Efficacy of diphenhydramine against cough in humans: a review

Aim To determine the efficacy of diphenhydramine against cough due to respiratory infection or irritation in patients/subjects without comorbidities. Method Two reviewers independently identified English language studies, searching on: clinical trials, randomized, diphenhydramine (OR dimenhydrinate), antitussive agents, cough (combine using AND). Sources were: Medline (1966–2005), Embase (1980–2005), Cochrane and references from retrieved articles. Two other reviewers, blinded to study origin selected studies, inclusion criteria being: diphenhydramine monotherapy against placebo, double-blinded, randomized, clinical trial, intention-to-treat, dropout information. The blinded reviewers evaluated the selected studies on a quality scale. Results Eleven articles were identified, 7 were rejected (4 not placebo controlled, 2 had no diphenhydramine, 1 not blinded), leaving 4 articles, that were included in the evaluation and scored 20, 21, 25 and 26 out of a maximum of 32. In these selected studies, a total of 162 people were examined, 65 on diphenhydramine, 63 on placebo and 34 in a crossover setting. There was a total of 13 dropouts. The crossover studies demonstrated significant effect; 27–56% reduction in 20 healthy volunteers and 21–26% reduction in 13 patients (originally 14, one outlier left out), whereas the active versus placebo studies did not. Conclusion In spite of the 60 years that the substance has been on the market, only few studies have properly evaluated the effect of diphenhydramine against cough. Presumptions about efficacy of diphenhydramine against cough in humans are not univocally substantiated in literature.     

Loss of p63 and cytokeratin 5/6 expression is associated with more aggressive tumors in endometrial carcinoma patients

p63 and cytokeratin (CK) 5/6 are markers of basal and squamous differentiation in several normal epithelia and human tumors and are also suggested to be markers of progenitor or stem cells in certain stratified epithelia. In endometrial carcinoma, there is very limited information about the expression pattern of p63 or CK5/6 and no prognostic information. The aim of our study was to examine whether the expression of these markers was associated with a certain tumor phenotype in terms of other biomarkers, clinicopathologic characteristics and patient prognosis. Immunohistochemical expression of p63 and CK5/6 was examined using tissue microarrays (TMAs) in a large population-based series of 276 endometrial carcinomas with long and complete follow-up. Selected cases of normal and hyperplastic endometrium were examined for comparison (n = 15). Absence of p63 expression (70%) was significantly associated with nonendometrioid carcinomas, high histologic grade (FIGO), higher mitotic count and tumor cell proliferation by Ki-67, microsatellite instability (MSI) and loss of hMSH6 expression. A tendency toward reduced patient survival was also seen (p = 0.098). Presence of CK5/6 expression was more frequent in endometrioid tumors with squamous differentiation, while loss of CK5/6 expression (54%) was significantly associated with high FIGO stage, reduced beta-catenin expression, MSI and reduced patient survival (p = 0.0001); the latter was also found within the endometrioid subgroup (p = 0.0004). Multivariate survival analysis revealed that loss of CK5/6 expression had an independent prognostic impact in addition to well-known prognostic variables. Expression of both markers was increased in simple hyperplasia compared with normal endometrium. In complex hyperplasia, p63 expression was also increased, whereas CK5/6 was positive in areas with squamous differentiation only. Thus, loss of p63 or CK5/6 was associated with features of aggressive tumors, and lack of CK5/6 was significantly associated with reduced survival in multivariate analysis.     

Vascular proliferation is important for clinical progress of endometrial cancer

Angiogenesis is essential for tumor growth, invasion, and metastatic spread. Whereas microvessel density (MVD) has been widely used as a measure of tumor-associated angiogenesis, we now wanted to examine the significance of other angiogenic markers, especially vascular proliferation (by Ki-67/factor VIII staining) and the degree of pericyte coverage [by alpha-smooth muscle actin (alpha-SMA)/factor VIII staining], in a large and population-based series of endometrial carcinoma with complete follow-up. Due to limited information on the role of lymphangiogenesis in these tumors, lymphatic vessel density (LVD) by LYVE-1 staining was also determined, as well as selected angiogenic factors [vascular endothelial growth factor (VEGF)-A, VEGF-C, VEGF-D and basic fibroblast growth factor (bFGF)], which could possibly be related to vascular proliferation and lymphangiogenesis. The information on angiogenic phenotype was related to clinicopathologic features and disease progress. Median vascular proliferation, as estimated by vascular proliferation index (VPI), was 3.9% and high VPI was associated with features of aggressive tumors and decreased survival. The prognostic effect of VPI was superior to that of MVD. Presence of pericyte coverage, as estimated by the alpha-SMA index (SMAI), was 35% and low SMAI was significantly associated with vascular invasion by tumor cells and impaired prognosis. Peritumoral lymphatic vessels (LVD-pt) were found in 39.5% of the cases and high LVD-pt was significantly associated with aggressive tumor features and decreased survival. In multivariate survival analysis, only the extent of vascular proliferation had independent prognostic effect, in addition to well-known clinicopathologic factors, whereas MVD did not have significant prognostic value. In conclusion, our study indicates that vascular proliferation is a meaningful variable in assessing the angiogenic phenotype of endometrial carcinoma.     

Even more suicide attempts in clinical trials with paroxetine randomised against placebo

Background

Following our previous publication we have received critical comments to our conclusions as well as new data that are strengthening our findings.

Results

With the new data, 11 suicide attempts among patients on paroxetine against 1 among patients on placebo, we found with a Bayesian technique that the posterior probability that medication with paroxetine is associated with an increased intensity per year of a suicide attempt is from 0.98 to 0.99, depending on the prior. We found that the comment to our article by GSK representatives contained errors, misunderstanding and unwillingness to accept Bayesian principles in the analysis of clinical trials.

Conclusion

We were in our previous publication, with preliminary data and a Bayesian approach, able to raise a concern that suicide attempts might be connected with the use of paroxetine. This suspicion has now been confirmed.