[Risks of magistral preparations in pediatrics]. / Risques des préparations magistrales en pédiatrie.

Vasoreactive pulmonary arterial hypertension (PAH) in children is a form of idiopathic PAH that responds to vasoreactive testing with nitric oxide (NO) by a significant decrease of pulmonary vascular resistances and pressure. Oral calcium channel antagonists (CCA) that allow pulmonary arterial vasodilation are the treatment of choice. The therapeutic effect is strongly depending on adequate drug intake. In growing children, drug dose must be adapted to weight. In case of unavailability of low-dose pharmaceutical preparations, officinal formulations become mandatory. Officinal formulations may be related to a multitude of errors at different steps including prescription, transcription, preparation and administration. This may have life-threatening consequences for the child.To illustrate this, we report a case of a compounding error with underdosage of CCA, leading to acute cardiovascular failure in an adolescent with vasoreactive PAH.

L'hypertension artérielle pulmonaire (HTAP) vasoréactive chez l'enfant est une forme d'HTAP idiopathique qui répond au test de vasoréactivité au monoxyde d'azote (NO) par une diminution significative des pressions et résistances vasculaires pulmonaires. Le traitement de choix de cette forme d'HTAP est l'administration d'antagonistes des canaux calciques (ACC) par voie orale. Ce traitement entraîne une vasodilatation artérielle pulmonaire, elle-même étroitement dépendante de la prise adéquate du médicament. Chez les enfants en croissance, la dose du médicament doit être adaptée au poids. De façon générale, en l'absence de préparation à faible dose disponible dans les laboratoires pharmaceutiques, l'utilisation de formulations officinales devient obligatoire. De la prescription à l'administration, en passant par la transcription et la préparation, de nombreuses erreurs humaines et techniques peuvent survenir qui peuvent impacter la morbi-mortalité de l'enfant. Nous rapportons le cas d'une adolescente avec HTAP vasoréactive chez qui une erreur de préparation magistrale avec sous-dosage de l'ACC a conduit à une décompensation cardio-vasculaire aiguë et discutons de mesures préventives potentielles.

ß-blockers, calcium antagonists, and mortality in stable coronary artery disease: an international cohort study.

AIMS: The effect of first-line antianginal agents, ß-blockers, and calcium antagonists on clinical outcomes in stable coronary artery disease (CAD) remains uncertain. METHODS AND RESULTS: We analysed the use of ß-blockers or calcium antagonists (baseline and annually) and outcomes in 22 006 stable CAD patients (enrolled 2009-2010) followed annually to 5 years, in the CLARIFY registry (45 countries). Primary outcome was all-cause death. Secondary outcomes were cardiovascular death and the composite of cardiovascular death/non-fatal myocardial infarction (MI). After multivariable adjustment, baseline ß-blocker use was not associated with lower all-cause death [1345 (7.8%) in users vs. 407 (8.4%) in non-users; hazard ratio (HR) 0.94, 95% confidence interval (CI) 0.84-1.06; P = 0.30]; cardiovascular death [861 (5.0%) vs. 262 (5.4%); HR 0.91, 95% CI 0.79-1.05; P = 0.20]; or cardiovascular death/non-fatal MI [1272 (7.4%) vs. 340 (7.0%); HR 1.03, 95% CI 0.91-1.16; P = 0.66]. Sensitivity analyses according to ß-blocker use over time and to prescribed dose produced similar results. Among prior MI patients, for those enrolled in the year following MI, baseline ß-blocker use was associated with lower all-cause death [205 (7.0%) vs. 59 (10.3%); HR 0.68, 95% CI 0.50-0.91; P = 0.01]; cardiovascular death [132 (4.5%) vs. 49 (8.5%); HR 0.52, 95% CI 0.37-0.73; P = 0.0001]; and cardiovascular death/non-fatal MI [212 (7.2%) vs. 59 (10.3%); HR 0.69, 95% CI 0.52-0.93; P = 0.01]. Calcium antagonists were not associated with any difference in mortality. CONCLUSION: In this contemporary cohort of stable CAD, ß-blocker use was associated with lower 5-year mortality only in patients enrolled in the year following MI. Use of calcium antagonists was not associated with superior mortality, regardless of history of MI.

Searching for calcium antagonists for hypertension disease therapy from Moutan Cortex, using bioactivity integrated UHPLC-QTOF-MS.

INTRODUCTION: Calcium channel blockers (CCBs) are currently the most commonly used drugs for the treatment of hypertension. Moutan Cortex (MC), a traditional Chinese herb, has been found to have an anti-hypertensive effect. However, its potential mechanisms in the regulation of intracellular calcium concentration ([Ca2+ ]i ) remain poorly understood. OBJECTIVE: The main objective of this work was to identify the potential calcium antagonists from MC and study their molecular mechanisms. METHODS: Ultra-high performance liquid chromatography-quadrupole-time-of-fight-mass spectrometry (UHPLC-QTOF-MS) analysis combined with a dual-luciferase reporter assay was utilised to systematically screen the calcium antagonistic active ingredients in the methanol extract of MC. Additionally, the molecular mechanism of these compounds was further studied using live-cell imaging analysis with the calcium ion (Ca2+ ) probe dye fluo-4/AM to monitor changes in [Ca2+ ]i . RESULTS: Three monoterpenoids (paeoniflorin, benzoylpaeoniflorin and mudanpioside C), one phenolic acid (paeonol) and one gallotannin (1,2,3,4,6-O-pentagalloylglucose) were screened out as potential calcium antagonists in MC. Among them, the calcium antagonistic activity of benzoylpaeoniflorin, mudanpioside C and 1,2,3,4,6-O-pentagalloylglucose is first reported. Additionally, paeoniflorin, benzoylpaeoniflorin, mudanpioside C and paeonol can effectively block voltage-operated Ca2+ channels (VOCCs) to exert calcium antagonism, while 1,2,3,4,6-O-pentagalloylglucose plays a role in blocking inositol 1,4,5-trisphosphate receptors (IP3Rs). CONCLUSION: This work indicated that the anti-hypertensive efficacy of MC acted through multiple components selectively antagonising multiple cell signalling pathways to regulate [Ca2+ ]i . Furthermore, they could be considered as a reference standard for controlling the quality of Chinese medicinal materials.

Identification of Chemical Markers for the Discrimination of Radix Angelica sinensis Grown in Geoherb and Non-Geoherb Regions Using UHPLC-QTOF-MS/MS Based Metabolomics.

This research aimed to discover chemical markers for discriminating radix Angelica sinensis (RAS) from different regions and to explore the differences of RAS in the content of four active compounds and anti-inflammatory activities on lipopolysacchride (LPS)-induced RAW264.7 cells and calcium antagonists on the HEK 293T cells of RAS. Nine compounds were selected as characteristic chemical markers by ultra-high-performance liquid chromatography-quadrupole/time-of-flight mass spectrometry (UHPLC-QTOF-MS/MS), based on metabolomics, in order to rapidly discriminate RAS from geoherb and non-geoherb regions. The contents of senkyunolide I and butylidenephthalide in geoherb samples were higher than those in non-geoherb samples, but the contents of ferulic acid and levistolide A were lower in the geoherb samples. Furthermore, the geoherbs showed better nitric oxide (NO) inhibitory and calcium antagonistic activities than the non-geoherbs. These results demonstrate the diversity in quality of RAS between geoherbs and non-geoherbs.

Ten years of follow-up in a large family with familial hemiplegic migraine type 1: Clinical course and implications for treatment.

Background Familial hemiplegic migraine (FHM) is a rare, genetic form of migraine with aura. The severity of the aura imposes an effective prophylaxis that is currently based on standard anti-migraine drugs. To this concern, only short-term reports are currently available. Methods Eight patients from a multigenerational FHM type 1 family harbouring a T666M mutation in the CACNA1A gene were referred to our ataxia outpatient clinic. Medical history, general and neurological examination as well as therapeutic approaches were recorded regularly on a routine basis for an average period of 13 years (range 9-15 years). Brain imaging studies and EEG data were also collected. Results Our long-term follow-up revealed that ictal manifestations, which usually improve after the adolescence, may reoccur later in the adulthood. Permanent neurological signs as assessed by means of clinical evaluation as well as follow-up MRIs, EEGs and neuropsychological testing remained stable. Interval therapy with non-selective calcium antagonists reduced the burden of migraine attacks and was well tolerated in the long term.

Acute blood pressure elevation: Therapeutic approach.

International guidelines have suggested to avoid the term "hypertensive crisis" for the description of an acute and severe increase in blood pressure (BP) and to consider the definition of 'hypertensive emergencies' or 'hypertensive urgencies'. These two clinical presentations are characterized by the presence of high BP values but imply a different diagnostic and therapeutic approach. Hypertension awareness, treatment and control are slightly increased in the last years mostly in the United States and in some European nations. Nevertheless the prevalence of hypertensive emergencies is still high and remains associated to a higher mortality. International Guidelines have also given some recommendations regarding the target BP during treatment and the use of antihypertensive drugs in hypertensive emergencies, although the adherence to these indications is frequently suboptimal. The present paper is aimed to update the currently available data on the treatment of hypertensive emergencies.

State-of-the-art treatment of hypertension: established and new drugs.

The treatment of essential hypertension is based essentially on the prescription of four major classes of antihypertensive drugs, i.e. blockers of the renin--angiotensin system, calcium channel blockers, diuretics and beta-blockers. In recent years, very few new drug therapies of hypertension have become available. Therefore, it is crucial for physicians to optimize their antihypertensive therapies with the drugs available on the market. In each of the classes of antihypertensive drugs, questions have recently been raised: are angiotensin-converting enzyme (ACE) inhibitors superior to angiotensin II receptor blockers (ARB)? Is it possible to reduce the incidence of peripheral oedema with calcium antagonists? Is hydrochlorothiazide really the good diuretic to use in combination therapies? The purpose of this review is to discuss these various questions in the light of the most recent clinical studies and meta-analyses. These latter suggest that ACE inhibitors and ARB are equivalent except for a better tolerability profile of ARB. Third generation calcium channel blockers enable to reduce the incidence of peripheral oedema and chlorthalidone is certainly more effective than hydrochlorothiazide in preventing cardiovascular events in hypertension. At last, studies suggest that drug adherence and long-term persistence under therapy is one of the major issues in the actual management of essential hypertension.

Trends in antihypertensive treatment--lessons from the National Acute Stroke Israeli (NASIS) registry.

BACKGROUND: Recent guidelines recommended different approaches to hypertension therapy. Our aim was to evaluate trends in blood pressure (BP) management among patients admitted with acute stroke over the past decade. METHODS: The study population comprised 6279 consecutive patients, admitted with an acute stroke, and included in a national registry of three consecutive periods conducted during the years 2004-2010. We compared patients' characteristics and temporal trends of antihypertensive therapy utilization before hospital admission. RESULTS: Among 4727 hypertensive patients, 3940 (83%) patients have taken antihypertensive drug therapy - 1430 (30.2%) a single agent, 1500 (31.7%) two agents and 1010 (21.4%) three or more antihypertensive agents. The most common class used was renin-angiotensin system (RAS) blockers (n = 2575; 54%) followed by beta-blockers (n = 2033; 43%). The same pattern was observed in patients treated with monotherapy. The use of RAS blockers and beta-blockers has increased over the years (p < 0.001 for both), whereas the use of diuretics decreased and the use of calcium antagonists remained stable. Among those who were treated with a single agent, the use of diuretics and calcium antagonists decreased and the use of RAS blockers increased, whereas the use of beta-blockers remained unchanged. CONCLUSIONS: RAS blockers and beta-blockers are the most common antihypertensive agents used in Israel. Over time, the use of RAS blockers and beta-blockers has increased, whereas the use of diuretics decreased.

Medication preventing postictal hypoperfusion and cognitive side-effects in electroconvulsive therapy: A retrospective cohort study.

Background: Electroconvulsive therapy (ECT) is associated with postictal confusion and cognitive side-effects. In rats, acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs) and calcium antagonists decreased postictal cerebral hypoperfusion along with reduction in postictal symptoms. In this study, in ECT-patients, we explore associations between use of these potentially protective medications and occurrence of postictal confusion and cognitive outcome. Materials and methods: In this retrospective, naturalistic cohort study, patient-, treatment-, and ECT-characteristics, were collected from medical files of patients treated with ECT for major depressive disorder (MDD) or bipolar depressive episode. To test for associations of use of these medications with occurrence of postictal confusion, 295 patients could be included. Cognitive outcome data were available in a subset of 109 patients. Univariate analyses and multivariate censored regression models were used to test for associations. Results: Occurrence of severe postictal confusion was not associated with use of acetaminophen, NSAIDs or calcium antagonists (n = 295). Regarding the cognitive outcome measure (n = 109), use of calcium antagonists was associated with higher post-ECT cognitive scores (i.e., better cognitive outcome; ß = 2.23; p = 0.047), adjusted for age (ß = -0.02; p = 0.23), sex (ß = -0.21; p = 0.73), pre-ECT cognitive score (ß = 0.47; p < 0.0001), and post-ECT depression score (ß = -0.02; p = 0.62), but use of acetaminophen (ß = -1.55; p = 0.07) as well as NSAIDs (ß = -1.02; p = 0.23) showed no associations. Conclusion: This retrospective study does not find arguments for protective effects of acetaminophen, NSAIDs or calcium antagonists against severe postictal confusion in ECT. As a preliminary finding, the use of calcium antagonists was associated with improved cognitive outcome after ECT in this cohort. Prospective controlled studies are necessary.

[Nimodipine in treatment of bipolar disorder]. / Primenenie nimodipina v terapii bipolyarnogo affektivnogo rasstroistva.

The purpose of this review is to correlate current data on the molecular mechanisms of action of the drug Nimodipine with its clinical effects and applicability in mental disorders belonging to the spectrum of affective pathology. The article discusses the prospects for using the calcium channel blocker nimodipine as a method of both mono and combination therapy for bipolar disorders with various types of course. Nimodipine is a selective blocker of voltage-dependent calcium channels, a dihydropyridine derivative. By blocking L type calcium channels, it prevents the entry of calcium ions into the cell. Due to its pronounced ability to penetrate the blood-brain barrier, it has a selective effect on brain neurons and has a vasodilating, antihypertensive and normotimic effect. Nimodipine blocks LTCC channels in brain neurons, thereby influencing synaptic plasticity, transmitter release and excitation-transcription coupling, which makes it possible to influence various clinical conditions with pathology in the area of affect, including bipolar disorders with ultra-rapid cycling, and also, in cases with high resistance and intolerance to other mood stabilizers.

New Aspects in the Management of Hypertension in Patients with Chronic Kidney Disease not on Renal Replacement Therapy.

With chronic kidney disease (CKD) being a global arising health problem, strategies for delaying kidney disease progression and reducing the high cardiovascular risk inherent to CKD, are the main objectives of the actual management of patients with kidney diseases. In these patients, the control of arterial hypertension is essential, as high blood pressure (BP) is a strong determinant of worst cardiovascular and renal outcomes. Achieving target blood pressures recommended by international guidelines is mandatory and often demands a multiple levels management, including several pharmacological and lifestyle measures. Even in the presence of adequate BP control, the residual cardiovascular risk remains high. In this respect, the recent demonstration that novel agents such as sodium glucose transporter 2 (SGLT2) inhibitors or the new non-steroidal mineralocorticoid antagonist finerenone can retard the progression of kidney diseases and reduce cardiovascular mortality on top of standard of care treatment with renin-angiotensin system inhibitors represent enormous progresses. These studies also demonstrate that cardiovascular and renal protection can be obtained beyond blood pressure control. Other promising novelties are still to come such as renal denervation and endothelin receptor antagonists in the setting of diabetic and non-diabetic kidney diseases. In the present review, we shall discuss the classic and the new aspects for the management of hypertension in CKD, integrating the new data from recent clinical studies.

[Medical expulsive treatment for ureteral stones.] / Tratamiento médico expulsivo de la litiasis ureteral.

INTRODUCTION: Medical Expulsive Treatment (MET) for ureteral stones has been questioned for the last few years. OBJECTIVES: The main goal of our study is to define the indications of MET, the different drugs that are used and their effectiveness and to propose a follow-up strategy. Secondary objectives include the effectiveness of MET in some special subgroups such as pregnant women and children and to assess aspects of MET cost-effectiveness compared with other options for ureteral lithiasis treatment (ureterorenoscopy or extracorporeal shock wave lithotripsy). MATERIAL AND METHODS: We have reviewed the most relevant clinical trials and meta-analysis evaluating the impact of the different drugs available for MET. For the research we used some keywords like "medical expulsive treatment/therapy", "ureteral lithiasis", "urolithiasis", "effectiveness", "alpha-blockers" and "calcium-antagonists". MEDLINE database was used for there search (using the portal web Pubmed). RESULTS: Highest quality studies currently availables how significant methodological limitations leading to heterogeneous and restricted evidence, which is only applicable to patients and lithiasis with specific conditions. Nevertheless, in general terms, it seems that MET can play a certain role in the expulsion of lithiasis ≥ 5mm y ≤ 10 mm located in the distal ureter, although it has not been possible to demonstrate that any of the drugs used may have special superiority in terms of effectiveness. In pregnancy and children, the recommendations of MET are also irregular. Finally, MET seemsto be an alternative cost-effective compared to active options of treatment. CONCLUSIONS: Higher quality clinical trials are needed to reliably advice MET. With the current evidence, it appears that MET can improve the expulsion of distal ureteral lithiasis ≥ 5 mm and ≤ 10 mm, even though we have not found differences between the drugs that are available for MET.

INTRODUCCIÓN: El Tratamiento Médico Expulsivo (TME) para litiasis ureterales ha sido puesto en cuestión durante los últimos años. OBJETIVOS: El objetivo principal de nuestro trabajo es definir las indicaciones del TME, los fármacos empleados y su efectividad y proponer un esquema de seguimiento. Los objetivos secundarios son analizar la efectividad del TME en algunos subgrupos especiales de la población como son las embarazadas y los niños y valorar aspectos de coste-efectividad del TME en comparación con otras opciones de tratamiento de litiasis ureterales (ureterorrenoscopia o litotricia extracorpórea por ondas de choque). MATERIAL Y MÉTODOS: Hemos realizado una revisión de los ensayos clínicos y metaanálisis de mayor relevancia que valoran la efectividad de los diferentes fármacos disponibles para el TME. Para la búsqueda bibliográfica hemos utilizado algunos términos como medical expulsive treatment/therapy", "ureteral lithiasis", "urolithiasis","effectiveness", "alpha-blockers" y "calcium-antagonists",siendo la principal base de datos consultada MEDLINE (a través del portal web PubMed). RESULTADOS: Aún los estudios de mayor calidad presentan importantes limitaciones metodológicas, lo que condiciona que la evidencia obtenida sea heterogénea y restringida a pacientes y litiasis que cumplan determinadas condiciones. En líneas generales, el TME puede tener cierto papel en la expulsión de litiasis de tamaño ≥5 mm y ≤10 mm localizadas en uréter distal, aunqueno se ha logrado demostrar que alguno de los fármacos utilizados pueda tener especial superioridad en términos de efectividad. En gestantes y niños las indicaciones delTME tampoco estan estandarizadas. Por último, el TME en comparación con opciones de tratamiento, parece ser una alternativa más coste-efectiva y la preferida por los pacientes según estudios sobre QoL. CONCLUSIONES: Es necesario realizar ensayos clínicos de mayor calidad para poder indicar el TME con unmayor nivel de evidencia. Con la evidencia actual, parece que el TME puede favorecer la expulsión de litiasis localizadas en uréter distal y con un tamaño ≥5 mm y ≤10 mm. A pesar de ello no se han podido encontrar diferencias entre las distintas opciones farmacológicas disponibles.

How Do I Manage Hypertension in Patients with Advanced Chronic Kidney Disease Not on Dialysis? Perspectives from Clinical Practice.

In the general population, the prevalence of moderate and severe chronic kidney disease (CKD) is usually below 5% but this figure is often higher in specific groups of patients such as those with type 2 diabetes. Patients with advanced CKD (CKD stage 3b and 4) are at high or very high cardiovascular risk, and their risk of progressing towards end-stage kidney disease (CKD stage 5) and the need of renal replacement therapy are elevated. Hypertension is a major cause of poor cardiovascular and renal outcomes in severe CKD. Therefore, an adequate control of blood pressure (BP) is mandatory. However, normalizing BP is often challenging in these patients because the clinical management of hypertension in advanced CKD is not well defined and rarely supported by large randomized controlled trials. In the present review, we discuss the characteristics of hypertension in advanced CKD, excluding dialysis, and its management integrating data from recent clinical studies and a pragmatic approach enriched by a long-standing clinical experience.

PAIT-Survey Follow-Up: Changes in Albuminuria in Hypertensive Diabetic Patients with Mild-Moderate Chronic Kidney Disease.

INTRODUCTION: Albuminuria is an early marker of kidney disease and reduction of albuminuria translates into a decreased occurrence of cardiovascular and renal outcomes. AIMS: To evaluate the changes in the prevalence of albuminuria in diabetic hypertensive patients treated with several combinations of renin-angiotensin aldosterone system with calcium channel blockers. METHODS: We analysed data from 668 unselected patients from the PAIT survey (mean age 60.4 ± 10.2 years, prevalence of males 38%), with and without albuminuria, maintained for 6 months with the previous treatment with amlodipine-valsartan, amlodipine perindopril, lercanidipine-enalapril, verapamil-trandolapril, nitrendipine-enalapril and felodipine-ramipril Albuminuria was assessed, as urinary albumin-creatinine ratio, using a Multistic-Clinitek device analyzer. Microalbuminuria was defined as a loss of 3.4-33.9 mg albumin/mmol creatinine (30-300 mg/g) and macroalbuminuria as a loss of > 33.9 mg albumin/mmol creatinine (> 300 mg/g). Blood pressure was measured with a validated digital device. RESULTS: At baseline, albuminuria was present in 310 subjects (46.4%) (microalbuminuria in 263 (84.8%), macroalbuminuria in 15.2%), and normoalbuminuria in 53.6% 358. After 6 months, the prevalence of subjects with albuminuria was significantly lowered (p < 0.01) by 23.5% (microalbuminuria - 23.9%, p < 0.01 and macroalbuminuria - 21.3%). The prevalence of subjects with microalbuminuria was reduced with all treatments: amlodipine-valsartan - 15.6%, amlodipine-perindopril - 11.8%, lercanidipine-enalapril - 41.3% and verapamil-trandolapril - 19.2%. Data with nitrendipine-enalapril and felodipine-ramipril were not analyzed, due to the low number of patients. The frequency of patients with normoalbuminuria was significantly higher (p < 0.01) with lercanidipine-enalapril compared with any other treatment. Blood pressure was significantly (p < 0.01) reduced, with a similar effect between treatments. CONCLUSIONS: The treatments decrease the prevalence of subjects with albuminuria, showing a significant difference among the different drug combinations, favoring the use of new dihydropyridine calcium channel blockers, such as lercanidipine, combined with RAAS inhibitors, to control albuminuria in diabetic hypertensive patients.

Ca2+ Flux: Searching for a Role in Efferocytosis of Apoptotic Cells in Atherosclerosis.

In atherosclerosis, macrophages in the arterial wall ingest plasma lipoprotein-derived lipids and become lipid-filled foam cells with a limited lifespan. Thus, efficient removal of apoptotic foam cells by efferocytic macrophages is vital to preventing the dying foam cells from forming a large necrotic lipid core, which, otherwise, would render the atherosclerotic plaque vulnerable to rupture and would cause clinical complications. Ca2+ plays a role in macrophage migration, survival, and foam cell generation. Importantly, in efferocytic macrophages, Ca2+ induces actin polymerization, thereby promoting the formation of a phagocytic cup necessary for efferocytosis. Moreover, in the efferocytic macrophages, Ca2+ enhances the secretion of anti-inflammatory cytokines. Various Ca2+ antagonists have been seminal for the demonstration of the role of Ca2+ in the multiple steps of efferocytosis by macrophages. Moreover, in vitro and in vivo experiments and clinical investigations have revealed the capability of Ca2+ antagonists in attenuating the development of atherosclerotic plaques by interfering with the deposition of lipids in macrophages and by reducing plaque calcification. However, the regulation of cellular Ca2+ fluxes in the processes of efferocytic clearance of apoptotic foam cells and in the extracellular calcification in atherosclerosis remains unknown. Here, we attempted to unravel the molecular links between Ca2+ and efferocytosis in atherosclerosis and to evaluate cellular Ca2+ fluxes as potential treatment targets in atherosclerotic cardiovascular diseases.

Withdrawal of prenylamine: perspectives on pharmacological, clinical and regulatory outcomes following the first QT-related casualty.

Prenylamine, an antianginal agent marketed since early 1960, became the first casualty of QT interval related proarrhythmias in 1988 when it was withdrawn from the market. The period of its synthesis and marketing is of particular interest since it antedated, first, any serious clinical safety concern regarding drug-induced prolongation of the QT interval which was, in fact, believed to be an efficient antiarrhythmic mechanism; second, the first description of torsade de pointes as a unique proarrhythmia, typically associated with prolonged QT interval; and third, the discovery and recognition of calcium antagonism as an important cardiovascular therapeutic strategy. This review, 30 years almost to the day following its withdrawal, provides interesting perspectives on clinical, pharmacological and regulatory outcomes that followed. Prenylamine underscored torsadogenic potential of other early antianginal drugs on the market at that time and identified QT-related proarrhythmias as a much wider major public health issue of clinical and regulatory concern. This resulted in various guidelines for early identification of this potentially fatal risk. Application of these guidelines would have readily identified its proarrhythmic potential. Prenylamine also emphasized differences in drug responses between men and women which subsequently galvanized extensive research into sex-related differences in pharmacology. More importantly, however, investigations into the mechanisms of its action paved the way to developing modern safe and effective calcium antagonists that are so widely used today in cardiovascular pharmacotherapy.

Neuroprotective Effect of Lercanidipine- A Novel Calcium Channel Blocker in Albino Mice.

BACKGROUND: The available conventional antiepileptics do not afford cure or prophylactic treatment and henceforth there is always a quest to explore new targets for management of convulsions. In this perspective, dihydropyridine calcium channel blockers have been investigated in various animal models of epilepsy. Lercanidipine, a newer dihydropyridine calcium antagonist, is a potential candidate with its favourable lipid profile and longer duration of action. OBJECTIVE: (1) To evaluate the anticonvulsant effect of lercanidipine alone and in combination with standard drug in adult male Swiss albino mice. (2) To evaluate the muscle relaxant and spontaneous locomotor activity of lercanidipine in adult male Swiss albino mice. MATERIALS AND METHODS: Adult male Swiss albino mice weighing 20-30g were used to study the anticonvulsant, muscle relaxant and spontaneous locomotor activity using electroconvulsometer, rotarod and actophotometer apparatus respectively. The mice were divided into six groups of six animals in each group. Group 1 and 2 served as control (vehicle treated) and standard group respectively. Standard drug used to evaluate anticonvulsant effect is phenytoin sodium 25 mg/kg I.P. whereas muscle relaxant activity and locomotor activity is diazepam 4 mg/kg I.P., Group 3 and 4 received lercanidipine 1 and 3 mg/kg I.P., respectively. Anticonvulsant models included group 5 and 6 and they were given combination of phenytoin sodium 12.5 mg/kg I.P., with lercanidipine 1 and 3 mg/kg i.p, respectively. Abolition or reduction of tonic hind limb extension was considered as index of anticonvulsant activity whereas the balancing time of the animals in rod was recorded to asses muscle relaxant activity. The locomotor activity was recorded for 5 minutes. The data were analysed with one-way Analysis of Variance followed by post-hoc 'Dunnett t-test'. RESULTS: Lercanidipine given alone in a dose of 1 and 3 mg/kg had significantly reduced the tonic hind limb extension. Combination of lercanidipine (3 mg/kg) and phenytoin had offered 100% protection. The results also revealed that the test drug didn't impair the motor coordination and locomotor activity in mice. CONCLUSION: The present study had demonstrated that lercanidipine could be potential novel candidate for the treatment of convulsions.

Characterization and bioactivity of novel calcium antagonists - N-methoxy-benzyl haloperidol quaternary ammonium salt.

BACKGROUND AND PURPOSE: Calcium antagonists play an important role in clinical practice. However, most of them have serious side effects. We have synthesized a series of novel calcium antagonists, quaternary ammonium salt derivatives of haloperidol with N-p-methoxybenzyl (X1), N-m-methoxybenzyl (X2) and N-o-methoxybenzyl (X3) groups. The objective of this study was to investigate the bioactivity of these novel calcium antagonists, especially the vasodilation activity and cardiac side-effects. The possible working mechanisms of these haloperidol derivatives were also explored. EXPERIMENTAL APPROACH: Novel calcium antagonists were synthesized by amination. Compounds were screened for their activity of vasodilation on isolated thoracic aortic ring of rats. Their cardiac side effects were explored. The patch-clamp, confocal laser microscopy and the computer-fitting molecular docking experiments were employed to investigate the possible working mechanisms of these calcium antagonists. RESULTS: The novel calcium antagonists, X1, X2 and X3 showed stronger vasodilation effect and less cardiac side effect than that of classical calcium antagonists. They blocked L-type calcium channels with an potent effect order of X1 > X2 > X3. Consistently, X1, X2 and X3 interacted with different regions of Ca2+-CaM-CaV1.2 with an affinity order of X1 > X2 > X3. CONCLUSIONS: The new halopedidol derivatives X1, X2 and X3 are novel calcium antagonists with stronger vasodilation effect and less cardiac side effect. They could have wide clinical application.

Potential for specific dihydropyridine calcium channel blockers to have a positive impact on cognitive function in humans: a systematic review.

BACKGROUND: There is some evidence to suggest a possible association between calcium channel blocker (CCB) use and a lower decline in cognitive function compared with use of other hypertensive treatments. In particular, there is an emerging interest in the potential for specific CCBs, particularly the dihydropyridine CCBs nitrendipine, nicardipine, cilnidipine, lercandipine, nimodipine, azelnidipine and nilvadipine. The aim of this review was to assess the evidence relating to these specific CCBs and incident cognitive decline or dementia in humans. METHODS: A systematic review of the literature was carried out. The databases MEDLINE, Embase and PsychINFO were searched from 1980 to 18 April 2014. All abstracts were reviewed by two independent reviewers. RESULTS: From 753 unique records, 16 full text articles were examined and three retained. The three articles reported data from two studies. A 12-week double-blind randomized controlled trial of nitrendipine compared with cilazapril and a longer and larger double-blind placebo-controlled trial also of nitrendipine, namely the Systolic Hypertension in Europe trial (SYST-EUR). Nitrendipine was associated with a reduction in incident dementia in the SYST-EUR trial. There was no association seen for cognitive outcomes in the smaller trial. CONCLUSION: At present there is limited evidence to suggest that nitrendipine may be associated with reduction in incident dementia. This association comes from a single trial and needs to be replicated. Furthermore, there is no high-quality evidence for any of the other potential candidate CCBs.

Long-term use of angiotensin II receptor antagonists and calcium-channel antagonists in Algerian hypertensive patients: effects on metabolic and oxidative parameters.

The effects of calcium antagonists (amlodipine) and angiotensin II receptor antagonists (telmisartan) on lipid profile and oxidative markers were investigated in Algerian hypertensive patients. At the beginning and after 1 year of antihypertensive therapy, blood samples are collected for determination of biochemical parameters (glucose, cholesterol, triglycerides, urea, creatinine) and oxidative markers (malondialdehyde, carbonyl proteins, nitric oxide, superoxide anion, vitamin C, glutathione, catalase, superoxide dismutase). The results of this study indicate that telmisartan and amlodipine are effective antihypertensive agents in the treatment of hypertension because a significant reduction in systolic and diastolic blood pressure was observed in all hypertensive patients after 1 year of treatment. Our results show also that telmisartan and amlodipine treatments counteracted hypertension-dependent lipid abnormalities and oxidative stress. Telmisartan treatment appears to be more efficient than amlodipine treatment. In addition, telmisartan, which reversed all lipid and redox changes associated with hypertension, should be prescribed, especially in hypertensive patients with hypertriglyceridemia and with severe oxidative stress.