Calcium Channel Blocking Activity Research Articles

Design, synthesis and pharmacological evaluation of some substituted dihydropyrimidines with L-/T-type calcium channel blocking activities

New dihydropyrimidines bearing various lipophilic pharmacophores and functionalities at position 3 were designed and synthesized. The basic framework of the new compounds was designed to maintain the main structural requirements for calcium channel blocking activity of the known dihydropyridines and dihydropyrimidines calcium channel blockers. The newly synthesized compounds were evaluated as antagonists for CaV1.2 and CaV3.2 using the whole-cell patch clamp technique. Seven compounds (4b, 4c, 6c, 9, 13c, 13e and 17b) showed promising dual calcium channel blocking activity and three compounds (13b, 14b and 17a) were selective against Cav3.2. Their drug-likeness has been assessed using Molinspiration and Molsoft softwares. Their physicochemical properties and pharmacokinetic profiles recommend that they can be considered as drug-like candidates.

Binding mechanism investigations guiding the synthesis of novel condensed 1,4-dihydropyridine derivatives with L-/T-type calcium channel blocking activity

Nifedipine and isradipine are prominent examples of calcium channel blockers with a 1,4-dihydropyridine (DHP) scaffold. Although successfully used in clinics since decades for the treatment of hypertension, the binding mechanism to their target, the L-type voltage-gated calcium channel Cav1.2, is still incompletely understood. Recently, novel DHP derivatives with a condensed ring system have been discovered that show distinct selectivity profiles to different calcium channel subtypes. This property renders this DHP class as a promising tool to achieve selectivity towards distinct calcium channel subtypes. In this study, we identified a common binding mode for prominent DHPs nifedipine and isradipine using docking and pharmacophore analysis that is also able to explain the structure-activity relationship of a small subseries of DHP derivatives with a condensed ring system. These findings were used to guide the synthesis of twenty-two novel DHPs. An extensive characterization using 1H NMR, 13C NMR, mass spectra and elemental analysis was followed by whole cell patch clamp assays for analyzing activity at Cav1.2 and Cav3.2. Two compounds were identified with significant activity against Cav1.2. Additionally, we identified four compounds active against Cav3.2 of which three were selective over Cav1.2. Novel binding modes were analyzed using docking and pharmacophore analysis as well as molecular dynamics simulations.

Solid Dispersion Incorporated Fast Dissolving Oral Wafers of Cinnarizine: Development and Evaluation

Cinnarizine is a piperazine derivative, antiallergic with antihistamine, sedative, and calcium-channel blocking activity. It is used for the symptomatic treatment of nausea and vertigo caused by Meniere’s disease and other vestibular disorders and for the prevention and treatment of motion sickness. The present study is focused on making fast dissolving wafers of solid dispersion incorporated Cinnarizine to enhance the bioavailability, dissolution of the drug and increasing the patient compliance. Fast dissolving films of Cinnarizine can be considered suitable for clinical use in the treatment of allergic rhinitis and other conditions of allergies, where a quicker onset of action is desirable along with the convenience of administration. Seven formulations of fast releasing wafers of solid dispersion incorporated Cinnarizine, dispersed in two different polymers; HPMC and PVA by solvent casting method were prepared. Solid dispersion was prepared by solvent evaporation method to enhance the solubility, dissolution rate and consequently, the bioavailability of Cinnarizine. These wafers were evaluated for various parameters like thickness uniformity, weight uniformity, folding endurance, swelling index, percentage moisture absorption, content uniformity, ex vivo permeation studies etc. The cumulative percentage amount of drug diffused was higher for fast releasing wafer made of 3% HPMC. The release kinetics data indicates that the release of drug from fast releasing wafer F4 follows first order release kinetics and model fits to Higuchi which is indicative of the diffusion mechanism of drug release. The mechanism of drug release was found to be non-Fickian. From all of these findings it was concluded that HPMC K4M is the best fast releasing wafer forming polymer.Keywords: Cinnarizine, Fast releasing wafers, Solid dispersion, HPMC, PVA.

Studies to determine antidiarrhoeal and spasmolytic activities of extract of Aegle marmelos. L fruit

Objective: To investigate and determine the antidiarrhoeal and spasmolytic potential of fruit of Aegle marmelos is due to CCBs compounds and not tannic acid.Materials and methods: The extract of ripe and dry fruit of A. marmelos (Am.Cr) was prepared in methanol: water (70:30). The antidiarrhoeal activities of the extract, loperamide and tannic acid were studied in vivo; in castor oil induced diarrhoeal model in mice whereas spasmolytic effect was studied in vitro; in isolated mice ileum. Calcium channel blocking (CCB) activity was investigated after preincubation of mice ileum by Am. Cr or loperamide and subsequent adding of K+80 mM.Results: Am. Cr inhibited castor oil-induced diarrhoea: onset of diarrhoea, total no. of faeces, and total no. of wet faeces dose-dependently, the dose of 800 mg/mL was found statistically significant, total weight of feces and total weight of wet faeces were also inhibited. Concentration-dependent inhibition of spontaneous contraction and contractile effect of K+80 mM after pre-incubation by Am. Cr were confirmed in isolated mice ileum. The results of Am. Cr are comparable with Loperamide. Tannic acid produced neither antidiarrhoeal effect nor exhibited CCB activity, however relaxant effect was observed in isolated mice ileum.Conclusion: The antidiarrhoeal and spasmolytic effects of Am.Cr may be mediated through compounds which posses CCB effect. Tannic acid exhibited relaxant effect only which is not sufficient evidence scientifically to classify as antidiarrhoeal.Bangladesh Journal of Medical Science Vol.17(2) 2018 p.205-211

Simultaneous Determination of Columbianadin and Its Metabolite Columbianetin in Rat Plasma by LC-MS/MS: Application to Pharmacokinetics of Columbianadin after Oral Administration.

Columbianadin and its metabolite columbianetin exhibited the anti-inflammatory, analgesic, calcium channel blocking and antitumor activities. To compare the differences between pharmacokinetics of columbianadin and its metabolite columbianetin after oral administration of pure columbianadin and Angelicae Pubescentis Radix (APR) extract, a simple and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was established and validated to simultaneously determine columbianadin and columbianetin in rat plasma. Two analytes and an internal standard (warfarin) were well separated and determined after liquid-liquid extraction with ethyl acetate. Ammonium acetate aqueous solution (1 mmol/L) and acetonitrile were used as the mobile phase and the flow rate was 0.3 mL/min. The lower limit of quantification (LLOQ) was 0.1 ng/mL for columbianetin and 0.5 ng/mL for columbianadin, respectively. There were significant differences between some pharmacokinetic parameters and bioavailability of columbianadin after oral administration of pure columbianadin and APR extract. The studies on comparative pharmacokinetics of columbianadin were of great use for facilitating the clinical application of columbianadin and were also highly meaningful for the potential development of APR.

SYNTHESIS AND EVALUATION OF NOVEL CALCIUM CHANNEL BLOCKING AGENTS

Benzothiopyran is a heterocyclic compound which contains sulphur as a heteroatom which is responsible for biological and pharmacological activity. Changing heterocyclic ring size will generate derivatives that are not only retained the calcium channel blocking activity but also resulted in several compounds that were more active than diltiazem. A receptor-binding model identifying the benzene ring as a lipophilic group that facilitates transport into the channel and the absolute stereochemistry for the selective binding. Benzothiopyran nucleus is similar to the benzothiazepine nucleuses which are used as calcium channel blockers. In these synthesis series, benzothiazepine nucleus containing nitrogen atom which is replace by bioisosterism of nitrogen.

Synthesis of fused 1,4-dihydropyridines as potential calcium channel blockers

Abstract Objective The aim of this study was to synthesize ten 1,4-dihydropyridine (DHP) derivatives in which substituted cyclohexane rings were fused to the DHP ring and to determine how different ester groups and the benzoyl substituent introduced in 4-phenyl ring affected their calcium channel blocking activity. Methods A microwave-assisted one-pot method was applied for the synthesis of compound 1–5 according to a modified Hantzsch reaction. The benzoyl moiety was introduced in the 4-phenyl ring of these dihydropyridines by refluxing with benzoyl chloride in acetone in the presence of anhydrous potassium carbonate. Synthesized products were characterized by elemental analysis, IR, 1H-NMR and 13C-NMR spectroscopy. The inhibitory actions of compounds 1–10 on calcium channel blocking activity were tested on isolated rat aorta preparations. Results The obtained pharmacological results showed that although all compounds are potent relaxing agents on isolated rat aorta smooth muscle, introduction of a benzoyloxy substitiuent on the phenyl ring (compound 6–10) decreased the relaxant effect of these compunds. Conclusion The reported 1,4-DHP derivatives have calcium channel blocking activity on rat aorta smooth muscle.

Synthesis of new N3-substituted dihydropyrimidine derivatives as L-/T- type calcium channel blockers

Cardiovascular diseases (CVDs) are the main cause of deaths worldwide. Up-to-date, hypertension is the most significant contributing factor to CVDs. Recent clinical studies recommend calcium channel blockers (CCBs) as effective treatment alone or in combination with other medications. Being the most clinically useful CCBs, 1,4-dihydropyridines (DHPs) attracted great interest in improving potency and selectivity. However, the short plasma half-life which may be attributed to the metabolic oxidation to the pyridine-counterparts is considered as a major limitation for this class. Among the most efficient modifications of the DHP scaffold, is the introduction of biologically active N3-substituted dihydropyrimidine mimics (DHPMs). Again, some potent DHPMs showed only in vitro activity due to first pass effect through hydrolysis and removal of the N3-substitutions. Herein, the synthesis of new N3-substituted DHPMs with various functionalities linked to the DHPM core via two-carbon spacer to guard against possible metabolic inactivation is described. It was designed to keep close structural similarities to clinically efficient DHPs and the reported lead DHPMs analogues, while attempting to improve the pharmacokinetic properties through better metabolic stability. Applying whole batch clamp technique, five compounds showed promising L- and T- type calcium channel blocking activity and were identified as lead compounds. Structure requirements for selectivity against Cav1.2 as well against Cav3.2 are described.

Ultra-long acting calcium channel blockers may decrease accuracy of the acetylcholine provocation test

BackgroundWhen drug-induced coronary spasm provocation tests are performed, a washout period of >48h for calcium channel blockers (CCBs) is uniformly recommended. However, each CCB has a distinct half-life, and little is known about the influence of prior oral administration of CCBs on acetylcholine provocation test to evaluate coronary vasomotor reaction. Methods and resultsWe examined 245 consecutive patients with suspected vasospastic angina who had undergone acetylcholine provocation test. Of those patients, 29 patients had been on amlodipine, an ultra-long term acting CCB (group A), 34 on other CCBs (group O), and 182 patients on no CCB (group N). After CCBs had been withheld > 48h, we performed acetylcholine provocation, which resulted in 152 positive, 36 intermediate, and 57 negative reactions. We evaluated coronary artery tone calculated as follows: (luminal diameter after nitrate−baseline luminal diameter)÷(luminal diameter after nitrate)×100 (%). In group A patients, coronary artery tone was lower (A:9.1±6.9% vs. O:11.7±8.3% vs. N:12.1±8.5%, p=0.0011) and the positive rate of acetylcholine provocation test was lower than group O and group N (A:41% vs. O:68% vs. N:64%, p=0.047). Multivariate logistic analysis showed that taking amlodipine until 2days before acetylcholine provocation test was a significant inverse predictor for acetylcholine-provoked coronary spasm (odds ratio 0.327; 95% confidence interval 0.125–0.858, p=0.023). ConclusionsResidual vasodilatory effects of ultra-long acting CCB may decrease coronary artery tone and the vasoconstrictive reaction to acetylcholine suggesting that a 2-day pre-test drug holiday may not be long enough.

Natural Organic Acid as Green Catalyst for Xanthenones Synthesis: Methodology, Mechanism and Calcium Channel Blocking Activity

Xanthenones were synthesized via one-pot tricomponent reaction, under solvent-free conditions, using aldehydes, phenolic and cyclic 1,3-dicarbonyl compounds. Natural organic acids (NOAs), compounds present in many living metabolisms, were used as potential green catalysts. NOA are considered to be more eco-friendly and user-friendly alternative to traditional methodologies. Optimization studies showed that oxalic acid was the best NOA catalyst for such reaction furnishing the xanthenones with up to 93% of yield. Theoretical calculations were performed to evaluate this reaction mechanism and regioselectivity. The results showed that the regiospecificity of this three-component reaction is kinetically and thermodynamically controlled by the addition of β-naphthol C2, instead of C10, to the aldehyde. Our results also disclosed two xanthenones as novel calcium channels blockers. Eco-friendly reaction conditions, easy workup procedure, short reaction times and good yields are some of the advantages of our methodology.

A mechanistic evaluation of the traditional uses of Nepeta ruderalis in gastrointestinal and airway disorders

Context: Nepeta ruderalis Buch.-Ham. (Lamiaceae), locally known as Badranj Boya, is an aromatic herb used traditionally as an antispasmodic, antidiarrhoeal, and anti-asthamatic remedy.Objective: Aqueous methanolic extract of N. ruderalis was studied to investigate its traditional uses.Materials and methods: Study was conducted from September 2015 to February 2016. In vitro spasmolytic and broncho-relaxant activity of crude extract of N. ruderalis (whole plant) was evaluated at 0.01–10 mg/mL final bath concentration in isolated rabbit jejunum and tracheal tissues, using PowerLab data acquisition system (Transonic Systems Inc., Ithaca, NY). In vivo antidiarrhoeal activity was evaluated in castor oil-induced diarrhoeal mice at the dose of 300 and 500 mg of crude extract orally.Results: Crude extract of N. ruderalis completely relaxed spontaneously contracting, high K+ (80 mM) and carbachol (1 μM) induced contracted jejunum with an EC50 value of 5.85 (5.45–6.27), 4.0 (3.80–4.23) and 2.86 (2.48–3.29), similar to verapamil. Nr.Cr relaxed high K+ and carbachol induced contractions, at 5 and 10 mg/mL with an EC50 value of 2.37 (2.11–2.67) and 3.26 (2.9–3.67), respectively, and also displaced calcium concentration–response curves toward right at 0.1 and 0.3 mg/mL. Nr.Cr exhibited antidiarrhoeal protection at a dose of 300 and 500 mg/kg, similar to verapamil, whereas no acute toxicity signs were seen up to 5 g/kg in healthy mice.Discussion and conclusion: Results suggest the presence of spasmolytic and broncho-relaxant effects in the crude extract of N. ruderalis, possibly mediated through calcium channel-blocking activity, providing the pharmacological basis for its traditional uses in gastrointestinal and airway disorders.

Neuroprotective effect of lercanidipine in middle cerebral artery occlusion model of stroke in rats

Oxidative stress, inflammation and apoptotic neuronal cell death are cardinal mechanisms involved in the cascade of acute ischemic stroke. Lercanidipine apart from calcium channel blocking activity possesses anti-oxidant, anti-inflammatory and anti-apoptotic properties. In the present study, we investigated neuroprotective efficacy and therapeutic time window of lercanidipine in a 2h middle cerebral artery occlusion (MCAo) model in male Wistar rats. The study design included: acute (pre-treatment and post-treatment) and sub-acute studies. In acute studies (pre-treatment) lercanidipine (0.25, 0.5 and 1mg/kg, i.p.) was administered 60min prior MCAo. The rats were assessed 24h post-MCAo for neurological deficit score (NDS), motor deficit paradigms (grip test and rota rod) and cerebral infarction via 2,3,5-triphenyltetrazolium chloride (TTC) staining. The most effective dose was found to be at 0.5mg/kg, i.p., which was considered for further studies. Regional cerebral blood flow (rCBF) was monitored till 120min post-reperfusion to assess vasodilatory property of lercanidipine (0.5mg/kg, i.p.) administered at two different time points: 60min post-MCAo and 15min post-reperfusion. In acute studies (post-treatment) lercanidipine (0.5mg/kg, i.p.) was administered 15min, 120min and 240min post-reperfusion. Based on NDS and cerebral infarction via TTC staining assessed 24h post-MCAo, effectiveness was evident upto 120min. For sub-acute studies same dose/vehicle was repeated for next 3days and magnetic resonance imaging (MRI) was performed 96h after the last dose. Biochemical markers estimated in rat brain cortex 24h post-MCAo were oxidative stress (malondialdehyde, reduced glutathione, nitric oxide, superoxide dismutase), blood brain barrier damage (matrix metalloproteinases-2 and -9) and apoptotic (caspase-3 and -9). Lercanidipine significantly reduced NDS, motor deficits and cerebral infarction volume as compared to the control group. Lercanidipine (60min post-MCAo) significantly increased rCBF (86%) as compared to vehicle treated MCAo group (64%) 120min post-reperfusion, but failed to show vasodilatation with 15min post-reperfusion group. Lercanidipine (13.78±2.78%) significantly attenuated percentage infarct volume as evident from diffusion-weighted (DWI) and T2-weighted images as compared to vehicle treated MCAo group (25.90±2.44%) investigated 96h post-MCAo. The apparent diffusion coefficient (ADC) was also significantly improved in lercanidipine group as compared to control group. Biochemical alterations were significantly ameliorated by lercanidipine till 120min post-reperfusion group and MMP-9 inhibition observed even with 240min group. Thus, lercanidipine revealed significant neuroprotective effect mediated through attenuation of oxidative stress, inflammation and apoptosis.

Current statins show calcium channel blocking activity through voltage gated channels.

BackgroundStatins are used for treatment of hypercholestremia. Common adverse reports associated with use of statins are generalized bodyache, rhabdomyolysis, muscles weakness and gastrointestinal disorders. The current work is an attempt to explain how smooth muscles of gastrointestinal tissues are affected by the current statins (Simvastatin, atorvastatin, fluvastatin and rosuvastatin).MethodsEffects of the current statins were studied on spontaneous activity of isolated rabbits’ jejunal preparations. Different molar concentrations (10−12–10−2M) of the statins were applied on spontaneously contracting rabbits’ jejunal preparations. As statins relaxed spontaneous activity, so we tested the statins on KCl (80 mM) induced contractions in similar test concentrations. Positive relaxant statins were tested again through construction of Calcium Concentration Response Curves (CCRCs) in the absence and presence of the statins using verapamil, a standard calcium channel blocker. CCRCs of statins were compared with CCRCs of verapamil.ResultsSimvastatin, atorvastatin, fluvastatin and rosuvastatin relaxed the spontaneous and KCl-induced contractions. IC50 for simvastatin on spontaneous rabbit’s jejunal preparations is −5.08 ± 0.1 Log 10 M. Similarly, IC50 for KCl-induced contractions is −4.25 ± 0.01 Log 10 M. Mean IC50 (Log 10 M) for atorvastatin on spontaneous rabbit’s jejunal preparations and KCl-induced contractions are −5.19 ± 0.07 and −4.37 ± 0.09, respectively. Fluvastatin relaxed spontaneous activity of rabbits’ jejunal preparations with an IC50 (Log 10 M) −4.5 ± 0.03. Rosuvastatin relaxed spontaneous as well as KCl (80 mM) induced contractions with respective IC50 (Log 10 M) −3.62 ± 0.04 and −4.57 ± 0.06. In case of CCRCs, tissues pre-treated with 4.6 μg/ml of simvastatin, have IC50 = −1.84 ± 0.03 [log (Ca++) M] vs control IC50 = −2.54 ± 0.04 [log (Ca++) M]. Similarly, atorvastatin, fluvastatin and rosuvastatin produced significant right shift in IC50 for CCRCs (P ≤ 0.05). In case of verapamil, IC50 for control curves is −2.45 ± 0.06 [log (Ca ++) M], while IC50 in presence of verapamil (0.1 μM) is −1.69 ± 0.05 [log (Ca ++) M]. Statins produced right shift in the IC50 of CCRCs. The effects of statins are like that of effects of verapamil, a standard calcium channel blocker.ConclusionsOur findings suggest that current statins have calcium antagonistic effects that act on voltage gated calcium channels that may provide a rationale for cause muscle weakness and gastrointestinal disorders.

NO-dependent attenuation of TPA-induced immunoinflammatory skin changes in Balb/c mice by pindolol, heptaminol or ATRA, but not by verapamil.

Recently a mouse skin carcinogenesis study reported that a β-blocker carvedilol displayed antitumor-properties via antihyperplastic effects. However, the antihyperplastic mechanism is unclear as the β-blocker is characterized with multiple pleiotropic effects including stimulation of endothelial NO release and verapamil-like calcium channel blocking activity. To investigate the nature and the origin of the antihyperplastic effects, we tested topical pretreatment with pindolol, heptaminol, ATRA or verapamil against Balb/c mouse ear skin hyperplasia that was induced by TPA. We found that pindolol, heptaminol or ATRA, but not verapamil, inhibited the TPA-induced immunoinflammatory skin changes in an NO-dependent manner, which included epidermal hyperplasia, skin edema and fibrosis. Furthermore, we also observed NO-dependent alleviation of the TPA-induced NK cell depletion in the ear tissues by heptaminol pretreatment. Together our results suggest that stimulation of NO generation from constitutive synthases may be primarily responsible for the reported antihyperplastic and NK cell-preserving effects of the β-blockers, and that similar effects may be observed in other immunity normalizing compounds that also promote endothelial NO synthesis.

Chemical composition and vascular and intestinal smooth muscle relaxant effects of the essential oil from Psidium guajava fruit

Context: Psidium guajava L. (Myrtaceae) is widely used in traditional medicine for the treatment of various ailments including cardiovascular and gastrointestinal disorders.Objectives: The current study investigated the chemical composition and cardiovascular and gastrointestinal effects of the essential oil of P. guajava.Materials and methods: The chemical composition of the essential oil was investigated using gas chromatography-mass spectrometry (GC-MS) technique. The biological activity of the essential oil was tested on rabbit aorta and jejunum. All changes in isometric tension were recorded through a force transducer coupled with a bridge amplifier data acquisition system.Results and discussion: GC-MS analysis showed the presence of butanoic acid methyl ester, 3-methyl glutaric anhydride, 1-butanol, 3-hexenal, cinnamyl alcohol, 1-hexanol and hexane as the major components. In isolated rabbit aorta preparations, the essential oil showed vasorelaxation at doses of 3-10 mg/mL against high K+ and phenylephrine pre-contractions with EC50 values of 5.52 (5–6.04) and 6.23 mg/mL (5.0–7.46). The essential oil inhibited spontaneous and high K+ induced contractions in isolated rabbit jejunum with EC50 values of 0.84 (0.3–1.38) and 0.71 mg/mL (0.3–1.12) and shifted Ca + 2 concentration curves to the right, similar to verapamil, suggesting spasmolytic activity mediated possibly through Ca + 2 channel blockade.Conclusions: In summary, the data indicated the presence of seven different phytoconstituents in the essential oil of P. guajava and calcium channel blocking activity, which provides a pharmacological base to the traditional use of P. guajava in cardiovascular and gastrointestinal disorders. Further studies are suggested to explore the molecular nature of these effects.

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.

Effect of losartan and amlodipine on insulin sensitivity in non-diabetic hypertensive patients

Background: Hypertensive patients show higher insulin levels than normotensive controls. Hypertension is linked to impaired glucose tolerance and resistance to the action of insulin. Untreated hypertensive patients are at risk of developing new onset diabetes mellitus. Different antihypertensive drugs affect the insulin sensitivity distinctly. Few studies have demonstrated the beneficial effects of losartan, an angiotensin receptor blocker on the glucose insulin metabolism, but other studies have failed to demonstrate the insulin resistance lowering effect of losartan. Amlodipine, a long acting calcium channel blocker is considered to have neutral effects on the glucose-insulin metabolism. Methods: In a prospective, open-label, parallel group study, non-diabetic patients with mild to moderate hypertension were randomized to either losartan (titrated from 50 to 100 mg /day, n=20) or amlodipine (titrated from 5 to 10 mg/ day, n=20) for period of 24 weeks. At baseline, 12 weeks and 24 weeks fasting plasma glucose, fasting plasma insulin, homeostasis model assessment for insulin resistance (HOMA-IR) apart from lipid parameters, mean systolic and diastolic blood pressures levels were determined. Results: Intragroup comparison shows that both losartan and amlodipine significantly reduced the HOMA-IR index (P < 0.05, 24 weeks vs. baseline). Losartan reduced HOMA-IR more than amlodipine but this reduction was not statistically significant. Conclusions: Losartan and amlodipine lowered insulin resistance in patients of mild to moderate hypertension.

Percutaneous Revascularization in a Case of Vasospastic Angina Associated with Polymorphic Ventricular Tachycardia

Abstract Introduction: Coronary vasospasm is a possible cause of ventricular tachyarrhythmias and is frequently associated with atherosclerotic lesions. The revascularization of mild to moderate coronary artery stenosis which causes symptoms only due to associated vasospasm is still a matter of debate, as the standard treatment of Prinzmetal angina is represented by the long term administration of calcium-channel blockers. Case presentation: We present the case of a 46 year old woman with an intermediate severity coronary artery stenosis complicated by vasospastic angina and subsequent polymorphic ventricular tachycardia. Although the functional significance of the fixed coronary artery lesion was equivocal at invasive fractional flow reserve measurement, a combined pharmacologic and interventional treatment strategy was chosen with stent implantation and long acting calcium channel blocker administration with a symptom-free, good clinical outcome. Conclusion: Patients with vasospastic angina and intermediate severity atherosclerotic coronary artery stenoses are at risk of malignant ventricular arrhythmias, therefore myocardial revascularization should be considered in addition to the standard medical treatment.

Treatment of chronic itch in systemic disease. Current standards

Chronic itch (CI) is a frequent and sometimes tormenting symptom in many skin and systemic diseases. In systemic diseases, it mostly appears on primarily unaffected skin. As a sequelae of intense scratching, secondary skin lesions such as excoriations, scars, and prurigo nodularis may occur. Due to the lack of valid pathogenetic concepts and good clinical trials, the therapy of CI remains mostly symptomatic. In Europe almost all drugs used to treat CI are not approved for this indication. CI is frequent in patients with chronic kidney diseases in advanced stages. Gabapentin and pregabalin, anticonvulsants, and centrally acting calcium channel blockers have been shown to exert a profound effect in CI. Furthermore, UVB phototherapy has been proven to attenuate pruritus in uremic patients. Randomized controlled studies have recently shown that nalfurafine, a κ-opioid receptor agonist, is able to ameliorate itch in patients with uremic itch. In patients suffering from cholestatic itch, the anion exchange resin colestyramine and rifampicin are effective antipruritic drugs. Furthermore, µ-opioid receptor antagonists and sertraline may be used to alleviate CI in hepatic diseases. In refractory cases, naso-biliary drainage or albumin dialysis are effective invasive procedures. For the treatment of chronic itch in hematological diseases no controlled trials have been performed so far. The mainstay in these cases is to treat the underlying disease.

DOSING ACCURACY AND STABILITY OF ENTERAL NIFEDIPINE FOR PAEDIATRIC PATIENTS

Administration of nifedipine, a short acting calcium channel blocker used to treat acute and chronic hypertension in paediatric patients, has been associated with large variations in treatment response to individual doses.1 Currently, there is no licensed paediatric nifedipine formulation available in the UK. The aim of this project was to determine the accuracy and precision of methods used in clinical practice to prepare paediatric doses of enteral nifedipine. Method Initially, qualitative data collection and observational studies using questionnaires to identify common preparation techniques used by nursing staff were performed at one children9s hospital. Weight and content uniformity of split and crushed modified release nifedipine tablets (Nifedipressâ MR 10), and an imported 20 mg/mL drop solution (Nifedipin-ratiopharmâ Tropfen), were analysed. The accuracy and precision of three different doses of enteral nifedipine (5 mg, 1 mg and 0.5 mg) prepared using eight techniques identified in clinical practice were determined using High Performance Liquid Chromatography (HPLC). Stability over two hours of nifedipine solutions 5 mg/ml prepared from tablets and the drop solution was determined using HPLC. Results Great variation in dose preparation methods was identified. Analysis of eight preparation techniques showed that doses between 50% and 264% of the intended dose were achieved. For techniques using manipulated tablets only one technique, using split tablets dispersed in an oral syringe, produced an accurate and reproducible dose for 1 mg and 5 mg doses (97.9% [range 96–99.2%] and 94% [range 93.1–95.1%] respectively). For the 0.5 mg dose none of the techniques produced an accurate and reproducible dose. Techniques using dilution of the imported liquid showed significant deviations and variability from the intended dose, particularly when the internal drop dosing device was used. Use of syringes to measure the dose improved accuracy and precision of the dose prepared, although significant carry-over of drug was seen if fresh syringes were not used at each dilution step. Stability studies observed rapid decomposition of nifedipine when exposed to light, forming an unstable preparation within 30 minutes of tablet manipulation and within 60 minutes of liquid manipulation. Conclusion A great variation of preparation techniques is employed by nursing staff to administer fractional doses of nifedipine to infants and children using the modification of either a licensed tablet or an imported drop formulation. Our small study investigating some of these techniques showed significant inaccuracy and imprecision of the doses delivered. Preparation of paediatric doses of nifedipine require specific standardised preparation protocols to ensure accuracy and consistency of doses delivered to the patient. Further studies should be performed to inform the development of these preparation protocols to identify methods which consistently deliver accurate doses across paediatric dosing ranges until more suitable licensed paediatric treatment alternatives become available in the UK.