No abstract

Given that cardiovascular safety liabilities remain a major cause of drug attrition during preclinical and clinical development, adverse drug reactions, and post‐approval withdrawal of medicines, the Medical Research Council Centre for Drug Safety Science hosted a workshop to discuss current challenges in determining, understanding and addressing ‘Cardiovascular Toxicity of Medicines’. This article summarizes the key discussions from the workshop that aimed to address three major questions: (i) what are the key cardiovascular safety liabilities in drug discovery, drug development and clinical practice? (ii) how good are preclinical and clinical strategies for detecting cardiovascular liabilities? and (iii) do we have a mechanistic understanding of these liabilities? It was concluded that in order to understand, address and ultimately reduce cardiovascular safety liabilities of new therapeutic agents there is an urgent need to: Fully characterize the incidence, prevalence and impact of drug‐induced cardiovascular issues at all stages of the drug development process. Ascertain the predictive value of existing non‐clinical models and assays towards the clinical outcome. Understand the mechanistic basis of cardiovascular liabilities; by addressing areas where it is currently not possible to predict clinical outcome based on preclinical safety data. Provide scientists in all disciplines with additional skills to enable them to better integrate preclinical and clinical data and to better understand the biological and clinical significance of observed changes. Develop more appropriate, highly relevant and predictive tools and assays to identify and wherever feasible to eliminate cardiovascular safety liabilities from molecules and wherever appropriate to develop clinically relevant and reliable safety biomarkers.

Twelve women with vaginal Candida krusei infection were evaluated. In vitro antifungal susceptibility testing and molecular typing were performed. Patients infected with C. krusei frequently had refractory vulvovaginal signs and symptoms that were otherwise indistinguishable from vaginitis due to other yeasts. Patients were 32-63 years old and had previously received multiple courses of antimycotic agents, including fluconazole and miconazole. The most active azole in vitro was clotrimazole, with a 90% minimum inhibitory concentration of 0.25 microg/mL. Four of 6 patients treated with boric acid had clinical and mycological cure. Two dominant genotypes of C. krusei were identified via contour-clamped homogenous electrical field analysis. No major genotypic change was observed in successive isolates from the same patient in most cases, suggesting that these refractory cases were relapses. C. krusei is a rare but important cause of refractory vaginitis and is unique because of its intrinsic resistance to fluconazole.

Background Bacterial biofilms are aggregation or collection of different bacterial cells which are covered by self-produced extracellular matrix and are attached to a substratum. Generally, under stress or in unfavorable conditions, free planktonic bacteria transform themselves into bacterial biofilms and become sessile. Main body Various mechanisms involving interaction between antimicrobial and biofilm matrix components, reduced growth rates, and genes conferring antibiotic resistance have been described to contribute to enhanced resistance. Quorum sensing and multi-drug resistance efflux pumps are known to regulate the internal environment within the biofilm as well as biofilm formation; they also protect cells from antibiotic attack or immune attacks. This review summarizes data supporting the importance of exopolysaccharides during biofilm formation and its role in antibiotic resistance. Conclusions Involvement of quorum sensing and efflux pumps in antibiotic resistance in association with exopolysaccharides. Also, strategies to overcome or attack biofilms are provided.

We have read with interest the recently published article by Shadania et al, entitled 'A retrospective 7-year study of aluminum phosphide poisoning in Tehran: Opportunities for prevention'. 1 As this is a common poisoning in Iran, [2][3][4][5][6] we appreciate the opportunity to read about this poisoning.There are two kinds of rice tablets which are used in Iran to protect stored grains and rice from rodents and other household pests. Aluminum phosphide (ALP), a fumigant which releases toxic phosphine when it comes into contact with moisture, is the most common type of rice tablet. It is marketed as 3-gm tablets (Phostoxin Celphos, Quickphos and Phostek). Another tablet used for this purpose is a herbal product also known as Rice Tablet (Figure 1). Although public sale of ALP tablets is banned in Iran, it is still available. Both rice tablets are indistinguishable to the lay person and are used often for suicide purpose. The points which help in differentiating the two are change in appearance of the tablet when exposed to air (Figure 2) and its garlic-like odor. The herbal rice tablet is potentially harmless as it contains only botanical products unlike ALP, which releases phosphine.When a poisoned patient is brought to the emergency room it is difficult to differentiate the two. However, from looking at the container brought by patient's relatives and clinical features, it is possible to differentiate the two. Further a silver nitrate breath test can be performed to detect phosphine. The mortality rate in ALP poisoning is high, resulting in 55-70% mortality in different studies. 3,7 The blood pH was higher in this study (mean 7.3) unlike the study by Singh et al. 7 where of 195 patients, 180 blood pH <7.3 with 62 having pH <6.9 in the study by Shadnia et al mortality was 31%. It is quite possible that in this study mortality was lower due to ingestion of exposed tablets which have lower phosphine content. As soon as ALP comes in contact with moisture, some phosphine gets released with resultant lower phosphine content in these exposed tablets and when someone ingests these tablets, lesser phosphine will be released in gut, resulting in less severe toxicity.A recent report from India suggests that a change in formulation from tablet to granulated powder has lead