Sildenafil: emerging cardiovascular indications

The discovery in 1989 of sildenafil, a highly selective inhibitor of phosphodiesterase-5 (PDE-5), was the result of extensive research on chemical agents targeting PDE-5 that might potentially be useful in the treatment of coronary heart disease. Initial clinical studies on sildenafil in the early 1990s were not promising with respect to its antianginal potential. However, the incidental discovery of its antiimpotence effect led to its approval of for the treatment of erectile dysfunction. Thereafter, several reports of adverse cardiac events in patients on sildenafil raised concerns about its safety in cardiovascular disorders. Novel therapeutic indications are emerging for sildenafil with the recent discovery that PDE-5 is expressed in various other tissues such as the arterial vasculature, including pulmonary and coronary arteries, venous vasculature, skeletal muscles, platelets, and visceral and tracheobronchial muscles. In this review we briefly summarize the pharmacology of sildenafil and the current available evidence on its potential therapeutic applications in cardiovascular disorders.     

Findings in 12-core transrectal ultrasound-guided prostate needle biopsy that predict more advanced cancer at prostatectomy: analysis of 388 biopsy-prostatectomy pairs

We analyzed 5 features on 12-core transrectal ultrasound-guided prostate needle biopsy (TRUS) to predict the extent of cancer at radical prostatectomy (RP). In 388 TRUS-RP pairs, number of positive cores (NPC), percentage of each core involved (%PC), perineural invasion (PNI), Gleason score (GS), distribution of positive cores (DPC), and preoperative prostate-specific antigen (PSA) were correlated with extraprostatic extension (EPE), seminal vesicle invasion (SVI), positive surgical margin (R1), positive lymph nodes (N1), and tumor volume. All features predicted EPE and SVI. NPC, GS, %PC, and PNI strongly predicted R1 status. RP tumor volume was directly proportional to the NPC and %PC. PSA alone and with selected biopsy findings correlated with tumor volume, stage, SVI, and N1 (P < .0001). Contiguous DPC was a significant risk for EPE and SVI (P < .0001) compared with isolated positive cores. Findings at 12-core TRUS along with preoperative PSA reliably predict advanced local disease and have practical value as guides to effective planning for surgical resections.     

Prevalence of post-traumatic stress disorder among children and adolescents who survive road traffic crashes: A systematic review of the international literature

While road traffic crashes are known to have a significant impact in terms of deaths and hospitalisations, quantifying the burden of psychological sequelae is more challenging. This systematic review critically evaluates published studies designed to estimate the prevalence of post‐traumatic stress disorder among children and adolescents who have survived a road crash. Most studies have focused on injured school‐aged children and adolescents, and estimate the occurrence of this condition to be between 12% and 46% in the first 4 months following crash involvement and between 13% and 25% 4–12 months following the crash. The relatively high prevalence of post‐traumatic stress disorder following one of the commonest causes of injury underscores the need for greater vigilance and active management to mitigate the adverse consequences on the health and development of young crash survivors. The findings also emphasise the important role that child health professionals must play in promoting strategies that prevent road traffic crashes.     

The Association of Lung Clearance Index with COPD and FEV1 Reduction in ‘Men Born in 1914’

Lung Clearance Index (LCI) provides an overall measurement of ventilation inhomogeneity. This population-based study examines whether LCI predicts pulmonary obstruction and incidence of chronic obstructive pulmonary disease (COPD) events over a long-term follow-up. Multiple breath nitrogen washout and spirometry were performed in 674 men from the cohort “Men born in 1914” at age 55 years. Subjects were classified into quartiles (Q) of LCI and according to LCI above and below upper limit of normal (ULN). Incidence of COPD events (COPD hospitalisations or COPD-related deaths) were monitored over the remaining life span of the men, by linkage with national hospital registers. In addition, development of pulmonary obstruction (i.e., FEV¹/vital capacity below lower limit of normal (LLN)) was studied in 387 men who were re-examined with spirometry at 68 years of age. Over 44 years of follow-up, there were 85 incident COPD events. Hazards ratios (HRs) for COPD across quartiles of LCI were: Q1 1.00 (reference), Q2 1.30 (95% confidence interval: 0.61–2.74), Q3 1.97 (0.97–3.98) and Q4 3.99 (2.06–7.71) (p value for trend <0.001). This relationship remained significant after adjustments for confounding factors, including smoking and FEV¹ (HR, Q4 vs Q1: 2.34 (1.17–4.69); p value for trend: 0.006). Reduction of FEV¹ between 55 and 68 years of age and incidence of pulmonary obstruction was highest in those with high LCI. High LCI is associated with future development of pulmonary obstruction and incidence of COPD hospitalisations in men from the general population.     

Prodrug strategies for antihypertensives

There is a great emphasis on research to discover methods aimed at enhancing the efficacy of drugs and reducing their toxicity and unwanted side effects. Prodrugs are biologically inactive compounds that are converted to actual drug molecule, through biotransformation, that combine with the receptors to produce the biological action. Prodrugs can thus be considered as drugs containing specialized nontoxic protective groups utilized in a transient manner to alter or eliminate the undesirable properties of the parent drug molecule. Hypertension is one of the leading risk factors for cardiovascular disease and represents a major health and economic burden. Most of the drugs for cardiovascular diseases have low oral bioavailability, short duration of action, first pass metabolism and variable lipohilicities. Out of the need to overcome these limitations, various prodrugs have been designed for antihypertensive agents. This review extensively focuses on various strategies used for design and development of prodrugs for the various classes of antihypertensives, emphasizing on the details regarding the need for prodrug synthesis for each class, structure, type of modification and goal achieved. It also provides an insight into the major advances in the field of antihypertensive prodrug research.