Search algorithms as a framework for the optimization of drug combinations

Combination therapies are often needed for effective clinical outcomes in the management of complex diseases, but presently they are generally based on empirical clinical experience. Here we suggest a novel application of search algorithms, originally developed for digital communication, modified to optimize combinations of therapeutic interventions. In biological experiments measuring the restoration of the decline with age in heart function and exercise capacity in Drosophila melanogaster, we found that search algorithms correctly identified optimal combinations of four drugs with only one third of the tests performed in a fully factorial search. In experiments identifying combinations of three doses of up to six drugs for selective killing of human cancer cells, search algorithms resulted in a highly significant enrichment of selective combinations compared with random searches. In simulations using a network model of cell death, we found that the search algorithms identified the optimal combinations of 6-9 interventions in 80-90% of tests, compared with 15-30% for an equivalent random search. These findings suggest that modified search algorithms from information theory have the potential to enhance the discovery of novel therapeutic drug combinations. This report also helps to frame a biomedical problem that will benefit from an interdisciplinary effort and suggests a general strategy for its solution.Comment: 36 pages, 10 figures, revised versio

'They're battle scars, I wear them well': A phenomenological exploration of young women's experiences of building resilience following adversity in adolescence

This is an Author's Accepted Manuscript of an article published in Journal of Youth Studies, 13(3), 273 - 290, 2010 [copyright Taylor & Francis], available online at: http://www.tandfonline.com/10.1080/13676260903520886.This phenomenological study explored young women's accounts of building resilience following chains of adverse life experiences in adolescence. Six participants were interviewed, aged 20–25 years. Most had, or were receiving, a university education. They described their recovery from adversity as starting with certain pivotal moments, followed by both short-term and longer-term strategies. Short-term strategies tended to offer respite from distress and emotional comfort, increased clarity about their experiences and social affirmation. Recovery involved gaining new perspectives on their adverse situation and recovering a positive self-image through three longer-term strategies. These involved making visible progress in their education, rebuilding relationships with family and friends, and participating in the ‘normalizing’ activities and developmental projects of adolescence. Participants believed that they were stronger and more compassionate although positive achievements co-existed with some regrets. Most perceived the adversity as catalyzing personal growth. These accounts of resilience revealed the complex psychosocial processes and resources available to some adolescents

The Role of Ivabradine in the Management of Angina Pectoris

Stable angina pectoris affects 2–4 % of the population in Western countries and entails an annual risk of death and nonfatal myocardial infarction of 1–2 % and 3 %, respectively. Heart rate (HR) is linearly related to myocardial oxygen consumption and coronary blood flow, both at rest and during stress. HR reduction is a key target for the prevention of ischemia/angina and is an important mechanism of action of drugs which are recommended as first line therapy for the treatment of angina in clinical guidelines. However, many patients are often unable to tolerate the doses of beta blocker or non-dihydropyridine calcium antagonists required to achieve the desired symptom control. The selective pacemaker current inhibitor ivabradine was developed as a drug for the management of patients with angina pectoris, through its ability to reduce HR specifically. The available data suggest that ivabradine is a well-tolerated and effective anti-anginal agent and it is recommended as a second-line agent for relief of angina in guidelines. However, recent clinical trials of ivabradine have failed to show prognostic benefit and have raised potential concerns about safety. This article will review the available evidence base for the current role of ivabradine in the management of patients with symptomatic angina pectoris in the context of stable coronary artery disease

Economic burden of adverse drug reactions and potential for pharmacogenomic testing in Singaporean adults.

Adverse drug reactions (ADRs) contribute to hospitalization but data on its economic burden is scant. Pre-emptive pharmacogenetic (PGx) testing can potentially reduce ADRs and its associated costs. The objectives of this study were to quantify the economic burden of ADRs and to estimate the breakeven cost of pre-emptive PGx testing in Singapore. We collected itemized costs for 1000 random non-elective hospitalizations of adults admitted to a tertiary-care general hospital in Singapore. The presence of ADRs at admission and their clinical characteristics were reported previously. The economic burden of ADRs was assessed from two perspectives: (1) Total cost and (2) incremental costs. The breakeven cost of PGx testing was estimated by dividing avoidable hospitalization costs for ADRs due to selected drugs by the number of patients taking those drugs. The total cost of 81 admissions caused by ADRs was US$570,404. Costs were significantly higher for bleeding/elevated international normalized ratio (US$9906 vs. US$2251, p = 6.58 × 10-3) compared to other ADRs, and for drugs acting on the blood coagulation system (US$9884 vs. US$2229, p = 4.41 × 10-3) compared to other drug classes. There were higher incremental laboratory costs due to ADRs causing or being present at admission. The estimated breakeven cost of a pre-emptive PGx test for patients taking warfarin, clopidogrel, chemotherapeutic and neuropsychiatric drugs was US$114 per patient. These results suggest that future studies designed to directly measure the clinical and cost impact of a pre-emptive genotyping program will help inform clinical practice and health policy decisions

Evidence and Extrapolation: Mechanisms for Regulating Off-Label Uses of Drugs and Devices

A recurring, foundational issue for evidence-based regulation is deciding whether to extend governmental approval from an existing use with sufficient current evidence of safety and efficacy to a novel use for which such evidence is currently lacking. This extrapolation issue arises in the medicines context when an approved drug or device that is already being marketed is being considered (1) for new conditions (such as off-label diagnostic categories), (2) for new patients (such as new subpopulations), (3) for new dosages or durations, or (4) as the basis for approving a related drug or device (such as a generic or biosimilar drug). Although the logic of preapproval testing and the precautionary principle—first, do no harm—would counsel in favor of prohibiting extrapolation approvals until after traditional safety and efficacy evidence exists, such delays would unreasonably sacrifice beneficial uses. The harm of accessing unsafe products must be balanced against the harm of restricting access to effective products. In fact, the Food and Drug Administration\u27s (FDA\u27s) current regulations in many ways reject the precautionary principle because they largely permit individual physicians to prescribe medications for off-label uses before any testing tailored to those uses has been done. The FDA\u27s approach empowers physicians, but overshoots the mark by allowing enduring use of drugs and devices with insubstantial support of safety and efficacy. This Article instead proposes a more dynamic and evolving evidence-based regime that charts a course between the Scylla and Charybdis of the overly conservative precautionary principle on one hand, and the overly liberal FDA regime on the other. Our approach calls for improvements in reporting, testing, and enforcement regulations to provide a more layered and nuanced system of regulatory incentives. First, we propose a more thoroughgoing reporting of off-label use (via the disclosure of diagnostic codes and detailing data) in manufacturers\u27 annual reports to the FDA, in the adverse event reports to the FDA, in Medicare/Medicaid reimbursement requests, and, for a subset of FDA-designated drugs, in prescriptions themselves. Second, we would substantially expand the agency\u27s utilization of postmarket testing, and we provide a novel framework for evaluating the need for postmarket testing. Finally, our approach calls for a tiered labeling system that would allow regulators and courts to draw finer reimbursement and liability distinctions among various drug uses, and would provide the agency both the regulatory teeth and the flexibility it presently lacks. Together, these reforms would improve the role of the FDA in the informational marketplace underlying physicians\u27 prescribing decisions. This evolutionary extrapolation framework could also be applied to other contexts

Alcohol use and alcohol-use disorders among older adults in India: a literature review.

OBJECTIVES: With changing attitudes to alcohol and an increasing life span in India, the prevalence of alcohol use and misuse in successive cohorts of older people is likely to increase. In this paper, we attempt to review the most recent evidence covering alcohol use and alcohol-use disorders in the Indian elderly. METHODS: PubMed, PsycINFO and Indmed databases were searched using relevant keywords. Papers meeting eligibility criteria were selected through a sequential process of screening title, abstract and full text. Data were extracted into Excel sheets. RESULTS: There was a dearth of pan-national studies. There were several methodological issues with many studies especially related to measurement. A substantial proportion of individuals above the age of 50 years are current consumers of alcohol and the prevalence is generally higher in urban compared to rural areas. Older women are generally likely to be alcohol abstainers. The general trend appears to be a reduction in current drinking among successive age cohorts over the age of 50. Alcohol consumption in the older adults is associated with educational status, health status, chronic morbidity, employment status, socioeconomic status, auditory/locomotor impairment and asthma. CONCLUSION: Alcohol use and misuse is a problem among the Indian older adults. With socio-demographic changes that will further increase longevity, this problem is likely to increase and policy-makers need to plan for it. Future research needs to improve validity and reliability in study methodology, as well as add to the current evidence base