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BMC Medicine Jul 2022Previous findings on the associations of thiazide use with skin cancers were conflicting. This study aimed to examine the associations of individual thiazide use with... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Previous findings on the associations of thiazide use with skin cancers were conflicting. This study aimed to examine the associations of individual thiazide use with skin cancer risk, differentiated by subtypes of skin cancers, geographic regions, and cumulative doses of individual thiazides.
METHODS
We searched PubMed, Embase, and Cochrane Central Register of Controlled Trials for relevant studies on January 5, 2022, scanned the references of included studies, and consulted experts. We included case-control and cohort studies or randomized trials reporting the associations of individual thiazide or thiazide-like diuretics use with skin cancers. Non-melanoma skin cancer (NMSC) and melanoma were analysed separately. A random-effects model meta-analysis was conducted for pooled odds ratio (OR) and hazard ratio (HR) for skin cancers related to individual thiazide use.
RESULTS
We included 15, 5, and 5 case-control or cohort studies reporting the risk for skin cancers associated with hydrochlorothiazide, bendroflumethiazide, and indapamide use, respectively, with 17,848,313 participants. The meta-analysis showed associations of hydrochlorothiazide use with increased risk of NMSC (OR 1.16, 95% CI 1.08-1.24; HR 1.26, 95% CI 1.04-1.54), squamous cell carcinoma (SCC) (OR 1.32, 95% CI 1.06-1.65; HR 1.61, 95% CI 0.97-2.67), and melanoma (OR 1.11, 95% CI 1.02-1.20; HR 1.03, 95% CI 0.93-1.14). The increased risks for SCC were associated with high cumulative doses of hydrochlorothiazide (OR 2.56, 95% CI 1.43-4.57; HR 1.20, 95% CI 1.00-1.45). Hydrochlorothiazide use was associated with different subtypes of melanoma including superficial spreading (OR 1.18, 95% CI 1.05-1.33), nodular (OR 1.23, 95% CI 1.08-1.39), and lentigo maligna melanoma (OR 1.33, 95% CI 1.08-1.65). Various cumulative doses of hydrochlorothiazide were associated with increased odds for melanoma. However, the associations of hydrochlorothiazide use with increased risk of NMSC and melanoma only appeared in non-Asian countries. No meaningful increase in the risk for skin cancers was associated with bendroflumethiazide and indapamide.
CONCLUSIONS
Hydrochlorothiazide is associated with an increased risk for NMSC (especially SCC) and melanoma in non-Asian countries, whereas bendroflumethiazide and indapamide are not associated with a meaningful risk for skin cancers. Healthcare professionals and patients should be informed of the different risk profiles of skin cancers associated with different thiazides, cumulative doses, and regions.
TRIAL REGISTRATION
PROSPERO CRD42021234317 .
Topics: Bendroflumethiazide; Carcinoma, Squamous Cell; Humans; Hydrochlorothiazide; Indapamide; Melanoma; Skin Neoplasms; Thiazides
PubMed: 35794547
DOI: 10.1186/s12916-022-02419-9 -
Danish Medical Journal Jun 2020Polypharmacy is associated with an increased risk of adverse health outcomes. This study aims to describe the prevalence of polypharmacy and medication use among older...
INTRODUCTION
Polypharmacy is associated with an increased risk of adverse health outcomes. This study aims to describe the prevalence of polypharmacy and medication use among older Danish citizens.
METHODS
From national registers, we extracted medicine use in relation to age group and residential region for the entire Danish population for the first half of 2016. The most frequently redeemed medicines among older citizens (≥ 75 years) in 2016 were grouped into clinically meaningful medication classes.
RESULTS
The prevalence of polypharmacy (> 5 different medicines) was 51% among citizens ≥ 75 years compared with 12% for the entire Danish population. The prevalence of polypharmacy increased with age and was 7% among citizens aged 40-49 years compared with 66% among citizens aged ≥ 90 years. There were only minor regional differences in the prevalence of polypharmacy. The most commonly redeemed medicine classes and individual medicines for older citizens were: 1) pain medication: paracetamol (50%) and tramadol (14%); 2) cardiovascular medicines: acetylsalicylic acid (26%), simvastatin (25%), metoprolol (22%), amlodipine (21%), furosemide (20%), bendroflumethiazide (17%), and losartan (14%); and 3) gastrointestinal medicines: pantoprazole (15%).
CONCLUSIONS
Polypharmacy is prevalent in Denmark with no relevant regional differences. The prevalence of polypharmacy increased with age, and more than half of the population aged ≥ 75 years redeemed prescriptions for > 5 different medicines. The most redeemed medicines among older citizens were against pain and cardiovascular disease.
FUNDING
none.
TRIAL REGISTRATION
not relevant.
Topics: Adolescent; Adult; Age Distribution; Aged; Aged, 80 and over; Child; Child, Preschool; Cross-Sectional Studies; Denmark; Drug Prescriptions; Female; Humans; Infant; Infant, Newborn; Male; Middle Aged; Polypharmacy; Prevalence; Young Adult
PubMed: 32741431
DOI: No ID Found -
Genome Medicine Oct 2021In spite of many years of research, our understanding of the molecular bases of Alzheimer's disease (AD) is still incomplete, and the medical treatments available mainly...
BACKGROUND
In spite of many years of research, our understanding of the molecular bases of Alzheimer's disease (AD) is still incomplete, and the medical treatments available mainly target the disease symptoms and are hardly effective. Indeed, the modulation of a single target (e.g., β-secretase) has proven to be insufficient to significantly alter the physiopathology of the disease, and we should therefore move from gene-centric to systemic therapeutic strategies, where AD-related changes are modulated globally.
METHODS
Here we present the complete characterization of three murine models of AD at different stages of the disease (i.e., onset, progression and advanced). We combined the cognitive assessment of these mice with histological analyses and full transcriptional and protein quantification profiling of the hippocampus. Additionally, we derived specific Aβ-related molecular AD signatures and looked for drugs able to globally revert them.
RESULTS
We found that AD models show accelerated aging and that factors specifically associated with Aβ pathology are involved. We discovered a few proteins whose abundance increases with AD progression, while the corresponding transcript levels remain stable, and showed that at least two of them (i.e., lfit3 and Syt11) co-localize with Aβ plaques in the brain. Finally, we found two NSAIDs (dexketoprofen and etodolac) and two anti-hypertensives (penbutolol and bendroflumethiazide) that overturn the cognitive impairment in AD mice while reducing Aβ plaques in the hippocampus and partially restoring the physiological levels of AD signature genes to wild-type levels.
CONCLUSIONS
The characterization of three AD mouse models at different disease stages provides an unprecedented view of AD pathology and how this differs from physiological aging. Moreover, our computational strategy to chemically revert AD signatures has shown that NSAID and anti-hypertensive drugs may still have an opportunity as anti-AD agents, challenging previous reports.
Topics: Aging; Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Cognitive Dysfunction; Disease Models, Animal; Drug Discovery; Female; Gene Expression Regulation, Neoplastic; Gene Knock-In Techniques; Humans; Mice; Mice, Inbred C57BL; Mice, Transgenic; Plaque, Amyloid; Proteomics; Transcriptome
PubMed: 34702310
DOI: 10.1186/s13073-021-00983-y -
Therapeutic Advances in Cardiovascular... 2022Management of high blood pressure (BP) typically requires adherence to medication regimes. However, it is known that the COVID-19 pandemic both interrupted access to...
Impact of the COVID-19 pandemic on cardiovascular heart disease medication use: time-series analysis of England's prescription data during the COVID-19 pandemic (January 2019 to October 2020).
BACKGROUND
Management of high blood pressure (BP) typically requires adherence to medication regimes. However, it is known that the COVID-19 pandemic both interrupted access to some routine prescriptions and changed some patient health behaviours.
AIM
This study, therefore, retrospectively investigated prescription reimbursement of cardiovascular (CVD) medicines as a proxy measure for patient adherence and access to medicines during the pandemic.
METHODS
A cohort study of all primary care patients in England prescribed CVD medicines. The exposure was to the global pandemic. Prescriptions were compared before and after the pandemic's onset. Statistical variation was the outcome of interest.
RESULTS
Descriptive statistics show changes to monthly prescriptions, with wide confidence intervals indicating varying underlying practice. Analysis of variance reveals statistically significant differences for bendroflumethiazide, potassium-sparing diuretics, nicorandil, ezetimibe, ivabradine, ranolazine, colesevelam and midodrine. After the pandemic began (March-October 2020), negative parameters are observed for ACE inhibitors, beta-blockers, calcium channel blockers, statins, antiplatelet, antithrombotics, ARBs, loop diuretics, doxazosin, bendroflumethiazide, nitrates and indapamide, indicating decelerating monthly prescription items (statistically significant declines of calcium channel blockers, antithrombotic, adrenoreceptor blockers and diuretics) of CVD medicines within the general population. Many data points are not statistically significant, but fluctuations remain clinically important for the large population of patients taking these medications.
CONCLUSION
A concerning decline in uptake of CVD therapies for chronic heart disease was observed. Accessible screening and treatment alongside financial relief on prescription levies are needed. A video abstract is (4 min 51 s) available: https://bit.ly/39gvEHi.
Topics: Humans; Pandemics; COVID-19; Angiotensin-Converting Enzyme Inhibitors; Bendroflumethiazide; Retrospective Studies; Cohort Studies; Angiotensin Receptor Antagonists; Cardiovascular Agents; Cardiovascular Diseases; Heart Diseases; Diuretics; Drug Prescriptions
PubMed: 36420815
DOI: 10.1177/17539447221137170 -
Bone Reports Dec 2020Thiazide diuretics (TD) may play a role in preventing osteoporosis. The objective was to investigate the effects of bendroflumethiazide in combination with...
PURPOSE
Thiazide diuretics (TD) may play a role in preventing osteoporosis. The objective was to investigate the effects of bendroflumethiazide in combination with bisphosphonates on bone mineral density, selected blood parameters, blood pressure, pulse, and muscle function.
METHODS
Double-blinded, randomized, placebo-controlled interventional study in postmenopausal osteoporotic women over the age of 50 years consisting of four arms: 1) 24 weeks with bendroflumethiazide +24 weeks of washout, 2) 24 weeks with placebo +24 weeks of washout, 3) 48 weeks with bendroflumethiazide, or 4) 48 weeks with placebo. At inclusion, participants were on oral bisphosphonates. Intervention consisted of either bendroflumethiazide or placebo. Dual energy X-ray absorptiometry (DXA), vertebral fracture assessment (VFA), quantitative CT (QCT) and selected blood parameters were acquired at baseline and at 48 weeks and Timed-Up-and-Go, handgrip strength, blood pressure, pulse and balance additionally at 24 weeks.
RESULTS
139 postmenopausal Caucasian women over 50 years were randomized (mean age 64.7 years (SEM 0.6, range 51-79)). 109 (78%) completed the study. No difference in the effect of bendroflumethiazide on DXA, VFA, QCT, biochemistry or muscle function were found between the treatment arms.
CONCLUSION
Bendroflumethiazide for 24- or 48 weeks in combination with bisphosphonates does not improve bone mineral density, selected blood parameters or muscle function compared to placebo combined with bisphosphonates. Studies with longer treatment periods and more patients are needed to further characterize the effects of bendroflumethiazide on bone and subpopulations that might benefit from the treatment.
PubMed: 33318971
DOI: 10.1016/j.bonr.2020.100737 -
British Journal of Clinical Pharmacology Dec 2019Thiazide diuretics have been the cornerstone of hypertension treatment for >5 decades. Most recent European and American guidelines recommend both thiazide-type and... (Review)
Review
Thiazide diuretics have been the cornerstone of hypertension treatment for >5 decades. Most recent European and American guidelines recommend both thiazide-type and thiazide-like diuretics as first-line drugs for all patients with hypertension. In contrast, diuretics are not regarded as first-line treatment in the UK and in patients who are to be initiated on a diuretic treatment, thiazide-like molecules, such as chlortalidone and indapamide are the preferred option. This review examines the prescribing trend of the 4 most commonly prescribed thiazide diuretics for the treatment of hypertension in the UK. Prescription cost analysis data were obtained for both 2010 and 2016/2017 for each region of the UK to analyse the impact of the 2011 National Institute for Health and Care Excellence hypertension guidelines on the trend in thiazide diuretic prescribing. Overall, the prescriptions of thiazide diuretics declined over the years. Bendroflumethiazide is the most commonly prescribed diuretic in the UK and despite some geographical differences, thiazide-type diuretics are more widely used than thiazide-like. The use of indapamide increased significantly between 2010 and 2016/2017 while chlortalidone was rarely employed. Of the many factors affecting trends in prescriptions, clinical inertia, treatment adherence, availability of the products and the lack of fixed dose combinations may play a role.
Topics: Antihypertensive Agents; Bendroflumethiazide; Blood Pressure; Drug Prescriptions; Drug Utilization; Humans; Hypertension; Indapamide; Practice Guidelines as Topic; Sodium Chloride Symporter Inhibitors
PubMed: 31471972
DOI: 10.1111/bcp.14109 -
Pilot and Feasibility Studies Mar 2022Obtaining evidence on comparative effectiveness and safety of widely prescribed drugs in a timely and cost-effective way is a major challenge for healthcare systems....
Evaluating Diuretics in Normal Care (EVIDENCE): a feasibility report of a pilot cluster randomised trial of prescribing policy in primary care to compare the effectiveness of thiazide-type diuretics in hypertension.
BACKGROUND
Obtaining evidence on comparative effectiveness and safety of widely prescribed drugs in a timely and cost-effective way is a major challenge for healthcare systems. Here, we describe the feasibility of the Evaluating Diuretics in Normal Care (EVIDENCE) study that compares a thiazide and thiazide-like diuretics for hypertension as an exemplar of a more general framework for efficient generation of such evidence. In 2011, the UK NICE hypertension guideline included a recommendation that thiazide-like diuretics (such as indapamide) be used in preference to thiazide diuretics (such as bendroflumethiazide) for hypertension. There is sparse evidence backing this recommendation, and bendroflumethiazide remains widely used in the UK.
METHODS
Patients prescribed indapamide or bendroflumethiazide regularly for hypertension were identified in participating general practices. Allocation of a prescribing policy favouring one of these drugs was then randomly applied to the practice and, where required to comply with the policy, repeat prescriptions switched by pharmacy staff. Patients were informed of the potential switch by letter and given the opportunity to opt out. Practice adherence to the randomised policy was assessed by measuring the amount of policy drug prescribed as a proportion of total combined indapamide and bendroflumethiazide. Routinely collected hospitalisation and death data in the NHS will be used to compare cardiovascular event rates between the two policies.
RESULTS
This pilot recruited 30 primary care practices in five Scottish National Health Service (NHS) Boards. Fifteen practices were randomised to indapamide (2682 patients) and 15 to bendroflumethiazide (3437 patients), a study population of 6119 patients. Prior to randomisation, bendroflumethiazide was prescribed to 78% of patients prescribed either of these drugs. Only 1.6% of patients opted out of the proposed medication switch.
CONCLUSION
The pilot and subsequent recruitment confirms the methodology is scalable within NHS Scotland for a fully powered larger study; currently, 102 GP practices (> 12,700 patients) are participating in this study. It has the potential to efficiently produce externally valid comparative effectiveness data with minimal disruption to practice staff or patients. Streamlining this pragmatic trial approach has demonstrated the feasibility of a random prescribing policy design framework that can be adapted to other therapeutic areas.
TRIAL REGISTRATION
ISRCTN Registry, ISRCTN46635087 . Registered on 11 August 2017.
PubMed: 35277204
DOI: 10.1186/s40814-022-01016-0 -
Therapeutic Drug Monitoring Apr 2020Therapeutic drug monitoring of antihypertensive drugs is being increasingly used to optimize treatment and to assess nonadherence. Separator gels are often used in blood...
BACKGROUND
Therapeutic drug monitoring of antihypertensive drugs is being increasingly used to optimize treatment and to assess nonadherence. Separator gels are often used in blood collection tubes to facilitate serum or plasma separation from other blood constituents before analyses. Drug adsorption into the separator gel presents a possible pre-analytical cause of falsely low concentrations or false negative results.
METHODS
Drug-free blood from blood donors was spiked with therapeutic concentrations of 21 antihypertensive drugs, transferred to serum tubes with and without separator gel (Vacuette gel plastic tubes and plain serum plastic tubes, respectively), and centrifuged. Serum was collected immediately after centrifugation and after 24 and 72 hours of room temperature storage, samples were analyzed in triplicates using liquid chromatography-mass spectrometry.
RESULTS
Serum samples collected immediately after centrifugation or 24 hours later, had the same drug concentrations in the gel and nongel tubes. After 72 hours of room temperature storage, verapamil and lercanidipine serum concentrations were 43% and 29%, respectively, lower in gel tubes than nongel tubes. Canrenone, diltiazem, and bendroflumethiazide showed between 10% and 20% concentration loss in gel tubes, compared with nongel tubes, with the 2 latter observed as unstable also in nongel tubes.
CONCLUSIONS
Except for verapamil, lercanidipine, and canrenone, which showed substantial concentration loss in gel tubes, gel tubes may be used for therapeutic drug monitoring purposes for the most commonly used antihypertensive drugs. Transferring serum to gel-free containers immediately after centrifugation minimizes concentration loss; however, bendroflumethiazide and diltiazem are generally unstable at room temperature.
Topics: Antihypertensive Agents; Blood Specimen Collection; Chromatography, Liquid; Drug Monitoring; Gels; Humans
PubMed: 31609885
DOI: 10.1097/FTD.0000000000000708