Does Price Really Matter for Generic Alternatives? Supervised learning Approaches in Deciding the Right Price for Acceptable Quality Attributes of Amlodipine Besylate among Generic Alternatives.

The price and safety of finished pharmaceutical preparations are two major concerns while prescribing medicine. In this work, machine learning-based classification models were developed with respect to the quality attributes of 258 samples covering 9 marketed amlodipine (AMLO) formulations. The quantitation of AMLO and its three sulfonate ester genotoxic impurities of besylate counter ion was settled using a validated high-performance liquid chromatography-diode-array detection method. The classification of correlation between dependent and independent variables was exercised using linear discriminant analysis models. The linear dispersion of acceptable quality attributes was significantly different for AMLO besylate formulation with unit price per tablet "<1 Rs." Although the correlations between price and quality are well-understood associations group centroid distance for price group "2-3 Rs." and "1-2 Rs." reveal that acceptable quality dispersion was similar for both groups. Nonetheless, a higher price could allow storage of the finished formulation to be kept on the shelf for a longer period.

Cost-effectiveness analysis comparing single-pill combination of perindopril/amlodipine/indapamide to the free equivalent combination in patients with hypertension from an Italian national health system perspective.

OBJECTIVE: To evaluate the cost-effectiveness of a single-pill combination (SPC) of perindopril/amlodipine/indapamide versus its free equivalent combination (FEC) in adults with hypertension in Italy. METHODS: A Markov model was developed to perform a cost-utility analysis with a lifetime horizon and an Italian healthcare payer's perspective. In the model, the additional effect of the SPC on blood pressure level compared with the FEC was translated into a decreased risk of cardiovascular events and CKD, which was modeled via Framingham risk algorithms. Difference in persistence rates of SPC and FEC were modeled via discontinuation rates. RESULTS: A perindopril/amlodipine/indapamide SPC is associated with lower cost and better health outcomes compared to its FEC. Over a lifetime horizon, it is associated with a 0.050 QALY gain and cost savings of €376, resulting from lower cardiovascular event rates. In the alternative scenario, where different approach for modeling impact of adherence was considered, incremental gain of 0.069 QALY and savings of €1,004 were observed. Results were robust to sensitivity and scenario analyses, indicating that use of this SPC is a cost-effective strategy. CONCLUSIONS: The findings indicate that a perindopril/amlodipine/indapamide SPC is a cost-saving treatment option for hypertension in Italy, compared to its FEC.

Fall risk and cardiovascular outcomes of first-line antihypertensive medications in nursing home residents.

BACKGROUND: Little evidence exists about the comparative effects of first-line antihypertensive medications (i.e., renin-angiotensin-aldosterone converting enzyme inhibitors (RAASi), amlodipine, or thiazide diuretics) in older adults with limited life expectancy. We compared the rates of injurious falls and short-term cardiovascular events between different first-line antihypertensive medication classes in adults receiving care in nursing homes (NH). METHODS: This was a retrospective cohort of Medicare fee-for-service beneficiaries receiving care in NHs. Patients newly dispensed first-line antihypertensive medications were identified using Part D claims (2015-2018) and linked with clinical assessments (i.e., Minimum Data Set). Fall-related injuries (FRI), hip fractures, and major adverse cardiac events (MACE) outcomes were identified using hospitalization claims. Patients were followed from the date of antihypertensive dispensing until the occurrence of outcomes, death, disenrollment, or 6-month follow-up. Inverse-probability-of-treatment-weighted (IPTW) cause-specific hazards regression models were used to compare outcomes between patients who were new users of RAASi, amlodipine, or thiazides. RESULTS: Our cohort included 16,504 antihypertensive users (RAASi, n = 9574; amlodipine, n = 5049; thiazide, n = 1881). Mean age was 83.5 years (± 8.2), 70.6% were female, and 17.2% were non-white race. During a mean follow-up of 5.3 months, 326 patients (2.0%) experienced an injurious fall, 1590 (9.6%) experienced MACE, and 2123 patients (12.9%) died. The intention-to-treat IPTW hazard ratio (HR) for injurious falls for amlodipine (vs RAASi) use was 0.85 (95% confidence interval (CI) 0.66-1.08) and for thiazides (vs RAASi) was 1.22 (95% CI 0.88-1.66). The rates of MACE were similar between those taking anti-hypertensive medications. Thiazides were discontinued more often than other classes; however, inferences were largely unchanged in as-treated analyses. Subgroup analyses were generally consistent. CONCLUSIONS: Older adults with limited life expectancy experience similar rates of injurious falls and short-term cardiovascular events after initiating any of the first-line antihypertensive medications.

A real-world analysis of outcomes and healthcare costs of patients on perindopril/indapamide/amlodipine single-pill vs. multiple-pill combination in Italy.

OBJECTIVES: This analysis compared adherence, cardiovascular (CV) events and all-cause mortality incidence, and healthcare costs among hypertensive patients treated with perindopril (PER)/indapamide (IND)/amlodipine (AML) in single-pill combination (SPC) vs. multiple-pill combination, in a real-world setting in Italy. METHODS: In this observational retrospective analysis of Italian administrative databases, adult patients treated with PER/IND/AML between 2010 and 2020 were divided into two cohorts: single-pill vs. multiple-pill. Patient data were available for at least one year before and after index date. Propensity score matching (PSM) was applied to reduce selection bias. Adherence was defined as proportion of days covered: non-adherence, <40%; partial adherence, 40-79%, and adherence ≥80%. Mortality incidence and CV events as single, or composite, endpoints were evaluated after first year of follow-up. Healthcare cost analyses were performed from the perspective of the Italian National Health Service. RESULTS: Following PSM, the single-pill cohort included 12 150 patients, and the multiple-pill cohort, 6105. The SPC cohort had a significantly higher percentage of adherent patients vs. the multiple-pill cohort (59.9% vs. 26.9%, P  < 0.001). Following the first year of follow-up, incidence of all-cause mortality, and combined endpoint of all-cause mortality and CV events were lower in the SPC cohort compared with multiple-pill cohort. Average annual direct healthcare costs were lower in the single-pill cohort (€2970) vs. multiple-pill cohort (€3642); cost of all drugs and all-cause hospitalizations were major contributors. CONCLUSION: The SPC of PER/IND/AML, compared with multiple-pill combination, is associated with higher adherence to medication, lower incidence of CV events and mortality, and reduced healthcare costs.

Pharmacoeconomic evaluation of stroke and myocardial infarction prevention in hypertensive patients: Markov model based on the ACCOMPLISH trial.

OBJECTIVE: We evaluated the pharmacoeconomics of amlodipine combined with benazepril and hydrochlorothiazide combined with benazepril in the treatment of hypertension using a Markov model to provide an evidence-based reference for clinical drug use. METHODS: In this retrospective study, we constructed two types of Markov model using data from the ACCOMPLISH (Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension) trial to dynamically simulate the development of hypertension. The models were subjected to rollback analysis and cohort analysis to obtain the cost and effectiveness of the two drug regimens in preventing stroke and myocardial infarction in hypertensive patients. We conducted sensitivity analysis to determine the stability of the results. RESULTS: The cost-effectiveness of amlodipine combined with benazepril was 66,196.97 RMB with 6.59 QALYs and that of hydrochlorothiazide combined with benazepril was 74,588.50 RMB with 6.46 QALYs. The incremental cost-effectiveness ratio of hydrochlorothiazide + benazepril was -64,550.23 compared with amlodipine + benazepril. The amlodipine + benazepril regimen was therefore more cost-effective than hydrochlorothiazide combined with benazepril. The sensitivity analysis results showed that the model was robust. CONCLUSION: Compared with the hydrochlorothiazide + benazepril treatment regimen, the amlodipine + benazepril regimen showed greater economic benefits.

MANAGEMENT OF RISKS OF ADVERSE DRUG REACTIONS ACCORDING TO ADR REPORT FORM DATA FROM LVIV REGION HEALTHCARE FACILITIES IN 2022.

The study aimed to analyse the adverse drug reactions report form data received by the State Expert Center of the Ministry of Health of Ukraine from healthcare professionals in the Lviv region in 2022. Regarding specific types of medicines, the ones with proven cause-and-effect relationships that caused the highest frequency of adverse drug reactions incidents were chemotherapeutic agents (35.5%), medicines affecting the cardiovascular system (20.3%), and non-steroidal anti-inflammatory drugs (8%). Within the penicillin class, amoxicillin potentiated by clavulanate (67%) and amoxicillin (29%) were the dominant drugs showing the highest incidence rate of adverse reactions. Among cephalosporins, ceftriaxone (46%) and cefixime (15%) were found to take the lead in terms of adverse reaction frequency. The highest proportion among all adverse drug reactions caused by penicillins and cephalosporins was attributed to allergic reactions. To confirm or rule out immediate or delayed type allergies in patients, as well as in patients with a history of immediate-type allergic reactions to ß-lactams and planned administration of another ß-lactam, it is necessary to conduct skin testing (skin prick test, or, in the case of parenteral administration, intradermal test) with the planned ß-lactam antibiotic. The second highest proportion of induced adverse drug reactions was attributed to drugs affecting the cardiovascular system (20.3%). The leading medications in the angiotensin-converting enzyme inhibitors category were enalapril (47%) and the combination of lisinopril with hydrochlorothiazide (24%). In the angiotensin II receptor blockers category of medications, valsartan (30%) and telmisartan-hydrochlorothiazide combination (20%) ranked highest. In the category of CCB drugs, amlodipine (66%) and nifedipine (20%) held the leading positions. among angiotensin-converting enzyme inhibitors, enalapril caused the most prevalent and predicted adverse reaction, that of cough, affecting 10.5% of patients, whereas, with the combination therapy of lisinopril and hydrochlorothiazide, the cough was observed in only 5.2% of patients. Angiotensin II receptor blockers have a better safety profile, particularly concerning cough. Analysis of adverse drug reactions reports for angiotensin II receptor blockers showed no cases of cough with valsartan and telmisartan-hydrochlorothiazide combination. Among calcium channel blocker medications, amlodipine emerged to rank highest, causing one of the predicted adverse drug reactions, that of lower extremity oedema in 64% of patients. The second position was taken by the combination of amlodipine with valsartan, which showed a statistically significant reduction of 14.3% (p≤0.05) in the incidence of oedema. Using amlodipine at a dose of 5 mg in combination with sartan medicines as angiotensin receptor blockers is an effective therapeutic alternative not only for enhancing blood pressure control in hypertensive patients but also for improving the safety profile of amlodipine. Among all the non-steroidal anti-inflammatory drugs prescribed to patients in the Lviv region in 2022, the highest number of adverse reactions was associated with the administration of diclofenac, ibuprofen, paracetamol, and nimesulide, causing adverse drug reactions in 22%, 19%, 17%, and 10% of cases, respectively. The most common systemic manifestations of adverse reactions with these non-steroidal anti-inflammatory drugs were allergic reactions (63.4%) and gastrointestinal disorders (26.8%). From an evidence-based medicine perspective, the most justified approach for primary and secondary prevention of gastrointestinal complications is the use of proton pump inhibitors.

Combinação fixa de benazepril associado a anlodipino para adultos com hipertensão arterial sistêmica com controle inadequado da pressão arterial / Fixed combination of benazepril associated with amlodipine for adults with controlled systemic arterial hypertension inadequate blood pressure

INTRODUÇÃO: A hipertensão arterial sistêmica (HAS), uma doença crônica, é um grave problema de saúde pública, caracterizada por níveis elevados e persistentes da pressão sanguínea, medidos em geral como uma razão da pressão arterial sistólica e diastólica (respectivamente maior ou igual a 140 mmHg; e/ou maior ou igual a 90 mmHg). Esta é uma doença altamente prevalente em todo o mundo. No Brasil, os números podem variar de acordo com a metodologia utilizada. Reportou-se na Pesquisa Nacional de Saúde de 2013, cujos dados são obtidos por autorrelato, a prevalência de hipertensão em 21% dos pacientes, mas ao considerar a aferição da pressão arterial e uso de medicamentos, o percentual de adultos com pressão arterial ≥140/90 mmHg foi de 32%. Sabe-se que a falta de controle da pressão arterial pode elevar o risco de ocorrência de eventos cardiovasculares, como infarto agudo do miocárdio, insuficiência cardíaca, acidente vascular cerebral, doenças renais, entre outros. Isso consequentemente pode causar problemas crônicos que reduzem a qualidade de vida do indivíduo, e até mesmo o

Financial implications of protocol-based hypertension treatment: an insight into medication costs in public and private health sectors in India.

Hypertension is a major public health challenge in low- and middle-income countries (LMICs) and calls for large-scale effective hypertension control programs. Adoption of drug and dose-specific treatment protocols recommended by the World Health Organization-HEARTS Initiative is key for hypertension control programs in LMICs. We estimated the annual medication cost per patient using three such protocols (protocol-1 and protocol-2 with Amlodipine, Telmisartan, using add-on doses and different drug orders, adding Chlorthalidone; protocol-3 with a single-pill combination (SPC) of Amlodipine/Telmisartan with dose up-titration, and addition of Chlorthalidone, if required) in India. The medication cost was simulated with different hypertension control assumptions for each protocol and calculated based on prices in the public and private sectors in India. The estimated annual medication cost per patient for protocol-1 and protocol-2 was $33.88-58.44 and $51.57-68.83 for protocol-3 in the private sector. The medication cost was lower in the generic stores ($5.78-9.57 for protocol-1 and protocol-2, and $7.35-9.89 for protocol-3). The medication cost for patients was the lowest ($2.05-3.89 for protocol-1 and protocol-2, and $2.94-3.98 for protocol-3) in the public sector. At less than $4 per patient per annum, scaling up a hypertension control program with specific treatment protocols is a potentially cost-effective public health intervention. Expanding low-cost generic retail networks would extend affordability in the private sector. The cost of treatment with SPC is comparable with non-SPC protocols and can be adopted in a public health program considering the advantage of simplified logistics, reduced pill burden, improved treatment adherence, and blood pressure control.

Machine Learning-Enabled NIR Spectroscopy in Assessing Powder Blend Uniformity: Clear-Up Disparities and Biases Induced by Physical Artefacts.

NIR spectroscopy is a non-destructive characterization tool for the blend uniformity (BU) assessment. However, NIR spectra of powder blends often contain overlapping physical and chemical information of the samples. Deconvoluting the information related to chemical properties from that associated with the physical effects is one of the major objectives of this work. We achieve this aim in two ways. Firstly, we identified various sources of variability that might affect the BU results. Secondly, we leverage the machine learning-based sophisticated data analytics processes. To accomplish the aforementioned objectives, calibration samples of amlodipine as an active pharmaceutical ingredient (API) with the concentrations ranging between 67 and 133% w/w (dose ~ 3.6% w/w), in powder blends containing excipients, were prepared using a gravimetric approach and assessed using NIR spectroscopic analysis, followed by HPLC measurements. The bias in NIR results was investigated by employing data quality metrics (DQM) and bias-variance decomposition (BVD). To overcome the bias, the clustered regression (non-parametric and linear) was applied. We assessed the model's performance by employing the hold-out and k-fold internal cross-validation (CV). NIR-based blend homogeneity with low mean absolute error and an interval estimates of 0.674 (mean) ± 0.218 (standard deviation) w/w was established. Additionally, bootstrapping-based CV was leveraged as part of the NIR method lifecycle management that demonstrated the mean absolute error (MAE) of BU ± 3.5% w/w and BU ± 1.5% w/w for model generalizability and model transferability, respectively. A workflow integrating machine learning to NIR spectral analysis was established and implemented. Impact of various data learning approaches on NIR spectral data.

Bioequivalence evaluation and food effect assessment of Lisinopril/amlodipine tablets in healthy Chinese subjects under fasting and fed conditions.

PURPOSE: The combination of lisinopril and amlodipine has a marked additional effect on blood pressure and fewer side effects than individual monotherapy. This study was conducted to compare the pharmacokinetic parameters and evaluate the bioequivalence between two Lisinopril/amlodipine tablets in healthy Chinese subjects. METHODS: A single center, randomized, open-label, single-dose, two-period crossover bioequivalence study was designed in healthy Chinese subjects under both fasting and fed conditions. Blood samples were collected before drug administration and at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 24, 36, 48, 72, 96, 144, 168 h after administration. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was applied to determine the plasma concentration of lisinopril and amlodipine. Maximum concentration (Cmax) and area under the concentration-time curve (AUC) were used to evaluate bioequivalence. Adverse events were recorded. RESULTS: Ninety-two healthy subjects were enrolled, and 75 completed the study. The 90% confidence intervals (CIs) of the ratio of geometric means (GMRs) of Cmax, AUC0-t, and AUC0-∞ of lisinopril and amlodipine under both fasting and fed conditions fell within the conventional bioequivalence criteria of 0.80-1.25. A high-fat meal appeared to decrease the Cmax and AUC of lisinopril. No severe adverse events were observed. CONCLUSION: The trial demonstrated that the test and the reference lisinopril/amlodipine tablets were bioequivalent and well tolerated in Chinese people under fasting and fed conditions. TRIAL REGISTRATION: Clinical Trails.gov identifier, NCT04885660 (retrospectively registered in 13/05/ 2021).

Clinical assessment of levamlodipine besylate combination therapy for essential hypertension: A protocol for systematic review and meta-analysis.

BACKGROUND: Essential hypertension has been regarded a significant risk factor for cardiovascular disease across the globe, and a significant escapable causation of early death as well as morbidity in the U.S. When angiotensin II receptor blockers and calcium channel blockers are used to treat essential hypertension, most patients will have inadequate blood pressure management. As a result, including a diuretic in the regimen is necessary. The current study's aim is to investigate the effectiveness as well as safety of levamlodipine besylate combination therapy in treating essential hypertension at varying degrees of severity. METHODS: In establishing the effectiveness and safety of the mix of levamlodipine besylate and dihydropyridine for essential hypertension, the authors will conduct a systematic review and, where applicable, a meta-analysis of randomized controlled clinical trials. A total of 8 electronic databases will be used in the search, including 4 English databases (PubMed, Web of Science, EMBASE, and Cochrane Library) and 4 Chinese databases (China National Knowledge Infrastructure, Chinese BioMedical Literature database, Chinese Scientific Journal database, and WanFang database). All articles published in the databases will be considered between their inception and January 18, 2022. Only articles published in English or Mandarin Chinese will be picked. A group of writers will independently evaluate each reference to see if it is eligible and whether there are any duplicates. The same authors will do data extraction for all eligible studies and use the Cochrane risk of bias tool to evaluate the risk of bias in the trials chosen for inclusion. RESULTS: The analysis will evaluate the efficiency and level of safeness of levamlodipine besylate combined treatment for essential hypertension. CONCLUSIONS: Our systematic review will offer evidence for judging whether levamlodipine besylate combination therapy can be considered an effective intercession for essential hypertension. ETHICS AND DISSEMINATION: Ethical approval will not be required as no original data will be collected as part of this review. REGISTRATION NUMBER: DOI 10.17605/OSF.IO/H8ZR2.

Assessment of a strategy combining ambulatory blood pressure, adherence monitoring and a standardised triple therapy in resistant hypertension.

PURPOSE: Poor adherence to drug therapy and inadequate drug regimens are two frequent factors responsible for the poor blood pressure (BP) control observed in patients with apparent resistant hypertension. We evaluated the efficacy of an antihypertensive management strategy combining a standardised therapy with three long acting drugs and electronic monitoring of drug adherence in patients with apparent resistant hypertension. MATERIALS AND METHODS: In this multicentric observational study, adult patients with residual hypertension on 24 h ambulatory BP monitoring (ABMP) despite the use of three or more antihypertensive drugs could be included. Olmesartan/amlodipine (40/10 mg, single pill fixed-dose combination) and chlorthalidone (25 mg) were prescribed for 3 months in two separated electronic pills boxes (EPB). The primary outcome was 24 h ambulatory systolic BP (SBP) control at 3 months, defined as mean SBP <130 mmHg. RESULTS: We enrolled 48 patients (36.0% women) of whom 35 had complete EPB data. After 3 months, 52.1% of patients had 24 h SBP <130 mmHg. 24 h SBP decreased by respectively -9.1 ± 15.5 mmHg, -22.8 ± 30.6 mmHg and -27.7 ± 16.6 mmHg from the tertile with the lowest adherence to the tertile with the highest adherence to the single pill combination (p = 0.024). A similar trend was observed with tertiles of adherence to chlorthalidone. Adherence superior to 90% was associated with 24 h systolic and diastolic blood pressure control in multiple logistic regression analysis (odds ratio = 14.1 (95% confidence interval 1.1-173.3, p = 0.039). CONCLUSIONS: A simplified standardised antihypertensive therapy combined with electronic monitoring of adherence normalises SBP in about half of patients with apparent resistant hypertension. Such combined management strategy enables identifying patients who need complementary investigations and those who rather need a long-term support of their adherence.

Fixed Dose Single Tablet Formulation with Differential Release of Amlodipine Besylate and Simvastatin and Its Pharmacokinetic Profile: QbD and Risk Assessment Approach.

PURPOSE: A differential release fixed dose matrix tablet of amlodipine besylate (AML-B) and simvastatin (SIM) was formulated to enhance patient compliance. MATERIAL AND METHOD: In the first phase, release controlling parameters of AML-B and SIM granules were identified and in the second phase a fixed dose AML-B and SIM tablet formulation was prepared and optimized for a differential release of the drugs using a quality by design (QbD) and risk assessment approach. A validated HPLC method was employed for simultaneous determination of AML-B and SIM for FDC formulation. A pharmacokinetics of the above drugs was studied in healthy dogs in the third phase. RESULTS: In QbD-based optimized formulation, Eudragit® RSPO-dicalcium phosphate (DCP) blend controlled the release of AML-B over 8 h, though this diffusion-controlled release assumed first order kinetics. DCP and Eudragit® RS 100 also retarded release of SIM causing SIM release over 8 h after AML-B release from the optimized FDC tablet formulation. The HPLC retention times of AML-B and SIM were 2.10 and 15.52 min, respectively. Linearity for AML-B was 5.0-50 ng/mL and 0.01-2.0 µg/mL for SIM with percent recoveries of 92.85-101.53% and 94.51-117.75% for AML-B and SIM. AUC0-∞ of AML-B was increased 3 fold, while AUC0-∞ of SIM was decreased 2 fold. The tmax values for AML-B and SIM were 12 and 6 h, respectively. AML-B was absorbed without any lag time (tlag) while tlag was 6.33 ± 0.81 h for SIM, thus met the study objective. CONCLUSION: The pharmacokinetic study showed an immediate absorption of AML-B while that of SIM was withheld for 6 h, close to the desired delay time of 8 h.

Population pharmacokinetic modelling to quantify the magnitude of drug-drug interactions between amlodipine and antiretroviral drugs.

PURPOSE: Drug-drug interactions (DDIs) with antiretroviral drugs (ARVs) represent an important issue in elderly people living with HIV (PLWH). Amlodipine is a commonly prescribed antihypertensive drug metabolized by CYP3A4, thus predisposed to a risk of DDIs. Guidance on the management of DDIs is mostly based on theoretical considerations derived from coadministration with other CYP3A4 inhibitors. This study aimed at characterizing the magnitude of DDIs between amlodipine and ARV drugs in order to establish dosing recommendations. METHODS: A population pharmacokinetic analysis was developed using non-linear mixed effect modelling (NONMEM) and included 163 amlodipine concentrations from 55 PLWH. Various structural and error models were compared to characterize optimally the concentration-time profile of amlodipine. Demographic and clinical characteristics as well as comedications were tested as potential influential covariates. Model-based simulations were performed to compare amlodipine exposure (i.e. area under the curve, AUC) between coadministered ARV drugs. RESULTS: Amlodipine concentration-time profile was best described using a one-compartment model with first-order absorption and a lag-time. Amlodipine apparent clearance was influenced by both CYP3A4 inhibitors and efavirenz (CYP3A4 inducer). Model-based simulations revealed that amlodipine AUC increased by 96% when coadministered with CYP3A4 inhibitors, while efavirenz decreased drug exposure by 59%. CONCLUSION: Coadministered ARV drugs significantly impact amlodipine disposition in PLWH. Clinicians should adjust amlodipine dosage accordingly, by halving the dosage in PLWH receiving ARV with inhibitory properties (mainly ritonavir-boosted darunavir), whereas they should double amlodipine doses when coadministering it with efavirenz, under appropriate monitoring of clinical response and tolerance.

Plasma Trough Concentrations of Antihypertensive Drugs for the Assessment of Treatment Adherence: A Meta-Analysis.

Biochemical drug screening by liquid chromatography-tandem mass spectrometry in plasma is an accurate method for the quantification of plasma concentrations of antihypertensive medications in patients with hypertension. Trough concentrations could possibly be used as drug-specific cutoff values in the biochemical assessment of (non-)adherence. We performed a literature review and meta-analysis of pharmacokinetic studies to determine plasma trough concentrations of amlodipine, hydrochlorothiazide, and valsartan. PubMed was searched for pharmacokinetic studies up to September 2020. Eligible studies reported steady-state mean trough concentration and their variance. Pooled trough concentrations were estimated using a three-level random effects meta-analytic model. Moderator analyses were performed to explore sources of heterogeneity. One thousand three hundred eighteen potentially relevant articles were identified of which 45 were eligible for inclusion. The pooled mean trough concentration was 9.2 ng/mL (95% CI, 7.5-10.8) for amlodipine, 41.0 ng/mL (95% CI, 17.4-64.7) for hydrochlorothiazide, and 352.9 ng/mL (95% CI, 243.5-462.3) for valsartan. Substantial heterogeneity was present for all 3 pooled estimates. Moderator analyses identified dosage as a significant moderator for the pooled trough concentration of amlodipine (ß1=0.9; P<0.05), mean age, and mean body weight for the mean trough concentration of hydrochlorothiazide (ß1=2.2, P<0.05, respectively, ß1=-4.0, P<0.05) and no significant moderators for valsartan. Plasma trough concentrations of amlodipine, hydrochlorothiazide, and valsartan, measured with liquid chromatography-tandem mass spectrometry, are highly heterogeneous over the different studies. Use of the pooled trough concentration as a cutoff in the biochemical assessment of adherence can result in inaccurate diagnosis of (non-)adherence, which may seriously harm the patient-physician relationship, and is therefore not recommended.

Effectiveness of Levoamlodipine Maleate for Hypertension Compared with Amlodipine Besylate: a Pragmatic Comparative Effectiveness Study.

PURPOSE: Antihypertensive treatment is the most important method to reduce the risk of cardiovascular events in hypertensive patients. However, there is scant evidence of the benefits of levoamlodipine maleate for antihypertensive treatment using a head-to-head comparison in the real-world. This study aims to examine the effectiveness of levoamlodipine maleate used to treat outpatients with primary hypertension compared with amlodipine besylate in a real-world setting. METHODS: This was a pragmatic comparative effectiveness study carried out at 110 centers across China in outpatients with primary hypertension treated with levoamlodipine maleate or amlodipine besylate, with 24 months of follow-up. The primary outcomes used for evaluating the effectiveness were composite major cardiovascular and cerebrovascular events (MACCE), adverse reactions, and cost-effectiveness. RESULTS: Among the included 10,031 patients, there were 482 MACCE, 223 (4.4%) in the levoamlodipine maleate group (n = 5018) and 259 (5.2%) in the amlodipine besylate group (n = 5013) (adjusted hazard ratio = 0.90, 95%CI: 0.75-1.08, P = 0.252). The levoamlodipine maleate group had lower overall incidences of any adverse reactions (6.0% vs. 8.4%, P < 0.001), lower extremity edema (1.1% vs. 3.0%, P < 0.001) and headache (0.7% vs. 1.1%, P = 0.045). There was a nearly 100% chance of the levoamlodipine maleate being cost-effective at a willingness to pay threshold of 150,000 Yuan per quality-adjusted life years (QALYs) gained, resulting in more QALYs (incremental QALYs: 0.00392) and cost savings (saving 2725 Yuan or 28.8% reduction in overall costs) per patient. CONCLUSION: In conclusion, levoamlodipine maleate could reduce cost by 29% with a similar MACCE incidence rate and lower occurrence of adverse reactions (especially edema and headache) compared with amlodipine besylate. TRIAL REGISTRATION: Clinicaltrials.gov NCT01844570 registered at May 1, 2013.

Assessment of suitable antihypertensive therapies: Combination with high-dose amlodipine/irbesartan vs triple combination with amlodipine/irbesartan/indapamide (ASAHI-AI study).

Angiotensin receptor blockers (ARBs) plus calcium channel blockers (CCBs) are a widely used combination therapy for hypertensive patients. In order to determine which combination was better as the next-step therapy for standard-dose combination of ARBs and CCBs, a combination with high-dose CCBs or a triple combination with diuretics, the authors conducted a prospective, randomized, open-label trial to determine which of the following combination is better as the next-step treatment: a combination with high-dose CCBs or a triple combination with diuretics. Hypertensive outpatients who did not achieve their target blood pressure (BP) with usual dosages of ARBs and amlodipine 5 mg were randomly assigned to treatment with irbesartan 100 mg/amlodipine 10 mg (Group 1: n = 48) or indapamide 1 mg in addition to ARBs plus amlodipine 5 mg (Group 2: n = 46). The primary end point was changes in the systolic BP (SBP) and diastolic BP (DBP) after the 12-week treatment period, while secondary end points were changes in BP after the 24-week treatment period and laboratory values. At 12 weeks, the SBP/DBP significantly decreased from 152.1/83.4 mm Hg to 131.5/76.1 mm Hg in Group 1 and 153.9/82.1 mm Hg to 132.7/75.9 mm Hg in Group 2. Although both groups produced a similar efficacy in reducing the SBP/DBP (-19.2/-9.2 mm Hg in Group 1 and -21.6/-8.8 mm Hg in Group 2; SBP P = .378, DBP P = .825), high-dose CCBs combined with ARBs controlled hypertension without elevation of serum uric acid. These results will provide new evidence for selecting optimal combination therapies for uncontrolled hypertensive patients.

A Drug Content, Stability Analysis, and Qualitative Assessment of Pharmacists' Opinions of Two Exemplar Extemporaneous Formulations.

Despite a decline in the number of active pharmaceutical ingredients prepared extemporaneously using proprietary products, there remains a need for such products in the community (for example, liquid medicines for paediatrics which may be otherwise commercially unavailable). A lack of experience and quality assurance systems may have diminished pharmacist's confidence in the extemporaneous preparation process; therefore, pharmacists were asked to prepare two proprietary products, omeprazole and amlodipine. The resulting products were characterised in terms of variability in drug quantity, stability, particle size and antimicrobial properties. Furthermore, a self-administered questionnaire was used to assess 10 pharmacists' opinions on the perceived complexity of the extemporaneous compounding process and their overall confidence in the final extemporaneously compounded products. Drug content studies revealed that 88.5% and 98.0% of the desired drug content was obtained for omeprazole and amlodipine, respectively. Antimicrobial properties were maintained for both drugs, however variability in particle size, particularly for amlodipine, was evident between formulations. While pharmacists who partook in the study had some or high confidence in the final products, they reported difficulty formulating the suspensions. Findings from this study provide insight into pharmacists' views on two extemporaneously prepared products and highlight the variability obtained in preparations prepared by different pharmacists.

Informe diário de evidências COVID-19: busca realizada em 16 e 18 de maio de 2020 / COVID-19 daily evidence report: search conducted on May 16 and 18, 2020

O Informe Diário de Evidências é uma produção do Ministério da Saúde que tem como objetivo acompanhar diariamente as publicações científicas sobre tratamento farmacológico e vacinas para a COVID-19. Dessa forma, são realizadas buscas estruturadas em bases de dados biomédicas, referente ao dia anterior desse informe. Não são incluídos estudos pré-clínicos (in vitro, in vivo, in silico). A frequência dos estudos é demonstrada de acordo com a sua classificação metodológica (revisões sistemáticas, ensaios clínicos randomizados, coortes, entre outros). Para cada estudo é apresentado um resumo com avaliação da qualidade metodológica. Essa avaliação tem por finalidade identificar o grau de certeza/confiança ou o risco de viés de cada estudo. Para tal, são utilizadas ferramentas já validadas e consagradas na literatura científica, na área de saúde baseada em evidências. Cabe ressaltar que o documento tem caráter informativo e não representa uma recomendação oficial do Ministério da Saúde sobre a temática. Foram encontrados 22 artigos e 10 protocolos.

Economic evaluation of olmesartan/amlodipine fixed-dose combination for hypertension treatment in China.

Objectives: To evaluate the cost-effectiveness of olmesartan/amlodipine fixed-dose combination vs olmesartan and amlodipine free combination, amlodipine single drug, and valsartan/amlodipine fixed-dose combination in the treatment of hypertensive patients from payer perspective in China.Methods: A Markov model was constructed, which included five health states of hypertensive patients who are aged 35-84 years at baseline and free of cardiovascular disease. Clinical data were obtained from a network meta-analysis. Epidemiology data, adverse events (AEs), cost, and utility data were obtained from the literature. The cost associated with AEs was estimated based on the cost of same symptoms of hypertensive patients in an electric medical record database. The model projected quality-adjusted life years (QALYs) gained, total costs per patient in a 20-year time horizon, and incremental cost-effectiveness ratios. Probability sensitivity analyses (PSA) and one-way sensitivity analyses were conducted for the main parameters to test the robustness of the model.Results: Compared to olmesartan and amlodipine free combination, amlodipine, and valsartan/amlodipine fixed-dose combination, treatment with olmesartan/amlodipine fixed-dose combination led to fewer CVD events and deaths; resulted in an incremental cost of ¥-5,439 ($-791.36), ¥6,530 ($950.09), and ¥-1,019 ($-148.26) and gained additional QALYs of 0.052, 0.094, and 0.037 per patient, respectively. Compared with olmesartan and amlodipine free combination and valsartan/amlodipine fixed-dose combination, olmesartan/amlodipine fixed-dose combination was dominant. Compared with amlodipine alone, the incremental cost-effectiveness ratios were below the WHO recommended cost-effectiveness threshold, indicating the olmesartan/amlodipine fixed-dose combination was a cost-effective option for hypertensive patients in China. The 10-years' time horizon scenario analysis showed similar results to the 20-years' time horizon. Probabilistic sensitivity analysis and one-way sensitivity analyses showed the robustness of the model results.Conclusions: Olmesartan/amlodipine fixed-dose combination confers better health outcomes and costs less compared with olmesartan and amlodipine free combination and valsartan/amlodipine fixed-dose combination, and is cost-effective compared to amlodipine for hypertension treatment in China.