Slow Calcium Channel Blocker Research Articles

The role of progesterone preparations in the prevention of premature birth: a modern view of the problem

Despite significant progress achieved in healthcare, preterm birth is an urgent problem in modern obstetrics. The preterm birth can be caused by various risk factors: for example, an ascending infection can trigger the onset of uterine contractions, cervical shortening followed by infection of the fetal membranes, amniotic fluid, and, in rare cases, the fetus itself. In most cases, the infectious and inflammatory process is the etiopathogenetic factor of isthmic-cervical insufficiency (ICI), one of the common causes of late miscarriages and preterm births. The period between 14 and 20 weeks of gestation is the most critical time for the development of ICI. The dynamic ultrasound cervicometry once every 7–14 days from week 16 through week 24 of pregnancy is recommended to the patients with ICI, as well as pregnant women in the high-risk group. Most professional societies guidelines addressing this issue recommend all pregnant women to perform routine transvaginal cervicometry during the second ultrasound screening for the timely formation of risk groups and optimization of approaches to the patient management. The following groups of drugs are used to prevent preterm birth: micronized progesterone, slow calcium channel blockers, β-adrenergic agonists, and non-steroidal anti-inflammatory drugs. The use of progesterone drugs to prevent preterm birth has generated much debate. Thus, the availability of several forms of progesterone and various routes of administration determine the complexity of the drug therapy. Micronized progesterone is the only progesterone drug that was approved for use after 20 weeks of gestation. The vaginal micronized progesterone has been found to be highly effective in the prevention of preterm birth, significantly reduce neonatal mortality and improve infant morbidity outcomes.

The role of beta blockers in the treatment of cardiovascular diseases

Beta-blockers are used to treat various cardiovascular diseases, including hypertension and chronic heart failure. They act by suppressing the effects of catecholamines through various pathways and affect heart rate, strength, and renin release, providing antihypertensive and anti-ischemic effects. The individual effects of various drugs on clinical outcomes in this group were determined according to characteristics of the patient, underlying disease, and type of beta-blocker used. In recent years, beta-blockers have faced a serious obstacle when new guidelines on hypertension suggest their use as second-line therapy after angiotensin converting enzyme inhibitors, angiotensin receptor blockers and slow calcium channel blockers in the absence of clear indications. In fact, these recommendations were based on meta-analyses that showed that beta-blockers have fewer beneficial effects on overall mortality, cardiovascular events, and brain stroke. In addition, according to currently available data, the appointment of beta-blockers for diseases such as heart failure with preserved ejection fraction and stable coronary heart disease can cause more harm than good outcomes. Bisoprolol is a beta-blocker with the highest selectivity for beta1-adrenergic receptors, which determines the rare frequency of side effects that develop because of its use. This review presents current data on the use of beta-blockers for treating cardiovascular diseases, with an emphasis on the use of bisoprolol.

Modern Fixed Combinations in the Correction of Arterial Hypertension and Dyslipidemia

Based on a clinical case report, the article shows the individual selection of effective therapy for a patient with arterial hypertension and dyslipidemia. Taking into account the risk factors for cardiovascular diseases, Equamer® was selected as a fixed combination of amlodipine + lisinopril + rosuvastatin capsules 10 mg+20 mg+10 mg (Gedeon Richter Plc, Budapest, Hungary). In the patient with hypertension, ischemic heart disease was verified, and stenting of the anterior descending artery was performed. According to the clinical guidelines, when arterial hypertension is associated with ischemic heart disease, the drug therapy of choice should be a combination of dihydropyridine slow calcium channel blockers with an angiotensin-converting enzyme inhibitor. The fixed triple combination of amlodipine, lisinopril, and rosuvastatin is one of the most appropriate in this clinical situation; this combination targets the two major risk factors for cardiovascular diseases, arterial hypertension and dyslipidemia.

Ефективність і безпечність фіксованих комбінацій блокаторів повільних кальцієвих каналів, блокаторів рецепторів ангіотензину та тіазидних діуретиків у лікуванні артеріальної гіпертензії

Наведено аналіз результатів дослідження ефективності й безпечності фіксованих комбінацій блокатора повільних кальцієвих каналів (БКК) амлодипіну й блокатора рецепторів ангіотензину (БРА) валсартану (Комбісарт) та амлодипіну, валсартану й тіазидного діуретика гідрохлортіазиду (Комбісарт Н) компанії ПАТ «Київський вітамінний завод» порівняно з препаратами Ексфорж й Ексфорж Н (Novartis Pharma, Швейцарія) у лікуванні хворих на артеріальну гіпертензію ІІ–ІІІ стадії. Установлена терапевтична еквівалентність Комбісарту і Комбісарту Н референтним — Ексфоржу й Ексфоржу Н. Продемонстрована ефективність досліджуваних препаратів щодо зниження артеріального тиску, покращення його контролю протягом доби при комбінації БРА і БКК із тіазидним діуретиком, добра переносимість Комбісарту і Комбісарту Н, що підвищує комплайєнтність пацієнтів до лікування артеріальної гіпертензії.

Postprandial hypoglycemia after upper gastrointestinal tract surgery: diagnosis and treatment (part 2)

The causes of postprandial hyperinsulinemic hypoglycemia (PHH) in patients who have under-gone an upper gastrointestinal tract surgery are still a matter of debate in the scientific community. Low postoperative body mass index, high postprandial beta-cell activity before the surgery, and younger age are all have been associated with higher PHH risk. It is hypothesized that the insulin-like growth factor-1 increases the tissue sensitivity to insulin and indirectly promotes the development of hypoglycemia. An increase in postprandial secretion of enteropancreatic hormones is still considered to be the main reason for PHH manifestation; however, a particular contribution has been ascribed to glycentin, which could be used as a marker of PHH risk in the future. At present, there are no clinical guidelines for the diagnosis of PHH. Undoubtedly, the first step in this direction should be the collection of the disease history. The provocative tests have been proposed for the detection of PHH. Today, the 72-hour fast test is still the gold standard in the diagnosis of hypoglycemia. However, most post-bariatric patients do not have fasting hypoglycemia, and insulinoma is extremely rare in this patient category. The use of a prolonged oral glucose tolerance test as the main method is associated with a risk of a false diagnosis, because about 12% of healthy individuals may have their glycemic levels at below 2.8 mmol/l. The mixed meal test has not been validated yet. The best results in the assessment of glucose variability have been obtained with “real time” continuous glucose monitoring the interstitial fluid for several days. The goal of PHH treatment is to reduce the stimulated insulin secretion. First of all, patients are advised to eat small meals consisting of carbohydrates with a low glycemic index in combination with proteins and lipids, with high fiber content. Should the nutritional modification be ineffective, it is possible to prescribe medical treatment, such as acarbose or somatostatin analogs. Diazoxide and slow calcium channel blockers can be used as the third line of therapy. A recent study has suggested that exogenous agonists of glucagon-like peptide-1 (GLP-1) receptors by stronger bonds with receptors, compared to those with endogenous GLP-1, could enhance glucagon response to hypoglycemia, thereby stabilizing glucose levels. In severe refractory PHH, reconstructive surgery and gastric banding are to be considered. If the expected decrease in insulin hypersecretion by reconstructive surgery is not achieved, partial or complete pancreatectomy remains the only possible approach to prevent hypoglycemia. However, due to the small number and short duration of the studies, effectiveness and safety of these techniques for PHH treatment have not yet been proven.

Features of antihypertensive pharmacotherapy in patients with metabolic syndrome and diabetes mellitus

The article describes the results of analyzing the available literature concerning specifics of pharmacotherapy for hypertension in elderly patients and patients with metabolic syndrome and diabetes mellitus. Authors present statistical data on the prevalence of hypertension among elderly patients and the incidence of obesity and diabetes in the Russian Federation. The paper highlights the characteristics of clinical course of hypertension in the older age group including the predominance of isolated systolic hypertension, vascular stiffness, and increased endothelial dysfunction. The need for administration of antihypertensive drugs to reduce the risk of complications and improve the quality of life even in older patients is confirmed. The analysis of data from numerous large studies allowed the authors to identify the main principles for selecting antihypertensive drugs in elderly patients. Slow calcium channel blockers, angiotensin converting enzyme inhibitors, and low-dose diuretics should be prescribed as first-line drugs. At the next stage of treatment, in case of unsatisfactory results of initial therapy, the addition of mineralocorticoid receptor antagonists, alpha-blockers, and selective imidazoline receptor agonists should be considered. The main approaches to antihypertensive therapy in patients with metabolic syndrome and diabetes mellitus are described. The authors note the fact of unfavorable impact of metabolic syndrome on cardiovascular system, which provides rationale for aggressive treatment of hypertension in such clinical cases where several drugs may be used to achieve a stable antihypertensive effect. Diuretics, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers are recommended as first-line antihypertensive pharmacotherapy in these patients. The authors argue in favour of the use of antihypertensive drug combinations in one dosage form as one of the effective ways to solve the problem of adherence to treatment in elderly patients and patients with concomitant metabolic disorders.

Rupture of aneurysm of the middle cerebral artery along with stenosis of the internal carotid and coronary arteries

This article presents the results of treatment of a patient with rupture of a giant intracerebral aneurysm of the left middle cerebral artery (MCA), hemodynamically significant stenosis of the internal carotid artery on the left and the trunk of the left coronary artery with multiple lesions of the coronary arteries (anterior descending artery, diagonal branch, right coronary artery). A phased surgical correction was performed, with the time period between stages being 2 months, as follows:Stage 1 — open microsurgical clipping of the aneurysm of the left MCA and removal of intracerebral hematoma. The usage of the standard treatment volume in the form of 3H therapy (hypertension, haemodilution and hypervolemia), as well as slow calcium channel blockers in the postoperative period, was associated with a high risk of developing cardiovascular complications due to the presence of occlusal–stenotic lesions of the coronary and brachiocephalic channels. In the postoperative period, the patient received antiplatelet therapy (acetylsalicylic acid 100 mg at lunch), lipid-lowering therapy (rosuvastatin 20 mg in the evening) and anti-hypertensive therapy (bisoprolol 2.5 mg in the morning; perindopril 2.5 mg in the evening; spironolactone 25 mg in the morning; torasemide 10 mg in the morning; valparin XP 500 mg 2 times a day). On day 14, the patient was transferred from the intensive care unit, and on day 20, the patient was discharged from the hospital in satisfactory condition.Stage 2 — a combined operation in the amount of carotid endarterectomy (CEE) with plastic surgery of the biological patch on the left with plastic reconstruction of the reconstruction zone with a patch from the xenopericardium and coronary bypass grafting (CABG). Tactics were confirmed as optimal, taking into account the stratification of the risk of complications in the postoperative period when applying the new interactive program ‘Program support for the decision-making process for choosing a surgical re-vascularisation strategy for multifocal atherosclerosis’ (certificate of registration of a computer program RU 2017619457). Brain protection during CEE was achieved by invasive measurement of retrograde pressure (60 % of systemic blood pressure (BP)) and intraoperative increase in blood pressure to 180/90 mm Hg. CABG was performed using cardiopulmonary bypass. An epiaortic ultrasound scan was used to select the position of the implantation of a venous shunt into the aortic wall. Intraoperative flowmetry was used to regulate the quality of the implanted shunts.The patient was discharged 10 days after the surgery from the hospital in satisfactory condition. Conservative therapy, initiated after stage 1 of re-vascularisation, was continued.Clipping of intracerebral arterial aneurysm during its rupture and reconstructive interventions on the internal carotid artery and coronary arteries could be performed combined with the possibility of endovascular correction. However, due to the presence of an unstable atherosclerotic plaque, the possibility of interventional correction of the internal carotid artery was excluded, and the condition of the coronary bed at the time of stage 1 remained unknown. An additional argument in favour of open microsurgical clipping of the aneurysm was the need for the removal of intracerebral hematoma.The treatment strategy chosen here was found to be safe and effective. Satisfactory outcome of the surgery was achieved due to a complete range of perioperative examinations. The implemented tactics prevented the development of complications. The data obtained here would form the basis for the development of recommendations for selecting the optimal tactics of re-vascularisation in combined lesions of intracranial, extracranial and coronary arteries. Received 21 April 2020. Revised 27 April 2020. Accepted 28 April 2020. Funding: The study did not have sponsorship. Conflict of interest: Authors declare no conflict of interest. Author contributionsConception and design: А.N. Kazantsev, R.S. TarasovLiterature review: K.P. Chernykh, N.E. Zarkua, R.Y. Leader, G.Sh. BagdavadzeDrafting the article: А.N. KazantsevIllustrations: А.N. Kazantsev, K.P. Chernykh, N.E. Zarkua, R.Y. Leader, G.Sh. BagdavadzeCritical revision of the article: N.E. Zarkua, R.S. Tarasov, Y.P. LinetsFinal approval of the version to be published: А.N. Kazantsev, R.S. Tarasov, K.P. Chernykh, N.E. Zarkua, R.Y. Leader, G.Sh. Bagdavadze, Y.P. Linets

Arterial hypertension after heart transplantation

Aim To evaluate incidence of arterial hypertension (AH) in the posttransplantation period and to identify risk factors for this complication.Materials and methods From January, 2010 through December, 2017, 96 heart transplantations (HT) (70 men and 26 women aged 46.5±13.9 years) were performed. During the first month following HT, 8 recipients died and were excluded from the analysis. The retrospective evaluation of results included 88 patients followed up for more than one year.Results For the entire post-HT period (maximum 92 months), AH was observed in 75 of 88 (85%) recipients. Post-HT AH was correlated with male gender (r=0.24; p=0.031), history of smoking before HT (r=0.45; p<0.001), history of ischemic heart disease (IHD) (r=0.28; p=0.01), older age (r=0.35; p=0.001), higher body weight index (r=0.37; p=0.0005), creatinine level (r=0.37; p=0.001), and low-density lipoprotein cholesterol level (r=0.27; p=0.04). Interrelations with other AH risk factors were not found. Most patients developed AH within the first two years after HT. During the first year, AH was diagnosed in 60% (53 of 88) of patients (relapse, 85% (n=29); newly diagnosed, 45% (n=24), p=0.0003). At two years, AH was detected in 79% (46 of 58) of patients (relapse, 53% (n=18); newly diagnosed, 53% (n=28), p=0.9). All recipients received an adequate antihypertensive therapy. 40-63% of patients required a single-drug therapy at different points of follow-up; from 29 to 45% of patients required a two-drug therapy, and 5-15% of patients required three or more drugs. During all 5 years of treatment, most patients used angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) (70-87%) and slow calcium channel blockers (SCCB) (48-53%). The presence of AH following HT was associated with development of all cardiovascular events (CVE; r=0.31; p=0.012) whereas persistent AH, which required a combination antihypertensive treatment, was associated with a high mortality (r=0.61; p=0.015).Conclusion AH is a frequent complication of HT (85%), which is newly diagnosed in most patients during the first two years. AH incidence was higher for male recipients with a history of IHD, hypertension, and smoking. Approximately half of patients required only a single-drug antihypertensive therapy. After HT, the most frequently prescribed drugs included ACE inhibitors or ARBs and SCCBs (70-87% and 48-53%, respectively, depending on the time elapsed after HT). Persistent AH requiring a treatment with two or more antihypertensive drugs was associated with development of all CVEs and a higher long-term mortality.

Влияние строения ароматических групп алкоксифенилтриазаалканов на их кардиотропную активность

Ранее нами были получены соединения АЛМ-802 (тригидрохлорид N1-(2,3,4-триметоксибензил)-N2-{2-[(2,3,4-триметоксибензил)амино]этил}-1,2-этандиамина) и АЛМ-803 (тригидрохлорид N1-(3,4,5-триметоксибензил)-N2-{2-[(3,4,5-триметоксибензил)амино]-этил}-1,2-этандиамина), сочетающие фармакофорные элементы ингибиторов окисления свободных жирных кислот триметазидина и ранолазина и блокатора медленных кальциевых каналов верапамила. Эти вещества обладали противоишемической и антиаритмической активностью. В данной работе получено новое соединение АЛМ-843 (тригидрохлорид N1-(3,4-диметоксибензил)-N2-{2-[(3,4-диметоксибензил)амино]этил}-1,2-этандиамина), проявившее только антиаритмическое действие. На основание этого сделано предположение о том, что антиаритмическая активность линейных производных алкоксифенилтриазаалканов обусловлена наличием в них 3,4-диметоксифенильного фармакофора, содержащегося и в верапамиле. Это предположение было подтверждено методом молекулярного докинга, с использованием которого выявлено сходство в связывании всех перечисленных производных алкоксифенилтриазаалканов с сайтом связывания верапамила потенциал-зависимого Ca2+-канала.

Analysis of adverse reactions of antihypertensive drugs registered in the Republic of Crimea for the period 2011-2016

The aim of study was to analyze and investigate the severity of adverse reactions (AR) on drugs used for arterial hypertension treatment in patients living in the Republic of Crimea for the period 2011—2016. Materials and methods . We studied notification cards about AR registered in the regional database of spontaneous messages ARCADe. We analyzed 211 notification cards about AR in patients with proven arterial hypertension diagnosis (ICD code П0—П5). Results. Drugs from the groups of angiotensin-converting enzyme inhibitors and slow calcium channel blockers most often cause AR, among them enalapril and amlodipine are the absolute leaders. AR occurred less frequently in application of drugs from the groups of в-blockers and angiotensin IIreceptor blockers. The study of the clinical manifestations of AR showed that most of them were allergic reactions of varying severity (skin itch, urticaria, swelling of lips, eyelids, tongue). The number of such cases was 70 (33.2 %) from all registered cases of AR on antihypertensive drugs. Examination of the outcomes of AR in patients taking antihypertensive drugs showed that the development of temporary disability was observed in 19 (9 %) cases, the hospitalization of outpatients as a result of AR development on drugs was required in 7 (3.3 %) cases, and in 2 cases patients had to prolong hospitalization. Life-threatening conditions in the form of Quincke’s edema were reported in 13patients. In the remaining 170 (80.6 %) cases AR were not serious and did not cause the above consequences. Assessment of AR severity revealed that mild AR were most common, much less often antihypertensive drugs caused severe AR (the incidence ranged from 5 to 13 %, depending on the method for severity assessment). Conclusion . The obtained results confirm our previously published data that in the structure of AR on antihypertensive drugs, bulk of the reports associated with angiotensin-converting enzyme inhibitors. Most often antihypertensive drugs caused mild AR.

ASSESSMENT OF ACHIEVEMENT OF THE TARGET LEVEL OF BLOOD PRESSURE IN PATIENTS WITH HYPERTENSION AND TYPE 2 DIABETES WITHOUT MANIFESTED MICRO-AND MACROVASCULAR COMPLICATIONS IN OUTPATIENT PRACTICE

Aim. To evaluate the background which antihypertensive therapy the most frequently achieved target blood pressure (BP) level in patients with hypertension and type 2 diabetes mellitus without manifested micro- and macrovascular complications in outpatient practice. Materials and methods. An open nonrandomized observational study wits analysis of primary medical records of patients was performed. Results. The data of 170 patients meeting the inclusion criteria were analyzed. Only 60 of patients reached the target BP level. In this case, slow calcium channel blockers (SCCB) and beta-blockers (BB) were most often prescribed - in 25,8 and 23,4 %, respectively. Angiotensin converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARBs) were prescribed in 14,5 and 15,3 %, respectively Fixed combinations (FC) prescribed in 15,4 % cases, most often this were diuretics combined with ACEI or ARBs. Conclusion. In the study group the target level of BP was reached in 35,3 % cases. Most often it was achieved against the background of two- and three-component therapy (31,7 and 45 %, respectively). FC were appointed only in 15,4 % cases. Low frequency of ACEI and ARBs prescriptions, which should be first-line drugs in these patients, was revealed.

Study of the influence of medicinal preparations on the indicators of mixed saliva in patients with essential hypertension

Aim. To identify the effect of drugs on the functional state of the salivary glands in patients with essential hypertension. Methods. A total of 38 hypertensive patients were examined. Depending on the prescribed drug therapy, all patients were divided into four groups: group 1 received an angiotensin-converting enzyme inhibitor; group 2 received a beta-blocker; group 3 received a slow calcium channel blocker, group 4 received a statin. For the analysis of salivary glands, the salivation rate was calculated, pH of the mixed saliva and activity of lactate dehydrogenase, alkaline phosphatase, aspartate aminotransferase, and alanine aminotransferase were measured. Results. In the mixed saliva of hypertensive patients, the salivation rate decreased in patients taking statins. The pH values of saliva in all groups were within neutral values, from 6.80 to 7.04. The amount of total protein was increased in patients taking angiotensin-converting enzyme inhibitors and statins, and was reduced in patients taking beta-adrenoblockers and slow calcium channel blockers. High activity of lactate dehydrogenase and aspartate aminotransferase was detected in patients taking statins, which indicates activation of anaerobic bacteria and inflammatory processes in the oral cavity. The increased activity of alkaline phosphatase, noted in patients taking beta-adrenoblockers, suggests possible violation of the processes of enamel mineralization. High activity of alkaline phosphatase and aspartate aminotransferase in the mixed saliva of observed patients coincides with the increase of papillary marginal alveolar index up to 27±4.6%, which indicates the development of pathology in the periodontal tissues. Conclusion. In patients receiving statins salivation function was suppressed; increased activity of lactate dehydrogenase and aspartate aminotransferase in the mixed saliva indicates activation of anaerobic microflora and tissue protein breakdown in the oral cavity.

Pathogenetic bases and efficacy of slow calcium channel blockers in the therapy of recurrent peptic ulcer disease associated with hypertension

To clarify blood calcium concentrations (BCCs) as an indicator of the functional state of the calcium-regulating system in the concomitant course of recurrent peptic ulcer disease (PUD) and hypertension, by comparing with the severity of a ulcerous process, with changes in regional microcirculation, and with the functions of the stomach. To elucidate the pathogenetic justification for and clinical efficacy of slow calcium channel blockers (SCCBs) in the treatment of this comorbidity. In the case-control study, each patient with recurrent PUD and grade 1, Stage I hypertension (Group 1; n=23) corresponded to a recurrent PUD patient matched for sex, age, and ulcer site (Group 2, n=23). The complex of treatment for these patients included the SCCB nifedipine. A control group consisted of 56 recurrent PUD patients who received combination therapy without nifedipine. All the patients over time underwent clinical and endoscopic examinations and determinations of BCCs, indicators of gastric secretory and motor functions, and regional microcirculation in the gastroduodenal mucosal biopsy specimens. Recurrent PUD was present with a reliable BCC increase that was more substantial when it was associated with hypertension. Calcium imbalance was accompanied by changes in regional microcirculation and gastric secretory and motor functional indicators forming an acid peptic factor, as well as by hypermotor dyskinesia, which were more pronounced in patients with comorbidity. Incorporation of a SCCB into a complex of therapy for recurrent PUD to eliminate the pathogenic effect of blood calcium contributed to more rapid arrest of the clinical symptoms of a recurrence, to elimination of acute-phase microcirculatory disorders in the gastroduodenal zone, and to the recovery of gastric functional indicators. Elevated blood pressure was ruled out during the therapy of concomitant diseases. Incorporation of a SCCB into the combination therapy of recurrent PUD associated with hypertension is pathogenetically sound and clinically effective.

Synthesis, Characterization and Pharmacological Evaluation of Thiosalicylamide Derivative as a Class of Calcium Channel Blocker

Objective: Hypertension is one of the major causes of the cardiovascular diseases and in the later stages, it also damages the brain, kidneys, eyes and coronary arteries. It is also life threatening as it causes heart strokes and attacks. The calcium channels regulates blood pressure by muscle contraction triggered by neurotransmitter release to electrical excitation. Method: Calcium channel blocker drugs reduce intracellular calcium transfer to limit ATP release to reduce muscle cell contractility. They act, especially on the nodal tissues in the heart and arterial smooth muscle cells in which only slow calcium channel blockers opens without triggering of fast sodium ion channels. Pharmacophore approach is employed to generate novel thiosalicylamide derivatives having calcium channel blocking activity for treatment of hypertension. Result: These novel thiosalicylamide derived lead molecules are synthesized and tested for their in-vivo pharmacological activity by using isolated guinea-pig ileum muscles.

The calcium-regulating system and recurrent peptic ulcer

To elucidate the functional state and value of the calcium-regulating system, calcium and phosphorus metabolism in the pathogenesis and sanogenesis of peptic ulcer (PU); to define the possible ways to correct shifts found in the treatment of disease relapse, by affecting the different levels of their disorders. A total of 220 patients with recurrent PU were examined by determining the blood levels of parathyrin, calcitonin, calcium and phosphorus, as well as gastric secretory and motor functions. Recurrent PU was accompanied by a considerable increase in the blood concentration of parathyroid hormone and calcium, a slight rise in that of calcitonin, and a significant reduction in that of phosphorus. These changes were attended by a substantial increase in gastric acid- and pepsinogen-forming functions, a decrease in the production of gastric mucoproteins, and hypermotor dyskinesia. The use of calcitrin, nifedipine, and etidronic acid, which eliminate dysfunction of the calcium-regulating system at different levels of its impairments, leads to a significant reduction in the time of alleviation of the clinical and endoscopic manifestations of a recurrence. Recurrent PU runs in the presence of calcium-regulating system dysfunction. Incorporation of the thyroid C-cell hormone preparation calcitrin, the slow calcium-channel blocker nifedipine, and etidronic acid bisphosphonate into a complex of treatment for a disease recurrence is pathogenetically sound and clinically effective.

Complex of Nifedipine with Glycyrrhizic Acid as a Novel Water-Soluble Antihypertensive and Antiarrhythmic Agent

Abstract: Present study describes the synthesis and pharmacological characteristics of the 18-glycyrrhizic acid com-plex with nifedipine, molecular composition 1:4. The study showed that complex decreases arterial pressure at the dose of nifedipine 10 times smaller than the therapeutic dose. Antiarrhythmic effect of nifedipine in this complex was obtained at the dosage 29 times lower than that ensuring antihypertensive action. Keywords: Nifedipine, Glycyrrhizic acid, Drug delivery, Complexation. INTRODUCTION Nifedipine, dimethyl ether 2,6-dimethyl-4-(2'-nitrophenyl)- 1,4-dihydropyridine-3,5-dicarboxylate, one of the commonly used 1,4-dihydropyridine derivatives, is a selective slow calcium channel blocker. Its prevalence as an enteral antihypertensive agent can be explained both by pharmacological properties, which garner attention of practi-cal cardiologists again, and by technological availability of the pharmacon substance. As for the drug formulations for intravenous administration for acute care applications, some problems arise in their usage. In particular, administration of the recommended injection forms of the drug requires spe-cial precaution because the pharmacon solvent contains ethanol. Therefore, developing water-soluble forms of nifedipine suitable for parenteral administration is still a challenging problem. It is known that the use of carbohydrate-containing me-tabolites of microbial and plant origin for formation of pharmacon complexes is a rather promising approach to de-veloping novel drug carriers for known drugs. Cyclodextrins (CD) appear to be the highest in the list of the most exten-sively studied and practically used agents. Complexation of pharmacons using CD ensures im-proved water solubility of pharmacons, which frequently enhances their biovitality as well. In complexes with CD pharmacons are shown to have an elongated therapeutic ef-fect and enhanced resistance to early unwanted metabolism in the gastrointestinal tract. Complexes with CD are known for more than 70 phar-macons with different types of activity. Twenty CD com-plex-based drugs are produced commercially, including 7 preparations for injections [1-3]. The complexes of nifedip-ine with hydroxypropylmethyl cellulose [4, 5], with

Value of the results of INSIGHT and ENCOR studies for clinical practice

The paper presents the latest data on the clinical efficacy and safety of OSMO adalate (Nifedepine GITS), a lomg-acting drug from a group of slow calcium channel blockers. In addition to its pronounced and steady-state antihypertensive effect during monotherapy, OSMO adalate, when long used, causes a significant reduction in the incidence of cardiovascular complications, including fatal events in particular, and in patients with prior myocardial infarction. The antihypertensive effect of this drug is not inferior to that of the routine diuretic therapy. However, OSMO adalate more favorably affects the metabolism of carbohydrates, lipids, and uric acid and less frequently induced peripheral arterial oclusions, gout, and diabetes mellitus. The use of this drug has been found to prevent an increase in the thickness of carotid intimomedial layers, as well as progression of coronary arterial calcinosis (the use of a diuretics does not). Moreover, the ENCOR study has revealed that OSMO adalate therapy also prevents spastic reactions in the coronary arteries due to their better endothelial function.

Slow channel calcium inhibition blocks proinflammatory gene signaling and reduces macrophage responsiveness.

This study investigates the possible intracellular mechanisms responsible for calcium antagonist protection in tissue-fixed macrophages, a central modulator of the proinflammatory phenotype. Rabbit alveolar macrophages were exposed to lipopolysaccharide in the presence of different specific calcium antagonists. Cellular and nuclear protein were extracted and analyzed by Western blot for the phosphorylated forms of PYK2, ERK 1/2, and p38, and nuclear translocation of NF-kappaB and AP-1. Tumor necrosis factor-alpha (TNF-alpha) expression was measured by an L929 bioassay on cellular supernatants. Statistical analysis was performed by unpaired Student's t tests. Cells pretreated with 100 to 500 micromol/L of diltiazem or 50 to 100 micromol/L of verapamil, both slow channel calcium blockers, led to dose-dependent reductions in lipopolysaccharide-induced PYK2 and ERK 1/2 phosphorylation, and nuclear translocation of AP-1 when compared with controls (p < 0.05). Neither inhibitor had any significant effect on p38 or NF-kappaB translocation. EGTA an extracellular calcium chelator, had no significant effect on any intracellular process studied. A dose-dependent reduction in TNF-alpha production was demonstrated with diltiazem and verapamil (p < 0.05), with no effect induced by EGTA. Slow channel calcium influx is essential for optimal intracellular signaling through PYK2 and ERK 1/2. This reduced intracellular signaling correlated with reduced AP-1 translocation and TNF-alpha production. Extracellular calcium chelation had no significant effect on intracellular signaling or TNF-alpha production. This study further elucidates the protective mechanism of action of calcium channel blockade by diltiazem and verapamil by reducing intracellular calcium release and down-regulating the excessive proinflammatory phenotype.

The use of Fourier analysis in the calculation of trough to peak ratio from ambulatory blood pressure measurements

The trough:peak (T:P) ratio serves as an index of efficacy of antihypertensive drugs with respect to their dose and dose interval. There is no consensus regarding the method for the calculation of the T:P ratio. We assessed the influences of curve smoothing, the average fall in 24-h mean arterial pressure (MAP) and the length of the peak effect period on the result of T:P ratio calculation. Forty-two patients with essential hypertension (aged 27-81 years; 20 males) had a 24-h ambulatory blood pressure (BP) measurement on two occasions. The first was performed at baseline, the second after 12 weeks of treatment with a beta-blocker, angiotensin-converting enzyme inhibitor, calcium slow-channel blocker, diuretic or a centrally acting drug, all taken once daily. BP data were analysed both by Fourier analysis (FA) with four harmonics and by time block analysis (TBA). The peak effect was defined as the maximum drop in MAP over a period of 0 to 3 h following drug intake at any time in the 24 h, and the trough effect as the fall in MAP over the last 2 h of the dose interval. FA gave higher T:P ratio values than TBA (0.51 vs 0.43; P < 0.05) and the variability of the results was reduced by FA (FA: 0.49-0.52; TBA: 0.35-0.46). A greater fall in 24-h MAP was associated with a higher T:P ratio (r = 0.42, P < 0.02; TBA: r = 0.31, P = 0.09). Half of the patients whose fall in 24-h MAP after treatment was <10 mm Hg, had higher trough BP values, resulting in negative T:P ratios. With increasing length of the peak period, the calculated peak effect was reduced and the T:P ratio increased (both FA and TBA: P < 0.001). The mean trough responses during the last 2 h of the dose interval were similar after TBA and FA. Based on these data, we recommend the use of FA for calculation of T:P ratios, especially when the magnitude of the antihypertensive effect is small. We also suggest using peak- and trough-effect periods of 2 h each. Whenever T:P ratios are calculated, the method used for curve smoothing and the length of peak- and trough-effect periods should be specified in order to obtain meaningful results. T:P ratios need to be interpreted individually together with the magnitude of the antihypertensive drug effect and the circadian BP profile.

Hemolink-induced effects on intestinal motor function and attenuation of these effects by selected agents.

Hemolink, an oxidized, ring-opened raffinose-crosslinked hemoglobin-based oxygen carrier produced by Hemosol Inc., stimulates esophageal peristalsis, possibly by interference with neural NO-mediated effects. The effects of Hemolink on jejunal tone and contractions, arterial pressure and heart rate were measured in anesthetized rats, and the effect of selected agents in attenuating or reversing these effects was studied. Infusion of L-NAME was used to validate the study model; it caused an immediate increase in tone and initiated phasic contractions indicating that the model was responsive to NO-mediated effects. Hemolink administration caused effects on intestinal motor function similar to those caused by L-NAME, including increases in basal tone and contraction amplitude. Rat whole blood caused none of these changes. The Hemolink-induced effects were less immediate in some animals compared to those observed after L-NAME. As well there was greater inter-animal variability on the effects. Hemolink administration also caused a mild increase in arterial blood pressure and a reciprocal decrease in heart rate in some animals. Co-administration of morphine, a common analgesic that has been reported to influence the motility of the GI tract; L-arginine, a substrate for NO synthesis; and glycopyrrolate, an anti-cholinergic agent, did not significantly modulate the Hemolink effects, whereas nitroglycerin, an NO donor; and nifedipine, a slow calcium-channel blocker, attenuated or reversed these effects.