Saving bones without risking brain—bisphosphonates and risk of stroke: matched case-control study

Introduction There is conflicting evidence on the link between bisphosphonates and stroke with studies variously showing increased, decreased or unchanged risk. We investigated the association between bisphosphonate treatment and the risk of stroke using a large routine clinical dataset. Methods We used a matched nested case-control study design analysing routinely collected electronic data from patients registered at primary care practices in England participating in the Royal College of General Practitioners Research and Surveillance Centre. Cases were patients aged 18 years or over, either living or dead, recorded as having had a stroke in the period 1st January 2005 to March 31st 2016. Each case was matched to one control according to age, sex, general practice attended and calendar time. Data were analysed using Stata, version 14.2. Conditional logistic regression was used to determine odds ratios for stroke according to bisphosphonate treatment and duration in cases compared with controls. We adjusted for disease risk groups, cardiovascular risk factors, treatments, smoking status, alcohol consumption, ethnicity , bisphosphonate types, fracture and socioeconomic status using IMD (Index of Multiple Deprivation). Results We included 31,414 cases of stroke with an equal number of matched controls. Overall, 83.2% of cases and controls were aged 65 years or older and there were similar proportions of females (51.5%) and males (48.5%). Bisphosphonate treatment was not associated with stroke after adjusting for the wide range of confounders considered (OR 0.86, 95% CI 0.62 - 1.19). Conclusions We found no association between bisphosphonate treatment and risk of stroke, after adjusting for other confounders

Supervised pharmacy student-led medication review in primary care for patients with type 2 diabetes: a randomised controlled pilot study

Objective: To pilot and feasibility-test supervised final year undergraduate pharmacy student-led medication reviews for patients with diabetes to enable definitive trial design. Method: Third year pharmacy students were recruited from one UK School of Pharmacy and trained to review patient's medical records and provide face-to-face consultations under supervision while situated within the patient's medical practice. Patients with type 2 diabetes were recruited by postal invitation letter from their medical practice and randomised via automated system to intervention or usual care. Diabetes-related clinical data, quality of life, patient reported beliefs, adherence and satisfaction with medicines information were collected with validated tools at baseline and 6 months postintervention. The process for collecting resource utilisation data was tested. Stakeholder meetings were held before and after intervention to develop study design and learn from its implementation. Recruitment and attrition rates were determined plus the quality of the outcome data. Power calculations for a definitive trial were performed on the different outcome measures to identify the most appropriate primary outcome measure. Results: 792 patients were identified as eligible from five medical practices. 133 (16.8) were recruited and randomised to control (n=66) or usual care (n=67). 32 students provided the complete intervention to 58 patients. Initial data analysis showed potential for impact in the right direction for some outcomes measured including glycated haemoglobin, quality of life and patient satisfaction with information about medicines. The intervention was found to be feasible and acceptable to patients. The pilot and feasibility study enabled the design of a future full randomised controlled trial. Conclusions: Student and patient recruitment are possible. The intervention was well received and demonstrated some potential benefits. While the intervention was relatively inexpensive and provided an experiential learning opportunity for pharmacy students, its cost-effectiveness remains to be determined. Trial registration number: ISRCTN26445805; Results. © 2015, BMJ Publishing Group. All rights reserved

Adverse drug reactions

Most drugs have side-effects, but there are many ways to reduce the risks. Above all else, patients need clear information about the balance between harm and benefi

Alpha- and beta-adrenoceptor-mediated responses of the guinea-pig ileum and the effects of neuronal uptake inhibition

The effects of noradrenaline and isoprenaline were examined on preparations of guinea-pig ileum, in which contractions were induced by three different methods; by transmural electrical stimulation, by exogenous carbachol and by potassium depolarization. Alpha- or beta-adrenoceptor-mediated responses were examined by construction of cumulative concentration-response curves in the presence of propranolol (10(-6) M) and phentolamine (5 X 10(-6) M) respectively. Stimulation of alpha-adrenoceptors by noradrenaline virtually abolished the twitches from transmural stimulation, but only partially inhibited the carbachol- and potassium-induced contractions. The effects on the last two preparations were attributed to a post-synaptic inhibition at alpha-adrenoceptors on the longitudinal smooth muscle. In the transmurally-stimulated preparation there was an additional pre-synaptic alpha-adrenoceptor-mediated inhibition of cholinergic transmission. The maximum beta-adrenoceptor-mediated inhibition of all three preparations to noradrenaline and isoprenaline was of the same magnitude and attributed only to a post-synaptic action on longitudinal smooth muscle. The predominant post-synaptic beta-adrenoceptor-mediated (carbachol-contracted ileum) and pre-synaptic alpha-adrenoceptor-mediated (transmurally-stimulated ileum) relaxations were significantly (P less than 0.05) potentiated by the neuronal uptake inhibitor desmethylimipramine. These receptors may therefore be considered to be closely associated with the sympathetic innervation. The effect on the post-synaptic alpha-adrenoceptor-mediated relaxation was equivocal. Additional minor excitatory responses were identified as a direct alpha-adrenoceptor-mediated contractile response to noradrenaline and as a beta-adrenoceptor-mediated potentiation of transmural stimulation by isoprenaline, possibly due to facilitation of cholinergic transmitter release

The Impact of Poly-Pharmacy on Mortality, Hospitalisation, Adverse Drug Reactions (ADR) and Falls in the Elderly

Background: Polypharmacy (commonly defined as the use of five or more medicines) is increasing in the elderly. It’s been known to increase the risk of adverse drug events. However, its impact on outcomes like mortality or hospitalization has not been clarified. Objective: The aim of this research was to determine the association between polypharmacy and mortality, falls, Adverse Drug Reactions (ADR) and hospitalisation in the elderly at one and five years. Methods: A retrospective cross-sectional study was carried out using 1000 patients aged 75 years and above from the Clinical Practice Research Datalink (CPRD). The follow up period for the one and five years analysis were January 2010 to December 2011 and January 2010 to December 2014 respectively. Sociodemographic and clinical variables were retrieved using medical and product codes from the CPRD code browser. The association between polypharmacy (estimated as the average number of medicines at a cutoff point of >5 medicines) and mortality, falls, ADR and hospitalisation was determined using logistic regression analysis whiles confounding for age, sex, Charlson’s Comorbidity Index (CCI), previous hospitalisation and previous falls. Results: Polypharmacy was associated with mortality and hospitalisation at one and five years. However, it was not associated with falls and ADR. Adjusted Odd Ratio (OR) for outcomes at one and five years were: mortality 10.30(5.4 – 19.50) and 1.89(1.4 – 2.5), hospitalisation 2.51(1.6 – 3.7) and 2.26(1.6 – 3.2), falls 0.57(0.2 – 1.7) and 1.38(0.8 – 2.3) and ADR 2.3(0.2 – 3.2) and 1.09(0.5 – 2.5) respectively. Conclusion: Polypharmacy was found to be associated with mortality and hospitalisation at one and five years. The risk of association was higher at one year than five years. However, it was not associated with falls or ADR

Mechanisms of cardiac supersensitivity to sympathomimetic amines

Supersensitivity of the beta-adrenoceptor-mediated positive inotropic and chronotropic responses of the heart to sympathomimetic amines is considered. The various types of supersensitivity of both pre- and post-synaptic origins are described and the possible mechanisms involved are discussed. Emphasis is given to the supersensitivity that arises from depletion of sympathetic catecholamine stores by reserpine and 6-hydroxydopamine. Results are presented which indicate that in both cases the supersensitivity develops slowly, is specific for the beta-adrenoceptor and is not associated with an increase in affinity of agonists for the receptor. Radioligand binding data is presented to show that there is no increase in the total number of beta-adrenoceptor binding sites in membrane fractions from ventricular homogenates of animals receiving reserpine. A review of the literature on binding studies indicates two opposing views with respect to the effects of reserpine on beta-adrenoceptor binding sites, one showing no change and the other showing an increase in total binding sites. Limited studies in the literature show that 6-hydroxydopamine may increase the number of sites. Binding data therefore remains inconclusive and must be interpreted with caution. The relationship between the development of depletion-induced supersensitivity and the innervation of the tissue and its receptor type is discussed

Cardiac postjunctional supersensitivity to β-agonists after chronic chemical sympathectomy with 6-hydroxydopamine

The sensitivity to sympathomimetic amines of isolated atria removed from sham-injected and 6-hydroxydopamine-treated (6-OHDA) guinea-pigs was examined in the presence of an extraneuronal uptake blocker and an alpha-adrenoceptor antagonist. Three weeks of pretreatment with 6-OHDA resulted in leftwards shifts of the dose-response curves for the positive chronotropic and inotropic responses of right and left atria to isoprenaline. The responses to the partial agonist salbutamol were also potentiated after 6-OHDA pretreatment, revealed as an increase in the maximum response relative to isoprenaline. The supersensitivity was post-synaptic in origin and independent of changes in disposition or metabolism, since it was observed with agonists immune to neuronal uptake and O-methylation, and in the presence of extraneuronal uptake inhibition by metanephrine. It was also specific for the beta-adrenoceptor, no supersensitivity to histamine being found. In the right atria, the supersensitivity was partially masked by an opposing depressant effect after 6-OHDA pretreatment which was observed with histamine. Dissociation constants (KA) for the left atrial inotropic responses to orciprenaline were determined by use of the antagonist Ro 03-7894. Atria from 6-OHDA-pretreated animals were supersensitive to orciprenaline, but the KA value did not differ from that after sham injection. It could therefore be concluded that the increase in sensitivity was not due to an increase in affinity for the beta-adrenoceptor

Bisphosphonates and risk of stroke: matched case control study

Introduction: There is evidence stating that calcium, vitamin D or bisphosphonates may prevent fractures, but it is also believed that they may be associated with cardiovascular diseases. For calcium and vitamin D, there exists evidence showing an association with a higher incidence of cardiovascular diseases (CVD) including stroke. There is uncertainty about the cardiovascular risks associated to bisphosphonates and concern about their safety. We aimed to investigate whether there is an association between bisphosphonate treatment and the risk of stroke. Methods: We used a matched 1:1 case-control design with data from the United Kingdom General Practice Research Database (GPRD). We compared cases, aged 18 years or above, either living or dead, with stroke during September 2001 to August 2009, with controls, matched for age, sex, calendar time and practice. Outcome measures were unadjusted and adjusted odds ratios and 95% confidence intervals for stroke associated with bisphosphonate treatment prior to the index date. We adjusted for disease groups, cardiovascular risk factors, treatments, GP consultations, home visits and IMD score. Results: We included 26,784 cases of stroke with equal number of matched controls. Two thirds of them were 65 or older and there were similar number of females than males (51.5% females and 48.5% males). The unadjusted analysis showed an association of bisphosphonates uptake with stroke (OR 1.14, 95% CI 1.07-1.22). However, the adjusted analysis did not find any link between bisphosphonate uptake and the risk of stroke (adjusted OR 1.00, 95% CI 0.92-1.09). Conclusions: We did not find any association between stroke and bisphosphonate treatment. Bisphosphonates could be used as a substitute of other drugs for the treatment of osteoporosis, such as calcium or vitamin D that has already been shown to have an influence in the risk of stroke

Bisphosphonates and risk of stroke: matched case control study

Introduction: There is evidence stating that calcium, vitamin D or bisphosphonates may prevent fractures, but it is also believed that they may be associated with cardiovascular diseases. For calcium and vitamin D, there exists evidence showing an association with a higher incidence of cardiovascular diseases (CVD) including stroke. There is uncertainty about the cardiovascular risks associated to bisphosphonates and concern about their safety. We aimed to investigate whether there is an association between bisphosphonate treatment and the risk of stroke.Methods: We used a matched 1:1 case-control design with data from the United Kingdom General Practice Research Database (GPRD). We compared cases, aged 18 years or above, either living or dead, with stroke during September 2001 to August 2009, with controls, matched for age, sex, calendar time and practice. Outcome measures were unadjusted and adjusted odds ratios and 95% confidence intervals for stroke associated with bisphosphonate treatment prior to the index date. We adjusted for disease groups, cardiovascular risk factors, treatments, GP consultations, home visits and IMD score. Results: We included 26,784 cases of stroke with equal number of matched controls. Two thirds of them were 65 or older and there were similar number of females than males (51.5% females and 48.5% males). The unadjusted analysis showed an association of bisphosphonates uptake with stroke (OR 1.14, 95% CI 1.07-1.22). However, the adjusted analysis did not find any link between bisphosphonate uptake and the risk of stroke (adjusted OR 1.00, 95% CI 0.92-1.09).Conclusions: We did not find any association between stroke and bisphosphonate treatment. Bisphosphonates could be used as a substitute of other drugs for the treatment of osteoporosis, such as calcium or vitamin D that has already been shown to have an influence in the risk of stroke.</p