How many SNPs does a genome-wide haplotype map require?

We derive and compare several estimates of the number of SNPs that would be required to form the basis of a complete haplotype survey of the human genome. Our estimates make use of reports published by Stephens et al. [1], Patil et al. [2] and Daly et al. [3]. The estimated number of SNPs required for a genome-wide haplotype survey ranges from 180K (based on a European sample of 16 chromosomes) to 600K (based on an ethnically diverse sample of 164 chromosomes). We discuss the implications of using cohorts of different size and ethnic composition and the usefulness of public SNP databases for this effort. Finally, we estimate the experimental effort and cost required to complete a genome-wide haplotype survey.     

Pharmacovigilance of over-the-counter products based in community pharmacy: a feasible option?

PURPOSE: With the increasing range of potent medicines available for sale 'over-the-counter' (OTC) in community pharmacies, this feasibility study set out to develop and validate a method for the pharmacovigilance of OTC medicine, using ibuprofen as a model. METHOD: A trained network of community pharmacies (n=61) in Grampian, Scotland, tested different methods for recruiting people buying ibuprofen for their own use (pilot 1) and then used the 'best' method to test two methods of follow-up (pilot 2). RESULTS: Recruitment rates-method 1 (pharmacy staff inserted the patient information sheet and recruitment questionnaire in the shop bag of eligible subjects): 18% (41/227) of questionnaires issued; method 2 (staff explained the study and asked eligible subjects to complete the questionnaire outwith the pharmacy): 31% (61/194); method 3 (staff explained the study and asked eligible subjects to complete the questionnaire in the pharmacy): 52% (100/192). A further 200 subjects were recruited in pilot 2. The majority of recruits (n=402) were female (75%), mean age 43 years (range 18-84 years), 73% drank alcohol, 72% were non-smokers, and 56% were in the two most affluent socio-economic categories. There was a strong association between the drug dose data collected prospectively and that collected retrospectively. The average response to postal follow-up was 80% (315/392) at 1 week and 79% (308/390) at 2 months. CONCLUSION: The study has confirmed the support of pharmacy personnel in undertaking research and indicated the feasibility of a major pharmacovigilance project of OTC medicines.     

Community pharmacists’ knowledge and perspectives of reporting adverse drug reactions in Australia: a cross-sectional survey

International Journal of Clinical Pharmacy - Background Under-reporting of adverse drug reactions (ADRs) by healthcare professionals is prevalent worldwide. Community pharmacists are the most...     

Evaluation of patients’ experiences with antidepressants reported by means of a medicine reporting system

Objective To assess experiences related to antidepressant use reported to an internet-based medicine reporting system and to compare the nature of the side effects reported by patients with those reported by health care professionals (HCPs). Methods All reports submitted from May 2004 to May 2005 to an internet-based medicine reporting system in The Netherlands related to the use of antidepressants were analysed. Spontaneous reports of adverse drug reactions on antidepressants from HCPs received by The Netherlands Pharmacovigilance Centre Lareb from May 2004 to May 2005 were included for comparison. Results Of the 2232 individuals who submitted a report to the internet-based medicine reporting system, 258 submitted a report on antidepressants. Of these, 92 individuals (36%) reported on effectiveness, 40 (16%) of whom reported on ineffectiveness, and 217 (84%) submitted a report on side effects, with 202 (78%) reporting a total of 630 side effects that were experienced as negative. Fourteen individuals (5%) reported a practical issue and four (2%) reported a reimbursement issue. Of all 630 side effects reported, 48% resulted in the patient discontinuing the antidepressant therapy; of these 29% did not inform their HCP. Of all the side effects reported, 52% were perceived as “very negative”. In comparison to the side effects reported by HCPs, patients more often reported apathy, excessive sweating, ineffectiveness, somnolence, insomnia, sexual problems and weight increase. Conclusion Patients report the ineffectiveness and side effects of antidepressant therapy as negative and leading to discontinuation of the therapy. Patients and HCPs differ in the nature of the reported side effects. Patient experiences should be included in the evaluation of antidepressant treatment in clinical practice.     

Saga of renin-angiotensin system and calcium channels in hypertensive diabetics: does it have a therapeutic edge?

Current understanding of the genesis of diabetic vascular disease suggests that vascular complications, such as atherosclerosis and hypertension, are associated with changes in structural and functional parameters. Experimental and epidemiological data suggest that activation of the renin-angiotensin-aldosterone system plays an important role in the development of micro- and macro-vascular complications. Most of the negative cardiovascular actions of angiotensin II are mediated through AT1 receptors, whereas the AT2 receptors mediate largely beneficial effects. Hence, compared to angiotensin converting enzyme inhibitors (ACEIs), selective AT1 receptor blockers (ARBs) should provide additional end organ protection via AT2 receptors activation. Although ACEIs are useful therapeutically, they are being currently displaced by ARBs. Enhanced calcium ion channel activity is reported in vascular smooth muscles from diabetic animal models. Clinical benefits of calcium channel blockers (CCBs) in diabetic hypertensive patients are controversial, but there is increasing experimental evidence for the beneficial effects of dihydropyridine-type CCBs. Although the treatment of hypertension in diabetics reduces cardiovascular and microvascular complications, the ideal strategy for treating hypertension in diabetics has not been well defined and warrants a combination approach. Only limited clinical data regarding the use of ARBs in combination with CCBs in diabetics are available. The experimental data suggest that combination of a CCB and an AT1 receptor blocker, or a hypothetical dual blocker of AT1 receptors as well as of calcium channels would be an ideal regimen. There is, however, no conclusive clinical evidence to support the combined use of these drugs. This review highlights the available experimental data that support the therapeutic benefits of this combination.     

Clinical pharmacy: Is it a credible academic discipline?

A review of the development of clinical pharmacy in the UK reveals that its origins stem from the mid 70's when many undergraduates received short clinical attachments with physicians. The evolution was accelerated by the appointment of pharmacists who held joint university and hospital contracts. Innovative postgraduate diploma and masters programmes in clinical pharmacy established in the early 80's secured a steady supply of skilled individuals to undertake the various roles that arose. Acceptance within academia was marked by the establishment of a series of Chairs in clinical pharmacy in the late 80's and early 90's along with PhD research programmes in clinical pharmacy. As an emerging discipline the forthcoming university research assessment exercise will mark a milestone in the progress of clinical pharmacy. There is, however, concern that the assessment exercise will use criteria not entirely sympathetic to the uniqueness of clinical pharmacy.     

Vascular effects of prostacyclin: does activation of PPARδ play a role?

Prostacyclin (PGI(2)) is a potent vasodilator that exerts multiple vasoprotective effects in the cardiovascular system. The effects of PGI(2) are mediated by activation of the cell membrane G-protein-coupled PGI(2) receptor (IP receptor). More recently, however, it has been suggested that PGI(2) might also serve as an endogenous ligand and activator of nuclear peroxisome proliferator-activated receptorδ (PPARδ). Consistent with this concept, studies designed to define pharmacological properties of stable PGI(2) analogs revealed that beneficial effects of these compounds appear to be mediated, in part, by activation of PPARδ. This review discusses emerging evidence regarding the contribution of PPARδ activation to vasoprotective and regenerative functions of PGI(2) and stable analogs of PGI(2).     

The ICPC coding system in pharmacy: developing a subset. ICPC‐Ph.

The ICPC system is a coding system developed for general medical practice, to be able to code the GPpatient encounters and other actions. Some of the codes can be easily used by community pharmacists to code complaints and diseases in pharmaceutical care practice. We developed a subset of the ICPC codes for community pharmacists. This article describes the method used and the resulting ICPCPh list.     

Fluoroquinolone-associated tendon-rupture: a summary of reports in the Food and Drug Administration’s adverse event reporting system

Objective: To review and summarize reports of tendon rupture associated with each fluoroquinolone (FQ) currently marketed in the United States (US), as reported to the FDA’s Adverse Event Reporting System (FAERS).

Methods: FAERS data were reviewed for reports of tendon rupture associated with each FQ from their respective approval date through September 2012. Disproportional reporting signal detection was estimated using empirical Bayes geometric mean (EBGM) with 95% confidence intervals (CI).

Results: There were 2495 FAERs reports of tendon rupture associated with currently approved FQs. Most FAERS reports were associated with levofloxacin (n = 1555) followed by ciprofloxacin (n = 606) and moxifloxacin (n = 230). Signal detection results for FQs were as follows: levofloxacin (EBGM = 55.2, 95% CI = 52.3 – 58.0), ciprofloxacin (EBGM = 20.0, 95% CI = 18.2 – 21.6), moxifloxacin (EBGM = 13.3, 95% CI = 11.7 – 15.1), norfloxacin (EBGM = 9.6, 95% CI = 6.5 – 13.5), ofloxacin (EBGM = 8.2, 95%CI = 6.3 – 10.2) and gemifloxacin (EBGM = 1.9, 95% CI = 0.7 – 4.5). The mean age of affected individuals was 59.6 ± 5.1 years. Corticosteroids were administered concomitantly with FQs in 21.2% of cases.

Conclusion: As noted in boxed warnings, FQ use is associated with increased tendon rupture risk. Risk factors for FQ associated tendon rupture include use in the elderly, and in patients with concomitant corticosteroids. Further monitoring may be needed due to antibiotic overuse and marketing of newer FQs.     

The effect of endocannabinoid system in ischemia-reperfusion injury: a friend or a foe?

Introduction: In recent years, the endocannabinoid system has emerged as a new therapeutic target in variety of disorders associated with inflammation and tissue injury, including those of the neuronal, liver, renal and cardiovascular system. The aim of the present review is to elucidate the effect of endocannabinoid system on ischemia reperfusion injury (IRI) in different organs and systems.

Areas covered: The MEDLINE/PubMed database was searched for publications with the medical subject heading Cannabinoids* (CBs), CB receptors*, organ*, ischemia/reperfusion injury*, endocannabinoid* and system*. The initial relevant studies retrieved from the literature were 91 from PubMed. This number was initially limited to 35, after excluding the reviews and studies reporting data for receptors other than cannabinoid.

Expert opinion: CB2 receptors may play an important compensatory role in controlling tissue inflammation and injury in cells of the neuronal, cardiovascular, liver and renal systems, as well as in infiltrating monocytes/macrophages and leukocytes during various pathological conditions of the systems (atherosclerosis, restenosis, stroke, myocardial infarction, heart, liver and renal failure). These receptors limit inflammation and associated tissue injury. On the basis of preclinical results, pharmacological modulation of CB2 receptors may hold a unique therapeutic potential in stroke, myocardial infarction, atherosclerosis, IRI and liver disease.     

Drug use and risk among regular injecting drug users in Australia: does age make a difference?

Introduction and Aims . To examine age‐related differences in drug use and risk among regular injecting drug users (IDU) in Australia. Design and Methods . Cross‐sectional data from the 2006 Illicit Drug Reporting System were examined for age‐related differences in demographic characteristics, drug use history and current use patterns and self‐reported risk behaviours. Results . IDU under 25 years of age were more likely to have initiated injecting at a younger age, to identify as Aboriginal and/or Torres Strait Islander, and to be injecting daily or more often than their older counterparts. They reported more frequent heroin use in the preceding 6 months, and were more likely to report morphine as the first drug injected than were IDU aged 35 years or over. Younger IDU were also more likely to report providing used needles to others, engaging in recent property crime and drug dealing and arrest in the last year. Conclusions . Younger IDU reported significantly different drug use patterns and higher rates of risk behaviours than their older counterparts. Treatment services need to ensure that harm and demand reduction services deliver messages to new cohorts of IDU, particularly given that their drug use patterns may be different to those of older users.     

Is reporting rate a good predictor of risks associated with drugs?

AIMS: Uncertainty as to relative under-reporting plagues the comparisons of spontaneous reporting rates as a tool for decision-making in pharmacovigilance. However, it is generally accepted that under-reporting should be reasonably similar for similar drugs sharing the same indication, country and period of marketing. To test this, we compared the adverse drug reaction reporting rates to the French regional pharmacovigilance centres for six pairs of identical drug marketed at the same time by different companies under different brand names (co-marketing). METHODS: All reaction reports were related to sales, to compute reporting rate; within each pair, the reporting rate ratio and its confidence interval were calculated. RESULTS: The rate ratios were all between 0.76 and 1.33. Two of them were significantly different from 1 (1.28; 95% C.I. [1.01; 1.60] and 1.33; 95% C.I. [1.06; 1.74]). CONCLUSIONS: These small differences in reporting rates would not warrant regulatory action and support the usual assumption of similar reporting for similar drugs.