1.02], p = 0.09), and postoperative wound dehiscence (OR 1.12 [95% CI 0.94–1.33], p = 0.25). A significantly higher likelihood of discharge to a long-term care facility (OR 1.03 [95% CI 1.00–1.07], p = 0.0467) and postoperative infection (OR 1.11 [95% CI 1.05–1.17], p = 0.0341) was observed in teaching hospitals in July compared with other months; however, incidence rates were similar regardless of admission month. Higher-risk patients (Charlson score ≥ 2) admitted to teaching hospitals in July had a similar likelihood of all outcomes regardless of admission month. Conclusions This study of nationwide hospitalizations demonstrates that the influx of new residents and fellows in July has a negligible effect on periprocedural outcomes following spinal surgery.

Class B GPCRs (G-protein-coupled receptors) share heptahelical topology and G-protein binding with other superfamily members, yet have unique structures and modes of activation. Natural ligands for these receptors are moderate-length peptides with C-terminal α-helices. NMR and crystal structures of the peptide-bound disulfide-bonded receptor N-terminal domains demonstrate that these helices occupy a conserved groove; however, the details of this interaction vary from one receptor to another. In this review, we focus on the prototypic secretin receptor and use extensive intrinsic photoaffinity labelling, structure–activity series, alanine-replacement mutagenesis and fluorescence analysis to define the molecular basis for this interaction. Additionally, experimental validation of predictions coming from in silico molecular modelling has provided a basis for enhancement of binding affinity. Such insights will be useful in the rational development of drugs acting at this important group of targets.

Abstract Learning Objectives Discuss methods for improving the efficiency of global clinical trials. Explain the need for national regulatory authorities and collaborative cancer groups to initiate efforts to quicken the activation process in their countries. Describe the activation process of phase III studies and its complex and heterogeneous regulation across different geographic and economic regions. Purpose. This study measured the time taken for setting up the different facets of Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO), an international phase III study being conducted in 44 participating countries. Methods. Time to regulatory authority (RA) approval, time to ethics committee/institutional review board (EC/IRB) approval, time from study approval by EC/IRB to first randomized patient, and time from first to last randomized patient were prospectively collected in the ALTTO study. Analyses were conducted by grouping countries into either geographic regions or economic classes as per the World Bank's criteria. Results. South America had a significantly longer time to RA approval (median: 236 days, range: 21–257 days) than Europe (median: 52 days, range: 0–151 days), North America (median: 26 days, range: 22–30 days), and Asia-Pacific (median: 62 days, range: 37–75 days). Upper-middle economies had longer times to RA approval (median: 123 days, range: 21–257 days) than high-income (median: 47 days, range: 0–112 days) and lower-middle income economies (median: 57 days, range: 37–62 days). No significant difference was observed for time to EC/IRB approval across the studied regions (median: 59 days, range 0–174 days). Overall, the median time from EC/IRB approval to first recruited patient was 169 days (range: 26–412 days). Conclusion. This study highlights the long time intervals required to activate a global phase III trial. Collaborative research groups, pharmaceutical industry sponsors, and regulatory authorities should analyze the current system and enter into dialogue for optimizing local policies. This would enable faster access of patients to innovative therapies and enhance the efficiency of clinical research.