Fifty-Eight Years and Counting: High-Impact Publishing in Computational Pharmaceutical Sciences and Mechanism-Based Modeling

With this issue of the Journal of Pharmaceutical Sciences, we celebrate the nearly 6 decades of contributions to mechanistic-based modeling and computational pharmaceutical sciences. Along with its predecessor, The Journal of the American Pharmaceutical Association: Scientific Edition first published in 1911, JPharmSci has been a leader in the advancement of pharmaceutical sciences beginning with its inaugural edition in 1961. As one of the first scientific journals focusing on pharmaceutical sciences, JPharmSci has established a reputation for publishing high-quality research articles using computational methods and mechanism-based modeling. The journal’s publication record is remarkable. With over 15,000 articles, 3000 notes, and more than 650 reviews from industry, academia, and regulatory agencies around the world, JPharmSci has truly been the leader in advancing pharmaceutical sciences.     

Enabling an HCV Treatment Revolution and the Frontiers of Solid Solution Formulation

The discovery and development of small molecule direct acting antiviral (DAA) drugs has revolutionized the treatment of Hepatitis C virus infection. Formulations based on solid solution technology have enabled the oral absorption of the majority of commercial DAA products starting with the approval of telaprevir in 2011. A particularly important class of DAA drugs are those targeting nonstructural protein 5A. In addition to simply promoting the oral absorption of nonstructural protein 5A compounds, solid solutions have been used within this class of compounds to mitigate changes in absorption caused by variations in food and stomach pH. This commentary reviews the formulation and biopharmaceutical aspects of the solid solutions used to enable the recent revolution in Hepatitis C virus infection treatment.     

A 2-Year Psychological Autopsy Study of Completed Suicides in the Athens Greater Area,Greece

ObjectiveTo study the characteristics of a sample of suicide victims from the Athens Greater Area using the psychological autopsy method for the first time in Greece.MethodsWe studied all recorded cases of completed suicide for the 2-year time period November 2007-October 2009 collecting data from the victims'' forensic records as well as from the completion of a psychological autopsy questionnaire.Results335 persons were recorded as suicide victims. We contacted relatives of 256 victims interviewing those of 248 of them (96.9%). The differences regarding sex, marital and employment status between our sample and the general population were statistically significant (p<0.001). The male/female ratio was 3:1. Comparatively more victims were divorced, separated or single and a greater proportion were pensioners or unemployed. 26.0% of the victims had history of prior attempts (64.4% once, 20.3% twice and 15.3% more times). 42.6% were taking psychiatric medication-significantly more women than men according to blood tests; 14.2% had been hospitalized in a psychiatric clinic the year prior to their death. 84.8% have deceased at the place of suicide and 15.2% died in the hospital; 80.3% died indoors and 19.7% outdoors. Men died primarily by hanging or shooting by a firearm while women preferred jumping from height instead (p<0.001). As many as 48.8% had expressed their intention to die to their relatives; 26.6% left a suicide note.ConclusionOur study has shown that the psychological autopsy method is applicable and widely accepted yielding results comparable to the international literature. Specific parameters associated with suicide have been studied for the first time in Greece.     

Efficacy of manidipine/delapril versus losartan/hydrochlorothiazide fixed combinations in patients with hypertension and diabetes

BACKGROUND: Hypertension markedly increases the already high risk for cardiovascular complications in patients with diabetes mellitus. Less than one in eight patients with hypertension and type 2 diabetes have adequately controlled blood pressure. As a result, antihypertensive combinations are now widely used in management of hypertension associated with diabetes. METHODS: This double-blind study investigated efficacy of a new fixed dose combination of a calcium antagonist, manidipine 10 mg, and an angiotensin-converting enzyme inhibitor, delapril 30 mg, compared with a combination of an angiotensin receptor blocker, losartan 50 mg, and a diuretic, hydrochlorothiazide 12.5 mg. Patients with hypertension (blood pressure > or = 130/80 mmHg) with controlled type 2 diabetes (HbA1c < or = 7.5%) were randomized to manidipine/delapril (n = 153) or losartan/hydrochlorothiazide (n = 161), administered once daily for 12 weeks. Patients underwent ambulatory blood pressure monitor evaluation at baseline and end of treatment. RESULTS: Mean decreases in 24-h systolic blood pressure were seen with both manidipine/delapril (-9.3 mmHg) and losartan/hydrochlorothiazide (-10.7 mmHg) combinations. The mean (95% confidence interval) treatment difference was -1.4 (-4.5/1.8) mmHg, demonstrating noninferiority of the manidipine/delapril combination. Reduction in 24-h diastolic blood pressure (-4.6 versus -4.5 mmHg) and daytime (systolic blood pressure -10.5 versus -11.1 mmHg) and night-time (systolic blood pressure -7.1 versus -9.3 mmHg) blood pressure were also not significantly different between treatments. Compliance and adverse events were comparable for both groups. CONCLUSION: The study demonstrated that the combination of manidipine and delapril is as effective as losartan and hydrochlorothiazide in treatment of hypertension in type 2 diabetes.     

Room for improvement in the treatment of pancreatic cancer: Novel opportunities from gene targeted therapy

Pancreatic cancer is one of the highest and in fact, unchanged mortality-associated tumor, with an exceptionally low survival rate due to its challenging diagnostic approach. So far, its treatment is based on a combination of approaches (such as surgical resection with or rarely without chemotherapeutic agents), but with finite limits. Thus, looking for additional space to improve pancreatic tumorigenesis therapeutic approach, research has focused on gene therapy with unexpectedly growing horizons not only for the treatment of inoperable pancreatic disease, but also for its early stages. In vivo gene delivery viral vectors, despite few disadvantages (possible immunogenicity, toxicity, mutagenicity, or high cost), could be one of the most efficient cancer gene therapeutic strategies for clinical application due to their superiority compared with other systems (ex vivo delivery strategies). Their dominance consists of simple preparation, easy operation and a wide range of functions. Adenoviruses are one of the most common used vectors, inducing strong immune as well as inflammatory reactions. Oncolytic virotherapy, using the above mentioned in vivo viral vectors, is one of the most promising non-pathogenic, highly-selective cytotoxic anti-cancer therapy using anti-cancer agents with high anti-tumor potency and strong oncolytic effect. There have been a variety of targeted therapeutic and pre-clinical strategies tested for gene therapy in pancreatic cancer such as gene-editing systems (e.g., clustered regularly interspaced palindromic repeats-Cas9), RNA interference technology (e.g., microRNAs, short hairpin RNA or small interfering RNA), adoptive immunotherapy and vaccination (e.g., chimeric antigen receptor T-cell therapy) with encouraging results.     

Pathogenesis of chronic heart failure: cardiovascular aging,risk factors,comorbidities, and disease modifiers

Heart Failure Reviews - Chronic heart failure (HF) is rare in the young and common in the elderly in the Western world. HF in the young is usually due to specific causes, predominantly or...     

Calcium Channels Blockers and Progression of Kidney Disease

We aimed to compare regimens including calcium channel blockers (CCBs) to non-CCBs agents such as angiotensin-converting enzyme inhibitors (ACEIs) and/or angiotensin receptor blockers (ARBs) regarding progression in nondiabetic chronic kidney disease (CKD). There was no difference in reaching serum creatinine concentration (Cr) to more than 7 mg/dL and/or commencing dialysis. The CCB group compared to non-CCBs displayed a higher mean Cr (as well as a higher rate of increase) and proteinuria. Medication with CCBs and younger age were associated with adverse renal function outcome. It is concluded that CCBs are less effective than ACEIs or ARBs on preserving renal function and ameliorating proteinuria in nondiabetic CKD.