Additional decrease in fractional flow reserve in the left anterior descending artery after hand-grip exercise during pharmacological coronary hyperemia.

Maximal hyperemia at the time of fractional flow reserve (FFR) measurement is generally induced by vasodilators, even when hyperemia at the onset of angina symptoms is caused by exercise stress. This study was designed to evaluate whether pharmacological hyperemia could be used as a substitute for exercise-induced hyperemia during FFR measurement. Twenty-two patients with angiographically intermediate stenosis in the left anterior descending artery (LAD) were prospectively enrolled. FFR measurements were repeated in the following two conditions while the pressure-wire was positioned in the same segment; (1) during pharmacological hyperemia induced by intracoronary administration of 2 mg nicorandil, (2) immediately after isotonic hand-grip exercise for 90 s (50% of maximum voluntary contraction) followed by intracoronary administration of 2 mg nicorandil. Isotonic hand-grip exercise increased systolic blood pressure (130 ± 19 versus 150 ± 22 mmHg, p < 0.001), heart rate (71 ± 11 versus 79 ± 13 bpm, p < 0.001), and cardiac output (5.1 ± 1.2 versus 5.9 ± 1.5 L/min, p < 0.001), which indicated an increased afterload on the left ventricle. After the hand-grip exercise, FFR significantly decreased from 0.86 ± 0.06 to 0.84 ± 0.06 (p < 0.001). A percent increase in systolic blood pressure and cardiac output after hand-grip exercise strongly correlated with ΔFFR (r = - 0.65, p < 0.001 and r = - 0.55, p < 0.001, respectively). An increase in cardiac output with hand-grip exercise during pharmacological hyperemia could induce an additional decrease in FFR for lesions located in the LAD.

Exogenous NO Therapy for the Treatment and Prevention of Atherosclerosis.

Amyl nitrite was introduced in 1867 as the first molecule of a new class of agents for the treatment of angina pectoris. In the following 150 years, the nitric oxide pathway has been the subject of a number of pharmacological approaches, particularly since when this elusive mediator was identified as one of the most important modulators of vascular homeostasis beyond vasomotion, including platelet function, inflammation, and atherogenesis. While having potent antianginal and antiischemic properties, however, nitric oxide donors are also not devoid of side effects, including the induction of tolerance, and, as shown in the last decade, of oxidative stress and endothelial dysfunction. In turn, endothelial dysfunction is itself felt to be involved in all stages of atherogenesis, from the development of fatty streaks to plaque rupture and thrombosis. In the present review, we summarize the agents that act on the nitric oxide pathway, with a particular focus on their potentially beneficial antiatherosclerotic and unwanted pro-atherosclerotic effects.

Development, optimization, and characterization of polymeric electrospun nanofiber: a new attempt in sublingual delivery of nicorandil for the management of angina pectoris.

The objective of the current investigation was to develop a novel biocomposite polymeric nanofiber for sublingual delivery of nicorandil in an attempt to reduce mucosal ulceration and to improve drug bioavailability. Polymeric nanofibers were achieved using vitamin B12 and a blend of hyaluronic acid and polyvinyl alcohol as polymeric constituents. The electrospinning method was used to prepare drug (nicorandil)-loaded nanofibers. The resulting nanofibers were characterized for morphology, drug loading, XRD, DSC, in vitro drug release, degree of swelling, and pharmacokinetic behavior. The prepared nanofibers were found to be uniform, non-beaded, and non-woven, with fiber diameter ranging from 200-450 nm. In vitro drug release substantiated the controlled release behavior of the developed formulation. Histopathology studies demonstrated no evidence of mucosal ulceration at the site of application. Pharmacokinetic studies established the preclinical safety and showed the maintenance of an effective therapeutic level for a prolonged period. The present investigation gives inputs showing that the biocomposite nanofiber assists as a perfect carrier system for sublingual delivery of anti-anginal drugs.

Design and development of controlled release floating matrix tablet of Nicorandil using hydrophilic cellulose and pH-independent acrylic polymer: in-vitro and in-vivo evaluations.

OBJECTIVES: The purpose of the study was to develop a floating matrix tablet of Nicorandil using blends of hydrophilic cellulose and pH-independent acrylic polymer to improve the therapeutic effectiveness of the drug in cardiovascular disease. METHODS: Nicorandil tablets were prepared by direct compression and evaluated for drug-excipients compatibility, in-vitro buoyancy and in-vivo γ-scintigraphy study. The selected formulation (FT5) was also evaluated for stability study and the in-vivo absorption in rabbits to compare the pharmacokinetic parameters with the commercially available immediate release tablet of Nicorandil. RESULTS: DSC and FT-IR studies confirmed the absence of incompatibility and were found stable at refrigerator temperature (2-8°C) and at 25ºC/60% RH. The in-vivo γ-scintigraphy studies revealed that the system was floated for a period of 6 -7 h in the stomach and in-vivo absorption study showed a significant difference (p < 0.05) in the pharmacokinetic parameters (AUC increased by 3 fold and MRT by 2.5 fold) as compared to the marketed formulation. CONCLUSION: In conclusion, the developed Nicorandil floating matrix tablet improved the pharmacokinetics parameters (AUC and MRT) in rabbit plasma with expected lowering in side effects potential.

Preparative isolation and high-resolution mass identification of 10 stressed study degradants of nicorandil tablets.

Nicorandil is a potent drug with a dual mechanism of action which results in its wide application in treating angina patients. Since the literature review showed no single preparative method for isolation and liquid chromatography-mass spectrometry (LC-MS) compatible [high-performance liquid chromatography (HPLC) or ultra performance liquid chromatography (UPLC)] method for identification for the impurities generated in process and by force degradation was reported. Thus an attempt was made to develop a single preparative method for isolation and HPLC and UPLC methods for identification of impurities of nicorandil in tablet dosage form. Ten degradants were found in the formulated drug under the stress conditions, [40°C/75% relative humidity for 2 months] in an LC-MS compatible method. A cost effective and high-throughput simple gradient preparative HPLC method was developed with a runtime of 30 min to isolate all the degradants. The method is capable and can be used to isolate further degradants. To detect these degradants, rapid and effecient HPLC and UPLC methods were developed and the same were identified by UPLC-time of flight mass spectrometry (TOF MS). The crux of this work involves a single preparative isolation method and UPLC identification method for all degradants with a very short runtime, i.e., 13.8 min, and, furthermore, the method has the potential to separate a wide range of degradants.

An impact of the ring substitution in nicorandil on its adsorption on silver nanoparticles. Surface-enhanced Raman spectroscopy studies.

The substituent effect on structure and surface activity of biologically active nicorandil was investigated by means of surface-enhanced Raman spectroscopy (SERS). Vibrational characterization was a basis for investigation of the adsorption profile of nicorandil and 1-methylnicorandil on silver nanoparticles. An assignment of SERS bands was performed by the comparison of the Raman spectra of both compounds in the solid state and in solutions, complemented by DFT calculations. Even though the nitro group was found to be the most attractive to the silver surface, the strong impact of the methyl substituent changed this preferable adsorption mechanism in 1-methylnicorandil. Protonation of the nitrogen atom in the pyridinium ring was also found to have an impact on absorption mechanism.

Simultaneous determination of sildenafil citrate and some nitric oxide releasing drugs in human plasma using UPLC MS/MS.

OBJECTIVE: The inadvertent combination of sildenafil (SLD) and nitric oxide releasing compounds (NRC) may cause a life threatening hypotension and conversion of coital angina into an irreversible one. The aim of this study was to develop and validate a UPLC MS/MS method for the simultaneous quantitative analysis of SLD, nicorandil (NRD), and ARG in human plasma to determine the safety margins for drug combinations. DESIGN AND METHOD: Chromatographic elution was achieved in 4min using gradient elution and an injection volume of 10µL. Electro-spray positive ionization (ESI+ve) detection and multiple-reaction monitoring mode (MRM) were used for detection. RESULTS: The method was found to be linear (10-900ng/mL for SLD and NRD while 1-30µg/mL for ARG), accurate and precise (99.35±1.58, 99.62±1.13, and 100.04±1.22% for SLD, NRD and ARG; respectively) and met all other validation requirements. CONCLUSION: The developed UPLC MS/MS method is suitable for fast, sensitive, accurate and simultaneous determinations of SLD, NRD, and ARG in plasma.

Synthesis, antinociceptive activity and pharmacokinetic profiles of nicorandil and its isomers.

Nicorandil (N-(2-hydroxyethyl)nicotinamide nitrate) is an antianginal drug, which activates guanylyl cyclase and opens the ATP-dependent K(+) channels, actions that have been suggested to mediate its vasodilator activity. We synthesized nicorandil and its two isomers, which vary in the positions of the side chain containing the nitric oxide (NO) donor, and also their corresponding denitrated metabolites. The activities of these compounds were evaluated in an experimental model of pain in mice. Pharmacokinetic parameters of nicorandil and its isomers, as well as the plasma concentrations of the corresponding denitrated metabolites and also nicotinamide and nitrite were determined. Nicorandil exhibited the highest antinociceptive activity, while the ortho-isomer was the least active. Nicorandil and para-nicorandil, which induced higher plasma concentrations of nitrite, exhibited higher antinociceptive activity, which suggests that the release of NO may mediate this activity.

In vitro and in vivo evaluation of hydrophilic and hydrophobic polymers-based nicorandil-loaded peroral tablet compared with its once-daily commercial sustained-release tablet.

CONTEXT: Hydrophilic and hydrophobic polymer-based nicorandil (10 mg)-loaded peroral tablets were prepared using the wet granulation technique. The influence of varying amounts of hydroxypropyl methylcellulose (HPMC) (30-50 mg), ethylcellulose (2-4 mg), microcrystalline cellulose (5-20 mg) and Aerosil® (5-12 mg) in conjunction with the constant amounts (3 mg) of glidant and lubricant (magnesium stearate and talc) on the in vitro performances of the tablets (hardness, friability, weight variation, thickness uniformity, drug content, and drug release behavior) were investigated. OBJECTIVE: The objectives of this study were (i) to select a nicorandil-loaded peroral tablet that matched the in vitro dissolution profile of once-daily commercial sustained-release tablet, and (ii) to compare the in vivo sustaining/controlling efficacy of the selected peroral tablet with that of its commercial counterparts. RESULTS AND DISCUSSION: Because the nicorandil (10 mg)-loaded tablet prepared based on F-IX composition (50 mg HPMC, 4 mg ethylcellulose, 10 mg MCC and 3 mg glidant and lubricant) showed a release profile comparable to that of the Nikoran® OD SR tablet release profile, the tablet with this composition was considered to be the optimized/selected formulation and, therefore, was subjected to stability study and in vivo study in rabbits. Despite of the higher C(max) and AUC values obtained with the optimized tablet, there was no sign of difference between the optimized- and Nikoran® OD SR- tablets following a single-dose crossover oral administration into rabbit. CONCLUSION: The optimized tablet could be used as an alternative to the commercial once-daily tablet.

Potassium channel openers and improvement of toxic stress: do they have role in the management of inflammatory bowel disease?

Inflammatory bowel disease (IBD) is a progressive condition in gastrointestinal tract, which refers to two idiopathic diseases; ulcerative colitis and Crohn's disease. Although certain etiology of these conditions is not known, it seems that an abnormality in reaction and regulation of the immune system plays an important role in adventure of the disease. According to the investigations, it is likely that oxidative and nitrosative stress have etiologic roles in IBD. Their destructive effects may contribute to the initiation or progression of the disease. Nowadays, the effectiveness of different medicines in the treatment of IBD has been proved, but none of them has shown a desirable result. Potassium channel openers (PCOs) are a class of drugs with various usages in the aspects of cardiovascular diseases and urinary incontinence. Their major mechanism is the opening of ATP-sensitive potassium (K-ATP) channels and contribute to the relaxation of smooth muscles. Nicorandil is a member of PCOs, with a special chemical structure. Recent investigations mention some novel effects and functions for this drug. Nicorandil reveals an anti-apoptosis property not only via a nitric oxide (NO)/cGMP-dependent mechanism, but also through activating mitochondrial K-ATP channels. Nicorandil can also elevate cGMP levels in some tissues, without direct NO generation. Gastroprotective activity via opening of the K channels, free radical scavenging, prostaglandin E2 elevation, decreasing pepsin and acid secretion, and prevention of the detrimental rise in NO has been proposed for nicorandil. According to these protective mechanisms and the role of oxidative/nitrosative stress in the expression of IBD, we herein hypothesize that nicorandil and other PCOs with similar structure can be used in the management of IBD. This approach offers new hope for the successful treatment of IBD. Further investigations on animal models are needed, to place nicorandil and similar drugs alongside IBD therapy.

Formulation approach for nicorandil pulsatile release tablet.

The purpose of this study was to obtain a nicorandil pulsatile release tablet that has a well-regulated release lag time. When nicorandil is used as an antiangina drug, administration time control is important. A pulsatile release tablet is one of the effective approaches to modified release to reduce daily administration frequency. In this study, a pulsatile release tablet of nicorandil was formulated by fumaric acid dry coating around the core tablet including nicorandil. The model tablets, which had different content ratios of excipients in the dry-coating layer, were characterized by a dissolution test. The results showed that the release lag time was generated with fast release profiles. Various lag time controls of tablets were achieved, from 60 to 310 min on average, by variation of outer layer composition. From an analysis of the relation between lag times and outer layer composition, the key ingredient for prolongation of lag time was found to be fumaric acid. To analyze the lag time generation mechanism, water penetration for tablet was measured. The results indicated that the penetration depth was proportionate to the square root of time and the lag time formation mechanism was simple water penetration through the matrix of fumaric acid to the tablet core. The results also showed that the Washburn equation could be used to design the lag time of the pulsatile release tablet in this study. In conclusion, novel release control technology using fumaric acid was appropriate to obtain a nicorandil pulsatile release tablet that has well regulated lag time.

Design and in vitro/in vivo evaluation of novel nicorandil extended release matrix tablets based on hydrophilic interpolymer complexes and a hydrophobic waxy polymer.

The purpose of this work was to develop an extended release matrix tablet of nicorandil; a freely water soluble drug used in cardiovascular diseases. Chitosan (CH)/hyaluronate sodium (HA), pectin (PE) or alginate sodium (AL) interpolymer complexes (IPCs) were prepared. The optimum IPCs (CH:HA, 40:60), (CH:PE, 30:70) and (CH:AL, 20:80) were characterized by Fourier transform infrared spectroscopy. The IPCs were based on electrostatic interactions between protonated amine groups of CH and carboxylate groups of HA, PE or AL. Nicorandil matrix tablets were prepared using the optimum IPCs, alone or in combination with Imwitor 900 K. Evaluations such as weight variation, thickness, content uniformity, friability, disintegration and in vitro release studies were performed. The tablets showed acceptable pharmacotechnical properties and complied with compendial requirements. Results of the dissolution studies revealed that formula F11 (CH:AL, 20:80) IPC:Imwitor 900 K, 3:1) could extend drug release > 8h. Most formulae exhibited non-Fickian diffusion drug release profiles. When compared to the immediate release Ikorel tablet, the duration of effective nicorandil therapeutic concentration from formula F11, in healthy human volunteers, was significantly (P<0.05) extended from 4 to 8 h with expected lowering in side effects potential.

Optimized and validated spectrophotometric methods for the determination of nicorandil in drug formulations and biological fluids.

Two simple, sensitive and economical spectrophotometric methods have been developed for the determination of nicorandil in drug formulations and biological fluids. Method A is based on the reaction of the drug with brucine-sulphanilic acid reagent in sulphuric acid medium producing a yellow-coloured product, which absorbs maximally at 410 nm. Method B depends on the formation of the intensely blue-coloured product which results due to the interaction of an electrophilic intermediate of 3-methyl-2-benzothiazolinone hydrazone hydrochloride (MBTH) with oxidized product of 4-(methyl amino) phenol sulphate (metol) in the presence of nicorandil as an oxidizing agent in sulphuric acid medium. The coloured product shows absorbance maximum at 560 nm. Under the optimized experimental conditions, Beer's law is obeyed in the concentration range of 2.5-35.0 and 0.40-2.2 microg ml(-1) for Methods A and B, respectively. Both the methods have been successfully applied to the determination of nicorandil in drug formulations and biological fluids. The results are validated statistically and through recovery studies. In order to establish the bias and the performance of the proposed methods, the point and interval hypothesis tests have been performed. The experimental true bias of all samples is smaller than +/-2%.