Assessment of calcium antagonist therapy protective effect on the thickness of the intima-media complex in patients with arterial hypertension

Aim. To evaluate the connection of calcium antagonist (amlodipine) therapy with the dynamics of the intima-media complex thickness in patients with arterial hypertension (AH), depending on genetic polymorphism.Methods. The study included representatives of the indigenous nationality (the Shors) – 901 people, of which a group of 367 people with hypertension was identified. The prospective stage of observation included 234 people who did not receive antihypertensive therapy. Based on the prescription of calcium antagonists, patients with hypertension were divided into two groups. Gene polymorphism was tested by polymerase chain reaction.Results. In the Shor cohort, the regression of the intima-media complex thickness of the carotid arteries was observed more often in hypertensive patients who received calcium antagonists if to compare them with those who did not take the drug [OR = 2.30]. In addition, the decrease in the atherosclerotic process is associated with the genotype carriage: I/I of the ACE gene [OR = 9.42], T/C of the AGT gene [OR = 3.52], 4b/4b and 4b/4a of the eNOS gene [OR = 2.26 and OR = 3.75], C/C of the MTHFR gene [OR = 2.62].Conclusion. Pharmacogenetic aspects are valuable from the point of view of an individual approach and obtaining the most pronounced pharmacological response in order to slow down the processes of vascular wall remodeling in patients with hypertension.

The analysis of the permeability process of calcium antagonists in developing transdermal forms with a cardiovascular effect

Aim. The aim of the work was to evaluate the possibility of using calcium antagonists, namely, nifedipine and amlodipine besylate, while conducting transdermal delivery, that included the analysis of in vitro permeability process as a primary preformulation stage of pharmaceutical development of a transdermal dosage form, determination of qualitative and quantitative characteristics of a permeability process and the expediency analysis of development of a therapeutic transdermal system (TTS) with a cardiovascular effect. Materials and methods. The active pharmaceutical ingredients (API) of nifedipine and amlodipine besylate. The study has been carried out in vitro by a dialysis method using a modified diffusion device of the Valia-Chien design. Results. Character analysis, description of the mathematical model and definition of the kinetic parameters in the process of permeability of the studied medicinal products (MP) of nifedipine and amlodipine besylate allowed to evaluate their potential for creating TTS as being positive and appropriate. The implemented methodological approaches allow to substantiate the further algorithm for the development of cardiovascular TTS with the mentioned API.

Modern strategy in the treatment of arterial hypertension: combination therapy and fixed combinations

The introduction of fixed combinations for the treatment of arterial hypertension (AH) is an effective strategy to address the public health burden of cardiovascular disease. This strategy is reflected in modern international guidelines for the treatment of AH and is supported by World Health Organization. The use of fixed combinations allows solving key practical problems to achieve better results and improve the prognosis of AH: ensuring the greatest decrease in blood pressure (BP) and a lower target BP level, shortening the time period for obtaining target BP, increasing adherence to treatment. Fixed combinations include classes of antihypertensive drugs, which, when combined, have an additive or synergistic effect in lowering BP, help to reduce/mitigate side effects, reduce the number of pills and increase patient adherence, solving the problem of polypharmacy. Single dosing per day of fixed combinations is another important benefit, providing adherence, longer duration of action, and reduced diurnal fluctuations in BP. The clinical benefits of fixed combinations have been confirmed in a number of large studies and meta-analyzes. The modern tactics of using fixed combinations provides for their use at different stages/degrees of BP increase. In this regard, fixed combinations with subtherapeutic, therapeutic and maximum therapeutic doses of components have been developed. For the use of fixed combinations as an initial therapy for AH, drugs with subtherapeutic doses of components that are not used in monotherapy are proposed. In such cases, thanks to the complementary selection of combined drugs, it is possible to achieve a more significant and timely BP reduction, with fewer side effects. Modern fixed combinations are based on three main classes of antihypertensive drugs – RAAS blockers (ACE inhibitors and ARBs), calcium antagonists and diuretics. There are 2 principal approaches to combinations: a combination of RAAS blockers with diuretics (diurethic-use) or a combination of RAAS blockers with calcium antagonists (diuretic-free). This preference is due to evidence-based medicine data, including questions of efficacy, tolerability, side effects, and confirmation in clinical trials. In the clinical guidelines for the treatment of hypertension, these combinations are considered preferred (evidence level A). Over time, more and more fixed combinations become generic and reliable generic combination drugs for the treatment of hypertension appear, which reduces the cost factor and makes the therapy economically acceptable.

Antihypertensive Drugs and Risk of Depression

Hypertension, cardiovascular diseases, and cerebrovascular diseases are associated with an increased risk of depression, but it remains unclear whether treatment with antihypertensive agents decreases or increases this risk. The effects of individual drugs are also unknown. We used Danish population-based registers to systematically investigate whether the 41 most used individual antihypertensive drugs were associated with an altered risk of incident depression. Analyses of diuretics were included for comparisons. Participants were included in the study in January 2005 and followed until December 2015. Two different outcome measures were included: (1) a diagnosis of depressive disorder at a psychiatric hospital as an inpatient or outpatient and (2) a combined measure of a diagnosis of depression or use of antidepressants. Continued use of classes of angiotensin agents, calcium antagonists, and β-blockers was associated with significantly decreased rates of depression, whereas diuretic use was not. Individual drugs associated with decreased depression included 2 of 16 angiotensin agents: enalapril and ramipril; 3 of 10 calcium antagonists: amlodipine, verapamil, and verapamil combinations; and 4 of 15 β-blockers: propranolol, atenolol, bisoprolol, and carvedilol. No drug was associated with an increased risk of depression. In conclusion, real-life population-based data suggest a positive effect of continued use of 9 individual antihypertensive agents. This evidence should be used in guiding prescriptions for patients at risk of developing depression including those with prior depression or anxiety and patients with a family history of depression.

PHARMACOEPIDEMIOLOGY OF USING OF ANTIHYPERTENSIVE DRUGS BY FAMILY PHYSICIANS

The purpose of the study: to study the features of the rational use of antihypertensive drugs (AHP) by family doctors on an outpatient basis and their analysis of compliance with current international recommendations.Materials and methods: According to questionnaires specially developed for studying the pharmacoepidemiology of hypertension, interviews were conducted with family doctors working in health houses located in different regions of the country and the specifics of their appointment of hypertension to patients with hypertension were studied. The duration of medical experience of doctors is on average 22.6 ± 11.0 years.Results: The main drugs in the prescription structure were ACE inhibitors (19.7%), beta-blockers (19.6%), calcium antagonists (19.1%, diuretics (18.9%) ARBs (12.8%). central action drugs – 8.5%, alpha-adrenergic blockers – 1.4%. ACE inhibitor administration structure: enalapril – 33.8%, lisinopril – 26.3%, captopril – 23.3%, perindopril – 10.1 %, ramipril – 4.7%, the rest - 1.3% Of the beta-blockers: atenolol – 35.7%, bisoprolol – 34.7%, propranolol -15.7%, metoprolol - 8.0%, nebivolol – 4.3% and carvedilol 1.7%. The structure of the appointment of calcium antagonists: amlodipine – 38,3%, nifedipine – 29.6%, verapamil 16.8%, nifedipine SR and verapamil SR 5.7% each, diltheazem 2.1%, the share of all the others no more than 1.8%. Diuretic structure: hydrochlorothiazide – 36.0 %, furosemide – 28.8%, spironolactone – 18.6%, indapamide – 13.5%, torasemide – 2.1%, acetazolamide – 0.9%. The main proportion of ARB was losartan (84.0%) valsartan (8.7%), candesartan (4.2%), all the rest – 3.1%. 38.1% of family doctors still prescribe a centrally acting drug – clofellin, an imidazoline receptor agonist moxonidine (physiotens) is prescribed by family doctors very rarely (1.8%).73.2% of respondents seek to reduce blood pressure to 140/90 mm Hg. Art., and the rest are limited to lowering blood pressure to a «working» level. 33.7% of family doctors start hypertension with monotherapy with the selection of an effective dose of one drug. 40.6% of doctors prefer free combination of AHP, 54.7% consider fixed combinations to be convenient, the rest are low-dose combinations.Conclusion: Our study confirms the need for further improvement of the rational use of AHP by family doctors

AB0546 IMMEDIATE TO INTERMEDIATE EFFICACY AND SAFETY OF PROSTAGLANDINS E1 (PGE1) INHIBITORS- ALPROSTADIL IN TREATMENT OF SYMPTOMATIC RAYNAUD’S IN SYSTEMIC SCLEROSIS; SINGLE TERTIARY RHEUMATOLOGY CENTRE EXPERIENCE FROM SRI LANKA

Background:Systemic sclerosis (SSc) is a multi-system connective tissue disease1. Raynaud phenomenon (RP) is a frequent (>90%) manifestation in SSc2& if untreated could lead to complications such as digital ulcers, gangrene and amputation.Calcium antagonists are considered as first-line therapy for symptomatic SSc-RP. In refractory cases phosphodiesterase type 5 (PDE-5) inhibitors- Sildenafil and PGI2 analogue- Iloprost are used. A meta-analysis of trials indicate that PDE-5 inhibitors reduce the frequency and severity of SSc-RP attacks.In addition a study done with PGE1 inhibitors- Alprostadil 60 micrograms infusion given for six consecutive days, had shown immediate efficacy in SSc- RP; as demonstrated by increased blood flow, digitally measured by telethermography. Furthermore there was a reduction of the number, frequency and severity of attacks3.Due to unavailability of Iloprost in Sri Lanka, based on the above evidence some rheumatology centres use Alprostadil 60 microgram infusion for 3 consecutive days in refractory symptomatic SSc-RP.Objectives:To assess immediate (Day 4) and intermediate (Day 42) efficacy of Alprostadil 60 microgram infusions given for 3 consecutive days in treating SSc-RP.Methods:An observational longitudinal study was conducted at the Rheumatology unit, Teaching Hospital Anuradhapura- Sri Lanka during 01.09.2019- 30.12.2019.Twelve diagnosed Systemic Sclerosis patients with symptomatic Raynaud’s (Raynaud’s score of >5) despite receiving maximum tolerable doses of calcium antagonists consisted of the study sample.Pre and post (on day 4 and 42) treatment frequency of Raynaud’s attacks and Raynaud’s score was recorded using a pre-tested interviewer administered questionnaire. Statistical analysis was done using SPSS version 22 with Wilcoxon Signed Rank test at 5% significance level.Results:All recruits were females (n=12). Median (IQR) age of the study population and disease-duration were 45 (40 to 53.5) years and 6 (2.8 to 9.5) years respectively. Among participants, 58.3% and 25% had previous or current digital ulcers and gangrene respectively.Table 1.Pre and post treatment mean frequency of attacks and mean Raynaud’s scorePre treatmentmedian (IQR)Post treatmentDay 4 median (IQR) and significance of the difference between the pre-treatment valuesPost treatmentDay 42 median (IQR) and significance of the difference between the pre-treatment valuesMean frequency of Raynaud’s attacks/ past 24hrs4.0 (2.3 to 5.0)0.0 (0.0 to 1.0)P<0.05*2.0 (0.3 to 3.8)P<0.05*Mean duration of attack/24hrs21.3 (1.1 to 32.5)0.5 (0.5 to 3.0)P<0.05*7.5 (3.0 to 25.0)P>0.05Mean Raynaud’s score6.5 (5.0 to 8.8)2.0 (0.3 to 2.8)P<0.05*3.0 (0.1 to 5.0)P<0.05**statistically significantConclusion:Alprostadil 60 microgram infusions demonstrated a statistically significant immediate and intermediate efficacy in treating symptomatic SSc- RP with reduction of frequency of Raynaud’s attacks and Raynaud’s score at both. Only immediate efficacy was seen for mean duration of attacks. Based on these and the observed satisfactory safety level, we recommend the use of Alprostadil for symptomatic Raynaud’s in SSc-RP as an alternative to Iloprost. Further studies of larger samples are recommended.References:[1]Kowal-Bielecka O, Fransen J, Avouac J EUSTAR Coauthors, et al Update of EULAR recommendations for the treatment of systemic sclerosis. Annals of the Rheumatic Diseases 2017;76:1327-1339[2]Carpentier P, Satger B, Poensin D, et al. Incidence and natural history of Raynaud phenomenon: a long-term follow-up (14years) of a random sample from the general population. J Vasc Surg 2006;44:1023–8[3]Bartolone S, Trifiletti A, DeNuzzo G. Efficacy evaluation of prostaglandin E1 against placebo in patients with progressive systemic sclerosis and significant Raynaud’s phenomenon. Minerva Cardioangiol 1999; 47: 137–143Disclosure of Interests:None declared

High Blood Pressure Variability is an Additional Cardiovascular Risk Factor

Blood pressure (BP) is a highly variable physiological indicator. Most people have BP changes within 40-50 mmHg during the day. Various external factors (from the patient’s position during BP measurement to poor adherence to therapy and abuse of short-acting antihypertensive drugs) affect the assessed indicators. Evaluation of the average daily, intra-visit, as well as long-term ("from visit to visit") BP variability is used in clinical practice. In the past twenty years a number of major studies demonstrated that increased BP variability is an independent prognostic factor that increases the risk of cardiovascular complications. The largest meta-analysis of 41 studies showed that an increase in long-term BP variability was associated with 15% and 18% increase in total and cardiovascular mortality, respectively. According to the IDHOCO project, the threshold coefficient of variation for day-today variability is >11.0/12.8. Different groups of antihypertensive drugs have an uneven effect on BP variability. Consistent data from ASCOT-BPLA, X-CELLENT and ACCOMPLISH studies indicate that among the main groups of antihypertensive drugs, calcium antagonists, mainly amlodipine, have the greatest potential for the variability reduction. A decrease in BP variability, as shown in a post-hoc analysis of CAMELOT and PREVENT studies, has a positive effect on the incidence of major adverse cardiac events (MACE). Thus, the BP variability is an important indicator that reflects the prognosis in hypertensive patients. BP variability reduction can be considered as one of the independent goals of therapy. Calcium antagonists can be considered as first-line drugs for patients with high BP variability.

Development and Validation of Stability Indicating RP-HPLC Method for Estimation of Cilnidipine

Cilnidipine is one of the dihydropyridine calcium antagonists. It was created combinedly by Fuji Viscera Pharmaceutical Company, Ajinomoto and Japan and was approved in the year 1995. Cilnidipine acts on N-type calcium channel where exist the end of sympathetic nerve in addition to common L-type calcium channel like that of other calcium antagonists. China, Japan, India, Korea and several other countries approved this drug. The objective of the method validation is to demonstrate whether the method was suited for the intended purpose. The method was validated as per the ICH guidelines. The method was validated for linearity, precision (repeatability, intermediate precision), accuracy, specificity, robustness, limit of detection and limit of quantification. Cosmosil (4.6 X 250mm, 5 μ) column was used for separation. The selected wavelength for Cilnidipine was 241 nm. The mobile phase consists Methanol: Potassium dihydrogen phosphate buffer (50:50). Flow rate was delivered at 1.0 mL/min. Appropriate dilutions of standard stock solutions were prepared as per the get desired concentrations in the range of 100-500 mcg/ml. The RT obtained was 4.8165 minutes. Keywords: Cilnidipine, UV spectroscopy, RP-HPLC, ICH

Reaching blood pressure guideline targets with the CNIC polypill in patients with a previous cardiovascular event in Mexico: a post hoc analysis of the SORS study

Aim: To determine the effectiveness of Centro Nacional de Investigaciones Cardiovasculares (CNIC)-polypill (acetylsalicylic acid 100 mg, ramipril 5/10 mg, simvastatin 40 mg) in achieving blood pressure (BP) goals. Patients & methods: A multicenter, observational, one cohort, prospective study. BP targets were analyzed in patients with cardiovascular disease after 12-months treatment with the CNIC polypill. Results: A total of 572 patients (59.4 ± 13.9 years, 57.3% men) were analyzed. At baseline, BP was 147.1 ± 18.1/88.3 ± 10.6 mmHg, 97.1% of patients were taken renin-angiotensin system inhibitors, 5.4% calcium antagonists, 1.9% diuretics and 13.1% β-blockers. The proportion of patients who achieved BP targets increased from 20.1 to 55.4% (p < 0.001). Conclusion: In routine practice, switching from usual care to the CNIC-polypill in patients with cardiovascular disease could facilitate achieving BP goals.

1422Prevalence and characteristics of medication non-adherence assessed by quantitative liquid chromatography-tandem mass spectrometry in patients with hypertension

Background/Introduction Antihypertensive medication screening by qualitative high performance chromatography-tandem mass spectrometry (LC-MS/MS) has recently become available to detect non-adherence to antihypertensive treatment. Because the result of this test is dichotomous (the drug is detected or not), it may incorrectly classify patients who take their medications infrequently. Therefore, a quantitative screening method has been developed to improve detection of non-adherence. Purpose The aim of this study was to determine the prevalence of medication non-adherence assessed by quantitative LC-MS/MS in referred hypertensive patients. In addition, we determined to what extent clinical characteristics, prescribed medication and self-reported perspectives, were associated with medication non-adherence assessed by quantitative LC-MS/MS. Methods In this cross-sectional study we included 197 newly referred hypertensive patients (mean age 56±14 years, 101 women, mean 24-hour ambulatory blood pressure 143/85±21/12 mmHg) prescribed at least one antihypertensive drug. Medication adherence was assessed by quantitative LC-MS/MS in plasma. The concentration of each prescribed drug (or its metabolite) was measured and divided by the literature-based population trough concentration, to get the concentration ratio (CR). If the CR of at least one of the prescribed drugs was ≤0.3 the patient was categorized as non-adherent: completely non-adherent if all were ≤0.3, partially non-adherent if not all were ≤0.3. Logistic regression analysis was performed to determine the association between clinical characteristics, prescribed medication and self-reported compliance (Hill & Bone), relational empathy (CARE) and beliefs about medicines (BMQ), and medication non-adherence. Results 29% was classified as partially non-adherent and 10% as completely non-adherent. Non-adherence to calcium antagonists (30%) and beta blockers (24%) prevailed non-adherence to other antihypertensive medication classes (6–11%). The odds of non-adherence were higher in patients with apparent resistant hypertension and increased with the number of antihypertensive medication types, tablets and daily defined dose prescribed (Figure 1). Combination pills were inversely associated with non-adherence. Self-reported measures were not associated. Older age was negatively associated with non-adherence to RAS inhibitors (OR 0.60, 95% CI 0.36–0.96) and beta blockers (OR 0.50, 95% CI 0.30–0.77). Figure 1 Conclusions Quantitative screening by LC-MS/MS in plasma shows a high prevalence of non-adherence in referred hypertensive patients, particularly for calcium antagonists and beta blockers. The observation that clinical characteristics and self-reported perspectives about medical treatment were not associated with non-adherence, supports the use of quantitative LC-MS/MS to detect non-adherence to antihypertensive medication in daily practice.