Calcium Channel Blocking Activity Research Articles

Chiral superficially porous stationary phases for enantiomeric separation of condensed 1,4-dihydropyridine derivatives

1,4-dihydropyridine (DHP) scaffold occupies a prominent position among all heterocyclic compounds owing to its versatile pharmacological properties, particularly its well-known calcium channel blocking activity. In the quest of developing new calcium channel blockers, fifty seven 5-oxo-hexahydroquinoline (HHQ) derivatives carrying DHP framework in a condensed ring system were recently synthesized as racemic mixtures. Due to their potential as drug candidates, enantiomers arising from the asymmetric center at the C-4 position of the HHQ ring were separated. Four modern columns packed with 2.7 µm superficially porous particles bonded with a chiral selector were used. The chiral selectors were three macrocyclic glycopeptide selectors: vancomycin, teicoplanin, and a macrocyclic derivative called nico. The fourth bonded selector was the dinitrobenzamido-tetrahydrophenanthrenyl derivative called Whelko. The four chromatographic modes were assayed with the mobile phase compositions: reversed phase with acetonitrile/buffer 30/70 %v/v, normal phase with hexane/ethanol 80/20 %v/v, and subcritical fluid chromatography with CO2/methanol 80/20 %v/v at 25 °C. The WhelkoShell column was the most effective in separating this set of 57 compounds. Several enantioresolution factors passed 20 with enantioselectivity ratios higher than 4. Molecular modeling showed that the compounds had a T-shape that fitted well the molecular structure of the WhelkoShell selector in the normal or subcritical modes. Additionally, seven compounds had a second chiral center. The NicoShell column was able to separate all four stereoisomers of these compounds in the reversed phase mode. The preparative production of pure enantiomers of these compounds would be straightforward using the WhelkoShell column in the subcritical mode.

Non-small cell lung cancer sensitisation to platinum chemotherapy via new thiazole-triazole hybrids acting as dual T-type CCB/MMP-9 inhibitors

Cisplatin remains the unchallenged standard therapy for NSCLC. However, it is not completely curative due to drug resistance and oxidative stress-induced toxicity. Drug resistance is linked to overexpression of matrix metalloproteinases (MMPs) and aberrant calcium signalling. We report synthesis of novel thiazole-triazole hybrids as MMP-9 inhibitors with T-type calcium channel blocking and antioxidant effects to sensitise NSCLC to cisplatin and ameliorate its toxicity. MTT and whole cell patch clamp assays revealed that 6d has a balanced profile of cytotoxicity (IC50 = 21 ± 1 nM, SI = 12.14) and T-type calcium channel blocking activity (⁓60% at 10 μM). It exhibited moderate ROS scavenging activity and nanomolar MMP-9 inhibition (IC50 = 90 ± 7 nM) surpassing NNGH with MMP-9 over −2 and MMP-10 over −13 selectivity. Docking and MDs simulated its receptor binding mode. Combination studies confirmed that 6d synergized with cisplatin (CI = 0.69 ± 0.05) lowering its IC50 by 6.89 folds. Overall, the study introduces potential lead adjuvants for NSCLC platinum-based therapy.

Mechanisms of antiviral action and toxicities of ipecac alkaloids: Emetine and dehydroemetine exhibit anti-coronaviral activities at non-cardiotoxic concentrations

The emergence of highly infectious pathogens with their potential for triggering global pandemics necessitate the development of effective treatment strategies, including broad-spectrum antiviral therapies to safeguard human health. This study investigates the antiviral activity of emetine, dehydroemetine (DHE), and congeneric compounds against SARS-CoV-2 and HCoV-OC43, and evaluates their impact on the host cell. Concurrently, we assess the potential cardiotoxicity of these ipecac alkaloids. Significantly, our data reveal that emetine and the (-)-R,S isomer of 2,3-dehydroemetine (designated in this paper as DHE4) reduce viral growth at nanomolar concentrations (i.e., IC50 ∼ 50–100 nM), paralleling those required for inhibition of protein synthesis, while calcium channel blocking activity occurs at elevated concentrations (i.e., IC50 ∼ 40–60 µM). Our findings suggest that the antiviral mechanisms primarily involve disruption of host cell protein synthesis and is demonstrably stereoisomer specific. The prospect of a therapeutic window in which emetine or DHE4 inhibit viral propagation without cardiotoxicity renders these alkaloids viable candidates in strategies worthy of clinical investigation.

The Promise of Cilnidipine in Hypertension with Comorbidities: National Consensus Statement: National Consensus Group Comprises Cardiologists, Nephrologists, and Diabetologists from India in a National Meet at New Delhi held on 22nd May 2022.

The rapidly increasing burden of hypertension is responsible for premature deaths from cardiovascular disease (CVD), renal disease, and stroke, with a tremendous public health and financial burden. Hypertension detection, treatment, and control vary worldwide; it is still low, particularly in low- and middle-income countries (LMICs). High blood pressure (BP) and CVD risk have a strong, linear, and independent association. They contribute to alarming numbers of all-cause and CVD deaths. A major culprit for increased hypertension is sympathetic activity, and further complications of hypertension are heart failure, ischemic heart disease (IHD), stroke, and renal failure. Now, antihypertensive interventions have emerged as a global public health priority to reduce BP-related morbidity and mortality. Calcium channel blockers (CCB) are highly effective vasodilators. and the most common drugs used for managing hypertension and CVD. Cilnidipine, with both L- and N-type calcium channel blocking activity, is a promising 4th generation CCB. It causes vasodilation via L-type calcium channel blockade and inhibits the sympathetic nervous system (SNS) via N-type calcium channel blockade. Cilnidipine, which acts as a dual L/N-type CCB, is linked to a reduced occurrence of pedal edema compared to amlodipine, which solely blocks L-type calcium channels. The antihypertensive properties of cilnidipine are very substantial, with low BP variability and long-acting properties. It is beneficial for hypertensive patients to deal with morning hypertension and for patients with abnormal nocturnal BP due to exaggerated sympathetic nerve activation. Besides its BP-lowering effect, it also exhibits organ protection via sympathetic nerve inhibition and renin-angiotensin-aldosterone system inhibition; it controls heart rate and proteinuria. Reno-protective, neuroprotective, and cardioprotective effects of cilnidipine have been well-documented and demonstrated.

Pitavastatin and Lovastatin Exhibit Calcium Channel Blocking Activity Which Potentiate Vasorelaxant Effects of Amlodipine: A New Futuristic Dimension in Statin's Pleiotropy.

Background and Objectives: We have recently reported that Fluvastatin, Atorvastatin, Simvastatin and Rosuvastatin have calcium channel antagonistic activities using rabbits' intestinal preparations. The current study is focused on the effects of Pitavastatin and Lovastatin for possible inhibition of vascular L-Type calcium channels, which may have vasorelaxant effect(s). Combined effects of Pitavastatin and Lovastatin in the presence of Amlodipine were also tested for vasorelaxation. Materials and Methods: Possible relaxing effects of Pitavastatin and Lovastatin on 80 mM Potassium chloride (KCL)-induced contractions and on 1 µM norepinephrine (N.E)-induced contractions were studied in isolated rabbit's aortic strips preparations. Relaxing effects on 80 mM KCL-induced vascular contractions were further verified by constructing Calcium Concentration Response Curves (CCRCs), in the absence and presence of three different concentrations of Pitavastatin and Lovastatin using CCRCs as negative control. Verapamil was used as a standard drug that has L-Type calcium channel binding activity. In other series of experiments, we studied drug interaction(s) among Pitavastatin, Lovastatin, and amlodipine. Results: The results of this study imply that Lovastatin is more potent than Pitavastatin for having comparatively lower EC50 (7.44 × 10-5 ± 0.16 M) in intact and (4.55 × 10-5 ± 0.10 M) in denuded aortae for KCL-induced contractions. Lovastatin amplitudes in intact and denuded aortae for KCL-induced contractions were, respectively, 24% and 35.5%; whereas amplitudes for Pitavastatin in intact and denuded aortae for KCL-induced contractions were 34% and 40%, respectively. A left shift in the EC50 values for the statins was seen when we added amlodipine in EC50 (Log Ca++ M). Right shift for CCRCs state that Pitavastatin and Lovastatin have calcium channel antagonistic effects. Lovastatin in test concentration (6.74 × 10-7 M) produced a right shift in relatively lower EC50 (-2.5 ± 0.10) Log Ca++ M as compared to Pitavastatin, which further confirms that lovastatin is relatively more potent. The right shift in EC50 resembles the right shift of Verapamil. Additive effect of Pitavastatin and Lovastatin was noted in presence of amlodipine (p < 0.05). Conclusions: KCL (80 mM)-induced vascular contractions were relaxed by Pitavastatin and Lovastatin via inhibitory effects on L-Type voltage-gated calcium channels. Lovastatin and Pitavastatin also relaxed Norepinephrine (1 µM)-induced contractions giving an insight for involvement of dual mode of action of Pitavastatin and Lovastatin.

Synthesis of Ethyl Methyl 4-aryl-1,4-dihydropyridine-3,5-dicarboxylates as Potential Calcium Channel Blockers for Hypertension

Aim: Several new dihydropyridine-based calcium channel blockers have been synthesized and pharmacologically evaluated for the treatment of hypertension Background: Dihydropyridines constitute an important class of calcium channel blockers (CCBs) due to their high potency, wide heterogeneity and tremendous biological usefulness. As a follow-up to our previous studies on 4-aryl-1,4-dihydropyridines as calcium channel blockers for the treatment of hypertension, four new series of methyl ethyl ester substituted 1,4-dihydropyridines are reported. Objectives: The aim of the work was to study the effects of unsymmetrical ester substitutions on calcium channel blocking activity of dihydropyridines (DHPs) while retaining the aminoalkoxy side chain at various positions of the 4-aryl ring. The type and location of the substituents on the 4-aryl ring have been extensively explored to study the structure-activity relationship (SAR) in this series of dihydropyridines as calcium channel blockers. Methodology: The target DHPs were synthesized using modified Hantzsch condensation and further derivatization. The compounds were screened for their inhibitory potential against L-type calcium channels at a single concentration of 10 μM on NG108-15 cells (Neuroblastoma X Glioma). The most potent DHP 12 was also tested for its vasodilatory activity using rat thoracic aortic rings precontracted with KCl (30 mM) and in vivo antihypertensive activity in rats using the tail-cuff method. Results: The newly synthesized DHPs displayed diversified calcium channel blocking activity with compounds 1e, 1h, 2d, 2f, 2h, 6, 9, 11, 12 and 14, producing more than 50% inhibition of veratridine response. 3-imidazolylpropoxy substituted analogue 12 turned out to be the most potent compound of the four series of compounds and produced fairly higher inhibition (78.6%) of veratridine response in comparison to nifedipine (70%) at 10 μM. In addition, compound 12 produced potent vasodilatory and antihypertensive properties. Conclusion: Both location of the side chain and the type of substituent on methyl ethyl ester substituted 4-aryl ring affected the response of dihydropyridine derivatives towards L-type calcium channels.

Synthesis and Evaluation of Some New Pyridines as Possible P-gp Inhibitors with Reduced Calcium Channel Blocking Activity

The 1,4-dihydropyridine derivatives (DHPs) (3a-b and 4a-c) were oxidized with iodine in methanol to produce five new, hitherto unreported pyridine derivatives (5a-b and 6a-c). The “Everted sac method” was used to assess the DHPs and their pyridines for potential p-glycoprotein (P-gp) inhibitory or multidrug resistance reversal action. Domperidone, a P-gp substrate, was examined for intestinal absorption in everted rat jejunal segments in the presence and absence of DHPs (3a-b and 4a-c) and pyridines (5a-b and 6a-c) at doses of 30 μg/mL and 100 μg/mL. The standard was Verapamil, a known P-gp inhibitor (30 μg/mL and 100 μg/mL). The P-gp inhibition of all the tested compounds was higher than Verapamil. The P-gp inhibition of compounds 5b and 6b was the highest. Utilizing isolated rat ileum, the newly synthesized pyridine derivatives calcium channel blocking efficacy was also investigated. The strongest Ca2+ channel-blocking action was seen with compound 5b. It was determined to be equivalent to Nifedipine, the gold standard. Strong P-gp inhibitor compound 6b has little calcium channel-blocking action.

Aqueous Extract of Malus domestica Inhibits Human Platelet Aggregation Induced by Multiple Agonists

Cardiovascular diseases such as hypertension, myocardial infarction, and atherosclerosis are the major cause of morbidity and mortality in humankind and not only afflict industrialized nations but also affect developing countries such as Pakistan. We attempted to screen one of the most common fruits, Malus domestica (MD or apple), used in Pakistan for its potential cardio-protective effects. The crude aqueous extract (MD-Aq) was prepared and investigated for inhibitory activity against several important cardiovascular drug targets. Activities of antioxidant enzymes such as glutathione peroxidase (GPx) and superoxide dismutase (SOD) were studied, as well as total antioxidant status (TAS). Calcium channel blocking activity was measured using guinea pig ileum in an isolated tissue bath setup. Platelet aggregation studies were carried out using a dual-channel aggregometer. MD-Aq showed dose-dependent improvement in the GPX activity. The highest SOD levels were observed with 10 mg/ml and were 185 U/L compared to 174 U/L for saline, which means no significant effect by MD-Aq. TAS levels were highest at 10 mg/ml of MD-Aq, reaching 1.75 mmol/L of plasma. At 10 mg/ml, close to 90% inhibition of KCl-induced opening of calcium channels was observed, compared with the effect of 1mM Verapamil. At each dose of 1, 5, and 10 mg/ml, a significantly higher arachidonic acid-induced inhibition of platelet aggregation was observed as compared to the saline effect. MD-Aq effects on platelet-activating factor-induced platelet aggregation were less potent. We concluded that MD-Aq could elevate GPX and TAS levels, is inactive at SOD, and is excellent as a calcium channel blocker, a more potent blocker of arachidonic acid-induced aggregation than platelet-activating factor-induced aggregation. These activities can help treat various cardiovascular diseases.

Effect of Dihydroartemisinin on contractility to Drugs in isolated smooth muscle Preparations in guinea pig in vitro models

This study was aimed at evaluating the effect of Dihydroartemisinin (DHA)on contractility to drugs in ileum isolated smooth muscle preparations in guinea pigs using in Vitro experimental procedures / standard protocols in an organ bath set up. dihydroartemisinin (1.0 x 10 - 8 - 1.0 x 10 – 5mg/mL) when applied alone and separately excited marked variable effects on guinea pig ileum . In some preparation it showed no response, while in others it produced slight phasic contraction when external calcium (Ca2+) ion was introduced. The slight phasic contractile activity was abolished by verapamil (5x10-3mg/mL). Dihydroartemisinin (1.0 x 10 - 6 - 1.0 x 10 – 5mg/mL) caused marked significant induced contraction – dependent inhibition of acetylcholine, potassium chloride and histamine in depolarizing tyrode solution (p &lt; 0.05).The Inhibitory response maxima of dihydroartemisinin on acetylcholine induced contraction is 17.0±0.1 mm(65.56% inhibition) ; and is moderate when compared to the inhibitory effect of atropine (10-5 M). The result shows that dihydroartemisinin seems to act via non-specific receptor mechanism, with appreciable calcium channel blocking activity and it is safe at therapeutic doses.

Design, Synthesis, Molecular Modeling, and Biological Evaluation of Novel Pyrimidine Derivatives as Potential Calcium Channel Blockers.

Pyrimidines play an important role in modern medical fields. They have a wide spectrum of biological activities such as antimicrobial, anticancer, anti-allergic, anti-leishmanial, antioxidant agents and others. Moreover, in recent years, 3,4-dihydropyrimidin-2(1H)ones have attracted researchers to synthesize them via Biginelli reaction and evaluate their antihypertensive activities as bioisosters of Nifedipine, which is a famous calcium channel blocker. Our new target compounds were prepared through one-pot reaction of thiourea 1, ethyl acetoacetate 2 and/or 1H-indole-2-carbaldehyde, 2-chloroquinoline-3-carbaldehyde, 1,3-diphenyl-1H-pyrazole-4-carbaldehyde, 3a-c in acid medium (HCl) yielding pyrimidines 4a-c, which in turn were hydrolyzed to carboxylic acid derivatives 5a-c which were chlorinated by SOCl2 to give acyl chlorides 6a-c. Finally, the latter were reacted with some selected aromatic amines, namely, aniline, p-toluidine and p-nitroaniline, producing amides 7a-c, 8a-c, and 9a-c. The purity of the prepared compounds was examined via TLC monitoring, and structures were confirmed by different spectroscopic techniques such as IR, 1HNMR, 13CNMR, and mass spectroscopy. The in vivo evaluation of the antihypertensive activity revealed that compounds 4c, 7a, 7c, 8c, 9b and 9c had comparable antihypertensive properties with Nifedipine. On the other hand, the in vitro calcium channel blocking activity was evaluated by IC50 measurement and results revealed that compounds 4c, 7a, 7b, 7c, 8c, 9a, 9b, and 9c had comparable calcium channel blocking activity with the reference Nifedipine. Based on the aforementioned biological results, we selected compounds 8c and 9c to be docked onto Ryanodine and dihydropyridine receptors. Furthermore, we developed a structure-activity relationship. The designed compounds in this study show promising activity profiles in reducing blood pressure and as calcium channel blockers, and could be considered as new potential antihypertensive and/or antianginal agents.

Synthesis, Biological Evaluation, in silico ADMET and Molecular Docking of new 1,4‐Dihydropyridine Derivatives Bearing Ether Substitution as Calcium Channel Blockers

AbstractA set of 1,4‐dihydropyridine derivatives were synthesized, possessing methyl or ethyl esters at positions 3 and 5, an aliphatic or aromatic ether group at position 2, and a thienyl ring at position 4. The calcium channel blocking activity of these derivatives was investigated using K+‐induced contraction on the longitudinal smooth muscles of guinea pig ileum (GPILSM). Our findings showed that the derivatives had IC50 ranging from 0.5 to 5.2 μM. Among the synthesized compounds, compound including methoxy group in position 2 and ethyl acetate in positions 3 and 5, with IC50=0.55±0.58 μM was almost comparable to that of nifedipine (IC50=0.27±1.23 μM). The results of docking studies and biological evaluation of synthetic compounds were consistent. According to the physicochemical and drug‐likeness parameters, it is predicted that the synthesized compounds can be a suitable candidate for calcium channel blocking.

Atorvastatin and Fluvastatin Potentiate Blood Pressure Lowering Effect of Amlodipine through Vasorelaxant Phenomenon.

Background and Objectives: We have recently reported that stains have calcium channel blocking activity in isolated jejunal preparations. In this study, we examined the effects of atorvastatin and fluvastatin on blood vessels for a possible vasorelaxant effect. We also studied the possible additional vasorelaxant effect of atorvastatin and fluvastatin, in the presence of amlodipine, to quantify its effects on the systolic blood pressure of experimental animals. Materials and Methods: Atorvastatin and fluvastatin were tested in isolated rabbits' aortic strip preparations using 80mM Potassium Chloride (KCl) induced contractions and 1 micro molar Norepinephrine (NE) induced contractions. A positive relaxing effect on 80 mM KCl induced contractions were further confirmed in the absence and presence of atorvastatin and fluvastatin by constructing calcium concentration response curves (CCRCs) while using verapamil as a standard calcium channel blocker. In another series of experiments, hypertension was induced in Wistar rats and different test concentrations of atorvastatin and fluvastatin were administered in their respective EC50 values to the test animals. A fall in their systolic blood pressure was noted using amlodipine as a standard vasorelaxant drug. Results: The results show that fluvastatin is more potent than amlodipine as it relaxed NE induced contractions where the amplitude reached 10% of its control in denuded aortae. Atorvastatin relaxed KCL induced contractions with an amplitude reaching 34.4% of control response as compared to the amlodipine response, i.e., 39.1%. A right shift in the EC50 (Log Ca++ M) of Calcium Concentration Response Curves (CCRCs) implies that statins have calcium channel blocking activity. A right shift in the EC50 of fluvastatin with relatively less EC50 value (-2.8 Log Ca++ M) in the presence of test concentration (1.2 × 10-7 M) of fluvastatin implies that fluvastatin is more potent than atorvastatin. The shift in EC50 resembles the shift of Verapamil, a standard calcium channel blocker (-1.41 Log Ca++ M). Conclusions: Atorvastatin and fluvastatin relax the aortic strip preparations predominantly through the inhibition of voltage gated calcium channels in high molar KCL induced contractions. These statins also inhibit the effects of NE induced contractions. The study also confirms that atorvastatin and fluvastatin potentiate blood pressure lowering effects in hypertensive rats.

Anti-ageing effects of FDA-approved medicines: a focused review.

Ageing is the process generated by senescent cells, free radicals, inflammation and other relevant factors. Ageing contributes to age-related diseases that affect the quality of life. People are interested in anti-ageing intervention and many scientists attempt to search for anti-ageing medicines. This review focused on describing invivo anti-ageing activity of US-FDA-approved drugs and found that alogliptin, canagliflozin and metformin might produce anti-ageing activity via AMPK activation. Rapamycin and canagliflozin are capable to inhibit mTOR to promote lifespan. Atracurium, carnitine and statins act as DAF-16 activators, which potentially contribute to anti-ageing activity. Hydralazine, lisinopril, rosiglitazone and zidovudine may help stabilize genomic integrity to prolong life expectancy. Other indirect mechanisms, including insulin-lowering effect by acarbose and calcium channel blocking activity by verapamil may also promote longevity. Interestingly, some drugs (i.e.,canagliflozin, metformin, rapamycin and acarbose) are likely to demonstrate a lifespan-promoting effect predominantly in male animals. These pre-clinical data might provide mechanistic and phenotypic perspectives to better understand the targets of anti-ageing interventions.

Novel Polyhydroquinoline-Hydrazide-Linked Schiff's Base Derivatives: Multistep Synthesis, Antimicrobial, and Calcium-Channel-Blocking Activities.

Polyhydroquinoline (PHQ) are the unsymmetrical Hantzsch derivatives of 1,4-dihydropyridines with several biological applications. In this work, twenty-five (3-27) new Schiff's base derivatives of polyhydroquinoline hydrazide were synthesized in excellent to good yields by a multi-component reaction. The structures of the synthesized products (1-27) were deduced with the help of spectroscopic techniques, such as 1H-, 13C -NMR, and HR-ESI-MS. The synthesized products (1-27) were tested for their antibacterial and in vitro calcium -channel-blocking (CCB) potentials using the agar-well diffusion method, and isolated rat aortic ring preparations, respectively. Among the series, sixteen compounds were found to inhibit the growth of Escherichia coli and Enterococcus faecalis. Among them, compound 17 was observed to be the most potent one at a dose 2 µg/mL, with an 18 mm zone of inhibition against both bacteria when it was compared with the standard drug amoxicillin. Eight compounds showed CCB activity of variable potency; in particular, compound 27 was more potent, with an EC50 value of 0.7 (0.3-1.1) µg/mL, indicating their CCB effect.

Flavonoids containing Vitex negundo extract displayed calcium channels blocking property underlying its anti-diarrheal and anti-spasmodic activities

Diarrhea is a major health problem and despite of interventions, it remains a substantial cause of mortality and morbidity. In this study, a flavonoids-rich Vitex negundo extract was mechanistically evaluated for its effectiveness in diarrheal diseases. The Vitex negundo ethanolic extract was subjected to extraction for isolation of total flavonoids and qualitative phytochemical analysis. The acute toxicity of flavonoids-extract was done in mice to assess its safety and tolerability. The anti-diarrhoeal activity was determined using the castor oil induced diarrhea mouse model at doses of 10, 30 and 100 mg/kg in relation to loperamide (10 mg/kg, oral). The antispasmodic profile was determined by using cut pieces of rabbit’s jejunum in Tyrode’s solutions, employing acetylcholine (0.03μM) as a tissue stabilizer and verapamil, as a calcium channel blocker. The preliminary qualitative analysis of extract revealed different phytochemicals, in addition to flavonoids. The acute toxicity profile showed that the flavonoids-extract is safe and tolerable (LD50 = 1678 mg/kg). In the tissue experiments, the total flavonoids exhibited an EC50 of 1.52 mg/mL and showed maximum relaxation of spontaneous contractions at 5.0 mg/mL and against high-K+ induced contractions at 3 mg/mL (EC50 = 0.43 mg/mL). The spasmolytic activity of total flavonoids was comparable to verapamil which suggests that the activity might be due to the blockade of calcium channels. The flavonoids extract (0.1, 0.3 and 1.0 mg/mL) produced an adequate right shift in the calcium concentration response curve as compared to the control (EC50 value = –2.67 mg/mL), which confirmed that the extract has calcium channel blocking activity.

Studies on the Actions of Calcium Channel Blockers, Anticholinesterases Agents on Experimentally Induced Spastic Paralysis in Normotensive Rats

Experimental paralysis was induced intramuscularly (i.m) in rats , using Suxa(1.08mg/kg ) , Deca (1.08mg/kg ) in normotensive rats weighing150-180g±2.5g (n=8).Various concentrations of these drugs ranging from (0.36—1.08mg/kg) were used , in order to assess at what concentrations will induced spastic paralysis sustained without death. Similarly, dose response concentrations effect was examined and the onset of action( ie time taken to observe paralysis and manifestation of pain and death was recorded. In some experiments, equimolar concentrations of Suxa(1.08mg/kg) and Deca(1.08mg/kg) was used to assess reaction time(RT) and potency of the agents. Thereafter the actions of Calcium Channel blockers (CCB), Diltiazem ( DTZ) and verapamil(VE) were studied in separate experiments. Anticholinesterase agent(AchE) in combination with Atropine a known antimuscarinic agent(AchE ) and investigated their actions on induced paralysis. The results obtained in these studies showed that CCB produced a significant potentiation of spastic paralysis on Suxa induced paralysis but non reversal effect with Deca , while AchE in combination ATR showed a reversal effect on paralysis induced by these agents in the concentrations used in his study. The aim of the study was to see interaction of these agents on sustained experimental paralysis in rodent.

Cardioprotective Effects of Malus Domestica (Apple) May be Mediated Through Antiplatelet, Calcium Channel Blocking, and Antioxidant Properties

Research on the cardioprotective potential of Malus domestica (MD or apple) has been of considerable importance and efforts are being increasingly focused on investigating their effects on human health. However, relatively little work has been done to investigate the cardioprotective effects of crude extract of MD. In the present study, the antioxidant potential of crude methanolic extract of MD fruit part was investigated by measuring its effects on glutathione peroxidase (GPx), superoxide dismutase (SOD) enzymes, and total antioxidant status (TAS) in blood samples. Anti-platelet and calcium channel blocking activities were also investigated. Our results reveal that crude methanolic extract of MD showed a significant concentration-dependent increase in GPx, and SOD, but not in TAS compared with saline solution (0.9% NaCl) used as negative control and vitamin C, as a positive control. Furthermore, crude extract of MD inhibited calcium channels and showed strong antiplatelet effects against arachidonic acid and platelet-activating factor-induced platelet aggregation. These results suggest that the cardioprotective effects of MD may be mediated through multiple pathways including calcium antagonizing, antiplatelet, and antioxidant properties.

Analytical Technique for Carvedilol and Ivabradine Determination from Pure and Pharmaceutical Dosage Forms: A Review

Carvedilol and ivabradine is a drug combination used to treat cardiovascular diseases like hypertension, chronic stable angina pectoris and, chronic heart failure. Both are different in their mode of action. Carvedilol prevents exercise-induced tachycardia via inhibition of beta-adrenoreceptor carvedilol, which also acts on alpha-1 adrenergic receptors and reduces blood pressure. In case of a higher dose also shows antioxidant and calcium channel blocking activity. Ivabradine is a heart rate-reducing drug that works by blocking cardiac pacemaker currents (If) selectively and specifically. The major goal of this review paper is to emphasize the characteristics of carvedilol and ivabradine, such as their pharmacological profiles, mechanisms of action, pharmacokinetic and pharmacodynamic studies, and previously described analytical methodologies for carvedilol and ivabradine determination. Various methods such as UV spectroscopy High-performance liquid chromatography (HPLC), Reverse phase -High performance liquid chromatography (RP-HPLC), Ultra-performance liquid chromatography (UPLC), Mass Spectrometry (MS), High-performance thin layer chromatography (HPTLC). is the most accurate easy method for estimation.

Design, Synthesis, Pharmacodynamic and In Silico Pharmacokinetic Evaluation of Some Novel Biginelli-Derived Pyrimidines and Fused Pyrimidines as Calcium Channel Blockers.

Some new pyrimidine derivatives comprising arylsulfonylhydrazino, ethoxycarbonylhydrazino, thiocarbamoylhydrazino and substituted hydrazone and thiosemicarbazide functionalities were prepared from Biginelli-derived pyrimidine precursors. Heterocyclic ring systems such as pyrazole, pyrazolidinedione, thiazoline and thiazolidinone ring systems were also incorporated into the designed pyrimidine core. Furthermore, fused triazolopyrimidine and pyrimidotriazine ring systems were prepared. The synthesized compounds were evaluated for their calcium channel blocking activity as potential hypotensive agents. Compounds 2, 3a, 3b, 4, 11 and 13 showed the highest ex vivo calcium channel blocking activities compared with the reference drug nifedipine. Compounds 2 and 11 were selected for further biological evaluation. They revealed good hypotensive activities following intravenous administration in dogs. Furthermore, 2 and 11 displayed drug-like in silico ADME parameters. A ligand-based pharmacophore model was developed to provide adequate information about the binding mode of the newly synthesized active compounds 2, 3a, 3b, 4, 11 and 13. This may also serve as a reliable basis for designing new active pyrimidine-based calcium channel blockers.

Vasorelaxant Effects of the Vitex Agnus-Castus Extract.

This study was undertaken to describe and characterize the relaxing effects of the medicinal plant Vitex agnus-castus (VAC) extract on isolated rabbit arterial rings. The VAC extracts (VACE) were extracted with ethanol and tested in aorta rings (3-4 mm) of rabbits suspended in an organ bath (Krebs, 37°C, 95% O2/5% CO2) under a resting tension of 1 g to record isometric contractions. After the stabilization period (1-2 hours), contractions were induced by the addition of phenylephrine (0.5 μM) or high KCl (80 mM) and VACE was added on the plateau of the contractions. Experiments were performed to determine the effects and to get insights into the potential mechanism involved in VACE-induced relaxations. The cumulative addition of VACE (0.15–0.75 mg/mL) relaxed, in a concentration-dependent manner, the rabbit aorta rings precontracted either with phenylephrine- or with high KCl thus suggesting calcium channel blocking activities. The VACE effect appeared to be endothelium-dependent. The preincubation with L-NAME (the inhibitor of nitric oxide synthases (NOS)), ODQ (the selective inhibitor of guanylyl cyclase), and indomethacin (the cyclooxygenase inhibitor), downregulated VACE-induced relaxation of aorta rings precontracted with phenylephrine, whereas the bradykinin (stimulator of NOS) and zaprinast (phosphodiesterase inhibitor) further upregulated relaxant effects induced by VACE. These results revealed that the aorta relaxation effect of VACE was mainly endothelium-dependent and mediated by NO/cGMP and prostaglandins synthesis. This vasodilator effect of VACE may be useful to treat cardiovascular disorders, including hypertensive diseases.