Drug repurposing: Iron in the fire for older drugs.

Repositioning or "repurposing" of existing therapies for indications of alternative disease is an attractive approach that can generate lower costs and require a shorter approval time than developing a de novo drug. The development of experimental drugs is time-consuming, expensive, and limited to a fairly small number of targets. The incorporation of separate and complementary data should be used, as each type of data set exposes a specific feature of organism knowledge Drug repurposing opportunities are often focused on sporadic findings or on time-consuming pre-clinical drug tests which are often not guided by hypothesis. In comparison, repurposing in-silico drugs is a new, hypothesis-driven method that takes advantage of big-data use. Nonetheless, the widespread use of omics technology, enhanced data storage, data sense, machine learning algorithms, and computational modeling all give unparalleled knowledge of the methods of action of biological processes and drugs, providing wide availability, for both disease-related data and drug-related data. This review has taken an in-depth look at the current state, possibilities, and limitations of further progress in the field of drug repositioning.

Assessing Drug Development Risk Using Big Data and Machine Learning.

Identifying new drug targets and developing safe and effective drugs is both challenging and risky. Furthermore, characterizing drug development risk, the probability that a drug will eventually receive regulatory approval, has been notoriously hard given the complexities of drug biology and clinical trials. This inherent risk is often misunderstood and mischaracterized, leading to inefficient allocation of resources and, as a result, an overall reduction in R&D productivity. Here we argue that the recent resurgence of Machine Learning in combination with the availability of data can provide a more accurate and unbiased estimate of drug development risk.

Low rate of intraperitoneal port placement in ovarian cancer patients, a population-based assessment.

INTRODUCTION: The National Comprehensive Cancer Network (NCCN) guidelines recommend intraperitoneal chemotherapy in optimally debulked stage III ovarian cancer patients. The objective of this investigation was to determine the rate of intraperitoneal port placement in patients undergoing surgery for ovarian cancer in a national database maintained by the American College of Surgeons. METHOD: We identified ovarian cancer patients in the National Surgical Quality Improvement Program database from 2006 to 2012. Demographics, comorbidities, operative outcomes, and postoperative complications were abstracted. Descriptive analyses were conducted using Wilcoxon rank-sum and Chi square tests, and multivariate regression models were used to analyze pre-operative and post-operative variables associated with intraperitoneal port placement. RESULTS: We identified 2659 ovarian cancer patients who underwent primary surgical management. Of these patients, only 128 (4.8%) had an intraperitoneal port placed at the time of surgery. In multivariable analyses, intraperitoneal ports were associated with body mass index ≤25, disseminated cancer, later portion of the study period (2009-2012), and operative time >200 min. Intraperitoneal port placement was not associated with any difference in surgical site infection, wound disruption, major postoperative complication, readmission within 30 days, or death within 30 days. DISCUSSION: Recent investigation of practice at NCCN institutions between 2003 and 2012 found only 35% of eligible ovarian cancer patients received intraperitoneal chemotherapy. Using intraperitoneal port placement as a surrogate for intraperitoneal chemotherapy administration, our investigation suggests an even lower rate (4.8%) nationally.

Optimal dynamic control approach in a multi-objective therapeutic scenario: Application to drug delivery in the treatment of prostate cancer.

Numerous problems encountered in computational biology can be formulated as optimization problems. In this context, optimization of drug release characteristics or dosing schedules for anticancer agents has become a prominent area not only for the development of new drugs, but also for established drugs. However, in complex systems, optimization of drug exposure is not a trivial task and cannot be efficiently addressed through trial-error simulation exercises. Finding a solution to those problems is a challenging task which requires more advanced strategies like optimal control theory. In this work, we perform an optimal control analysis on a previously developed computational model for the testosterone effects of triptorelin in prostate cancer patients with the goal of finding optimal drug-release characteristics. We demonstrate how numerical control optimization of non-linear models can be used to find better therapeutic approaches in order to improve the final outcome of the patients.

Patient Acceptance of Sustained Glaucoma Treatment Strategies.

PURPOSE: To assess patient acceptance of different methods for delivering sustained-release, intraocular pressure (IOP)-lowering medications. METHODS: Electronic surveys were administered to 150 patients at 2 glaucoma clinics. Participants were questioned on their willingness to accept: (1) drug-eluting contact lenses, (2) ring inserts (3) punctal plugs, and (4) subconjunctival injections as alternatives to IOP-lowering eye drops based on various success levels. Multivariable logistic regression models determined the association between device type and treatment acceptance adjusting for age, sex, study site, cost burden of drops, and previous contact lens use. RESULTS: The majority (69%) of participants were 55 to 74 years of age, and white (65%), and half were female. The majority of participants would accept contacts (59%), rings (51%), plugs (57%), and subconjunctival injections (52%) if they obviated glaucoma surgery; fewer would accept these devices if they reduced (23% to 35%) or eliminated (27% to 42%) drops. Most participants would also accept contacts (56%), plugs (55%), and subconjunctival injections (53%) if they were more effective than eye drops, whereas only 47% would accept a ring; fewer would accept any device if it were equally or less effective than drops. Participants were also 36% (95% confidence interval=0.44-0.92; P=0.02) less likely to accept rings and 32% (95% confidence interval=0.47-0.98; P=0.04) less likely to accept subconjunctival injections as compared with contacts. CONCLUSION: Most glaucoma patients considered sustained drug-delivery modalities acceptable alternatives to IOP-lowering eye drops, but only when they were said to obviate surgery or demonstrate greater efficacy than eye drops.

Use of Electronic Nicotine Delivery Systems Among Adolescents: Status of the Evidence and Public Health Recommendations.

Although the prevalence of tobacco smoking has been declining in recent years, the use of electronic nicotine delivery systems (ENDS) such as of electronic cigarettes, vaporizers, and hookahs has been steadily rising, especially among adolescents. ENDS are not only advertised to children, but their sale via the Internet has made them easily accessible to youth. In general, children perceive ENDS as safe, or at least safer than smoking traditional combustible tobacco products; however, exposure to nicotine may have deleterious effects on the developing brain. Concern also persists that ENDS may be a "starter" drug that may lead to further tobacco, drug, and/or alcohol use. In contrast to this precautionary stance that is associated with calls for legislative oversight of ENDS marketing and sales, harm reductionists claim that the risks posed by ENDS are minor in comparison with those of combustible tobacco products and that ENDS may be used as a means of nicotine replacement for smoking cessation, despite no concrete evidence to support this assertion. Many medical and health-related organizations have produced position statements concerning ENDS use, including among adolescents. This article summarizes the advantages and disadvantages of using ENDS espoused in these position statements, especially as they relate to use among adolescents. [Pediatr Ann. 2017;46(2):e69-e77.].

Control Law Design for Propofol Infusion to Regulate Depth of Hypnosis: A Nonlinear Control Strategy.

Maintaining the depth of hypnosis (DOH) during surgery is one of the major objectives of anesthesia infusion system. Continuous administration of Propofol infusion during surgical procedures is essential but increases the undue load of an anesthetist in operating room working in a multitasking setup. Manual and target controlled infusion (TCI) systems are not good at handling instabilities like blood pressure changes and heart rate variability arising due to interpatient variability. Patient safety, large interindividual variability, and less postoperative effects are the main factors to motivate automation in anesthesia. The idea of automated system for Propofol infusion excites the control engineers to come up with a more sophisticated and safe system that handles optimum delivery of drug during surgery and avoids postoperative effects. In contrast to most of the investigations with linear control strategies, the originality of this research work lies in employing a nonlinear control technique, backstepping, to track the desired hypnosis level of patients during surgery. This effort is envisioned to unleash the true capabilities of this nonlinear control technique for anesthesia systems used today in biomedical field. The working of the designed controller is studied on the real dataset of five patients undergoing surgery. The controller tracks the desired hypnosis level within the acceptable range for surgery.

The potential utility of high-intensity ultrasound to treat osteoarthritis.

Osteoarthritis (OA) is a widespread musculoskeletal disease that reduces quality of life and for which there is no cure. The treatment of OA is challenging since cartilage impedes the local and systemic delivery of therapeutic compounds (TCs). This review identifies high-intensity ultrasound (HIU) as a non-contact technique to modify articular cartilage and subchondral bone. HIU enables new approaches to overcome challenges associated with drug delivery to cartilage and new non-invasive approaches for the treatment of joint disease. Specifically, HIU has the potential to facilitate targeted drug delivery and release deep within cartilage, to repair soft tissue damage, and to physically alter tissue structures including cartilage and bone. The localized, non-invasive ultrasonic delivery of TCs to articular cartilage and subchondral bone appears to be a promising technique in the immediate future.

Trends in use of electronic nicotine delivery systems by adolescents.

Electronic nicotine delivery systems (ENDS) have been gaining in popularity. The few prevalence studies in adults have found that most ENDS users are current or former smokers. The objectives of this study were to estimate the prevalence of ENDS usage in adolescents, and examine the correlates of use. Self-administered written surveys assessing tobacco use behaviors were conducted in multiple waves as part of a larger intervention study in two large suburban high schools. The prevalence of past-30 day ENDS use increased from 0.9% in February 2010 to 2.3% in June 2011 (p=0.009). Current cigarette smokers had increased odds of past-30 day ENDS use in all study waves. When adjusted for school, grade, sex, race and smoking status, students in October 2010 (Adjusted OR 2.12; 95% confidence interval (CI): 1.12-4.02) and June 2011 (Adjusted OR 2.51; 95% CI: 1.17-4.71) had increased odds past-30 day ENDS use compared to February 2010. The prevalence of ENDS use doubled in this sample of high school students, and current cigarette smoking is the strongest predictor of current use. Continued monitoring of ENDS is needed to determine whether it increases the likelihood of cigarette smoking initiation and maintenance in youth.

Comparison of visual and ultraviolet light inspection versus DNA/protein biomarkers to assess product adherence with vaginal microbicide applicators.

BACKGROUND: Objective biomarkers of product use and protocol compliance are urgently needed. We compared the sensitivity and specificity of DNA and protein-based biomarkers, obtained from used vaginal gel applicators, to visual inspection of those applicators under ambient light (visual inspection of returned applicator [VIRA]) and ultraviolet light (UVL). METHODS: Forty women inserted hydroxyethylcellulose placebo gel vaginal applicators under direct observation. Applicators were evaluated by VIRA, UVL, and DNA/protein-based methods at 2 time points: within 7 days of the visit and after storing applicators for approximately 30 days. Semen biomarkers were assayed from vaginal swabs and returned applicators. RESULTS: The overall sensitivity and specificity of DNA and protein-based biomarkers in determining vaginal insertion versus sham handling of returned applicators were 98.3% and 100%, respectively, at both 7- and 30-day evaluations. The overall sensitivity and specificity of VIRA at 7 and 30 days after collection were significantly lower than those of DNA and protein-based biomarkers. Ultraviolet light inspection also had significantly lower overall sensitivity and overall specificity compared with DNA and protein biomarkers. The sensitivity of DNA and protein-based biomarkers for detecting insertion of wiped applicators was 95%, whereas the sensitivity of VIRA (range of 24%-28%) and UVL inspection (range, 38%-84%) was low for this subset. It was feasible to obtain semen biomarkers from vaginal swabs and returned used applicators. CONCLUSIONS: DNA and protein-based biomarkers offer significantly higher sensitivity and specificity compared with VIRA and UVL assessment. The accuracy of these objective biomarkers is maintained despite storage of returned products for approximately 30 days and under conditions potentially modeling field use.

Optimal robust control of drug delivery in cancer chemotherapy: a comparison between three control approaches.

During the drug delivery process in chemotherapy, both of the cancer cells and normal healthy cells may be killed. In this paper, three mathematical cell-kill models including log-kill hypothesis, Norton-Simon hypothesis and Emax hypothesis are considered. Three control approaches including optimal linear regulation, nonlinear optimal control based on variation of extremals and H∞-robust control based on µ-synthesis are developed. An appropriate cost function is defined such that the amount of required drug is minimized while the tumor volume is reduced. For the first time, performance of the system is investigated and compared for three control strategies; applied on three nonlinear models of the process. In additions, their efficiency is compared in the presence of model parametric uncertainties. It is observed that in the presence of model uncertainties, controller designed based on variation of extremals is more efficient than the linear regulation controller. However, H∞-robust control is more efficient in improving robust performance of the uncertain models with faster tumor reduction and minimum drug usage.

Dose finding when the target dose is on a plateau of a dose-response curve: comparison of fully sequential designs.

Consider the problem of estimating a dose with a certain response rate. Many multistage dose-finding designs for this problem were originally developed for oncology studies where the mean dose-response is strictly increasing in dose. In non-oncology phase II dose-finding studies, the dose-response curve often plateaus in the range of interest, and there are several doses with the mean response equal to the target. In this case, it is usually of interest to find the lowest of these doses because higher doses might have higher adverse event rates. It is often desirable to compare the response rate at the estimated target dose with a placebo and/or active control. We investigate which of the several known dose-finding methods developed for oncology phase I trials is the most suitable when the dose-response curve plateaus. Some of the designs tend to spread the allocation among the doses on the plateau. Others, such as the continual reassessment method and the t-statistic design, concentrate allocation at one of the doses with the t-statistic design selecting the lowest dose on the plateau more frequently.

The use of tissue sealants to deliver antibiotics to an orthopaedic surgical site with a titanium implant.

BACKGROUND: Orthopaedic surgery is associated with unacceptable infection rates that respond poorly to systemic antibiotics. The objective of this study was to use an animal model for orthopaedic implant infection to examine the ability of a new-generation fibrin tissue sealant to effectively deliver antibiotics to the surgical site. METHODS: The antibiotics cefazolin, fusidic acid or 5-fluorouracil were blended into Vitagel tissue sealant. The release rate of the drugs was measured using HPLC methods and bioactivity was measured by the zone of inhibition method with pathogenic Staphylococcus aureus. The antibiotic activity of the drug-loaded sealant was then tested in rats using infected orthopaedic surgical sites (titanium clip on spine). Efficacy was evaluated by residual bacterial counts on clips, clinical observations of infection, and histological findings. RESULTS: The drugs were released in a controlled manner over 2-4 days. All three antibiotics demonstrated strong antibacterial activity when released from the sealants. None of the treated animals demonstrated systemic illness. Post mortem dissection revealed a well-encapsulated abscess surrounding the titanium clip with erosion of the bony process. Using an inoculum of 1-5 × 10(3) CFU, treatment with antibiotic-loaded fibrin sealant demonstrated reduced infective swelling and reduced bacterial counts on surgical clip swabs compared to control rats or rats treated with antibiotic only. This model allowed for almost 100 % infectivity with a 0 % mortality rate due to infection, mimicking the clinical features of human implant infection. CONCLUSION: The results support the use of antibiotic-loaded commercially available fibrin sealants to prevent infection after implant surgery.

[Importance of the information systems in public health programs: diabetic patients databases]. / Importancia de los sistemas de información en programas de salud publica: bases de datos de pacientes diabéticos.

AIMS: To describe the characteristics of diabetic patients' population attended in the public health sector of Alta Gracia city. To analyze the use of amount of monthly dispensations as indicator of adherence to treatment, by comparing the results between settings. To assess the coordination of public facilities for patients attention. DESIGN: observational descriptive-analytical study. SETTINGS: Hospital Arturo Umberto Illia (HAUI) and Dirección de Salud Pública (DSP). Alta Gracia (province of Córdoba, Argentina). SUBJECTS: diabetic patients belonging to health programs at public facilities. MAIN MEASURES: demographic and epidemiological variables, amount of monthly dispensations, percentage of global adherence and coordination of settings. RESULTS: From diabetic patients' total (n=540): 52% were attended at HAUI, 39% at DSP, and 9% at both settings; 55% were female, and the average age was about 56 years old; 81% were type 2 Diabetes Mellitus (DM), 1% type 2 insulin-requiring DM, and 17% type 1 DM; the general mean of amount of monthly dispensations by patient was 4,9 in 12 months. Lack of trained personnel for information managing in both facilities was observed. CONCLUSIONS: The databases allowed knowing some demographic characteristics of diabetic population attended in the public sector of Alta Gracia. The dispensing frequency during 12 months was able to be used as an adherence to treatment indicator. The scarce coordination between care levels and jurisdictions (provincial and municipal) were confirmed. For decision making it is necessary to generate and maintain information systems.

Crowd sourcing a new paradigm for interactome driven drug target identification in Mycobacterium tuberculosis.

A decade since the availability of Mycobacterium tuberculosis (Mtb) genome sequence, no promising drug has seen the light of the day. This not only indicates the challenges in discovering new drugs but also suggests a gap in our current understanding of Mtb biology. We attempt to bridge this gap by carrying out extensive re-annotation and constructing a systems level protein interaction map of Mtb with an objective of finding novel drug target candidates. Towards this, we synergized crowd sourcing and social networking methods through an initiative 'Connect to Decode' (C2D) to generate the first and largest manually curated interactome of Mtb termed 'interactome pathway' (IPW), encompassing a total of 1434 proteins connected through 2575 functional relationships. Interactions leading to gene regulation, signal transduction, metabolism, structural complex formation have been catalogued. In the process, we have functionally annotated 87% of the Mtb genome in context of gene products. We further combine IPW with STRING based network to report central proteins, which may be assessed as potential drug targets for development of drugs with least possible side effects. The fact that five of the 17 predicted drug targets are already experimentally validated either genetically or biochemically lends credence to our unique approach.

Solanum tuberosum lectin-conjugated PLGA nanoparticles for nose-to-brain delivery: in vivo and in vitro evaluations.

Solanum tuberosum lectin (STL) conjugated poly (DL-lactic-co- glycolic acid) (PLGA) nanoparticle (STL-NP) was constructed in this paper as a novel biodegradable nose-to-brain drug delivery system. The in vitro uptake study showed markedly enhanced endocytosis of STL-NP compared to unmodified PLGA nanoparticles (NP) in Calu-3 cells and significant inhibition of uptake in the presence of inhibitor sugar (chitin hydrolysate). Following intranasal administration, coumarin-6 carried by STL-NP was rapidly absorbed into blood and brain. The AUC((0→12 h)) of coumarin-6 in blood, olfactory bulb, cerebrum and cerebellum were about 0.77-, 1.48-, 1.89- and 1.45-fold of those of NP, respectively (p < 0.05). STL-NP demonstrated 1.89-2.45 times (p < 0.01) higher brain targeting efficiency in different brain tissues than unmodified NP. Enhanced accumulation of STL-NP in the brain was also observed by near infrared fluorescence probe image following intranasal administration. The fluorescence signal of STL-NP appeared in olfactory bulb, cerebrum and brainstem early at 0.25 h. The signal in olfactory bulb decreased gradually after 2 h, while the obvious signal in brainstem, cerebrum and cerebellum lasted for more than 8 h. The STL-NP safety experiments showed mild cytotoxicity and negligible cilia irritation. These intriguing in vitro and in vivo results suggest that STL-NP might serve as a promising brain drug delivery system.