Dihydropyridine Calcium Channel Antagonist Research Articles

Enhancement of Solubility by Hydrotropic Techniques of Lercanidipine HCl: In-situ Nasal Gel Development

Lercanidipine HCl is a novel, third-generation, potent, vasoselective 1, 4- dihydropyridine calcium channel antagonist and a Biopharmaceutical Classification System (BCS) class II drug that aids in preventing hypertension. The final aim of the present work was to promote the solubility of lercanidipine HCl via hydrotrophy and then include it in the in-situ gel formulation. This enhancement of drug solubility was carried out by using citric acid as a hydrotropic agent. Simultaneously, using a mixture of two polymers, namely Poloxamer 407, a thermosensitive polymer with reversible thermal characteristics. Carbopol 940P is a high-viscosity builder exploited for developing in-situ gel. The optimization of preliminary batches of mixtures of both polymers was highly accepted by using 32 factorial designs. F4 was found to be highly optimized, according to all the evaluation parameters and Poloxamer 407 (18% w/v) and Carbopol 940P (0.2% w/v), with drug release of 93.23%. Goat mucosa ex-vivo investigation yielded a value of 79.14% flux at 6 hours. According to ICH guidance, the in-situ Lercanidipine HCl gel has turned up to be stable following a 6-month stability investigation. Thus, the subsequent thermoreversible in-situ gel was scouted to act as a potent nasal distributor with greater bioavailability and patient compliance for the nasal medication.

Fixed triple combination of amlodipine, perindopril and atorvastatin in the focus of cardiovascular effectiveness and safety

The review outlines modern concepts of the relevance of fixed-dose combination therapy comprising angiotensin-converting enzyme inhibitor and dihydropyridine calcium channel antagonist as an antihypertensive component with the HMG-CoA reductase inhibitor when treating hypertensive patients. We have identified the realms of its possible clinical use taking into consideration the comorbidity peculiarities. In addition, we provide main features of the current drugs’ clinical pharmacodynamics and outline their role in real clinical practice. Nevertheless the emphasis was placed on the modern single-pill combination of amlodipin, atorvastatin and perindopril. We concisely report the results data collected from the large, randomized, double-blind major clinical trials regarding the effectiveness of single pill combination of amlodipine, atorvastatin and perindopril , primary focusing on their cardioprotective features and overall safety profile.

Simultaneous estimation of Azelnidipine and Metoprolol succinate with greenness assessment using HPLC and UV-spectrophotometric methods

Azelnidipine is a novel dihydropyridine calcium channel antagonist and Metoprolol succinate is a beta blocker, this combination was approved by CDSCO for Phase III clinical trial in April 2021. This combination is utilized to achieve a better outcome in the treatment of stage 2 hypertension. The present research includes an HPLC and Absorbance Correction UV method for the determination in synthetic mixture.The HPLC chromatography was performed using a gradient technique on a reversed-phase C18 column with mobile phase based and optimized depending on the polarity of the molecules. The Unesphere C18 column Agela Tech., (250 mm x 4.6 mm i.d, 5 μm,) as stationary phase and Acetonitrile: Phosphate Buffer pH 3.5 (40:60%v/v) as mobile phase with UV detection at 275 nm at 1 ml/min for gradient elution was used to achieve chromatographic separation over the linearity 10.0 - 30.0 μg/mL and 50.0–150.0 μg/mL with r2 0.9995 and 0.9993 for Azelnidipine and Metoprolol succinate respectively. The retention time was found to be 6.367 and 2.308 min for Azelnidipine and Metoprolol succinate respectively.% RSD of intraday precision of AZL and MET was found to be 0.01 – 0.03% and 0.01 – 0.03%, respectively. Interday presion was found to be 0.02 – 0.06% and 0.02 – 0.05%, respectively which are indicated that the method is precise.% recovery for AZL and MET by this method was found in the range of 99.85 - 100.76% and 99.23 - 99.89%, respectively. The system suitability test parameters theoretical plates were found to be 7042.56 (AZL) and 2231.74 (MET) and tailing factor was found to be 1.47 (AZL) and 1.52 (MET).The Absorbance Correction UV method was developed validated at 313 nm (λmax of Azelnidipine) and 275.40 nm (λmax of Metoprolol succinate) in methanol: distilled water (20:80, v/v) for estimation of AZL and MET respectively and show linearity 5.0 - 25.0 μg/mL and 25.0 - 125.0 μg/mL with r2 0.9998 and 0.9991 for Azelnidipine and Metoprolol succinate respectively.% RSD of intraday precision of AZL and MET was found to be 0.46 – 0.64% and 0.42 – 0.71%, respectively and for interday precision was found to be 0.40 – 0.65% and 0.22 – 0.75%, respectively.% recovery for AZL and MET by this method was found in the range of 100.50 - 100.77% and 100.30 - 100.78%, respectively. The value of% RSD within the limit indicated that the method is accurate and% recovery shows that there is no interference from the excipients.Both methods were validated as per ICH Q2(R1) guidelines. The analytical method validation parameters were found to be as per acceptance criteria. In terms of accuracy and precision, statistical testing employing an analysis of variance test did not find any significant differences between the two methods. The ICH Q2R1 recommendations extensive statistical validation of the two established methodologies, proving their effective use in the simultaneous study of the two medications in bulk and tablets made within the laboratory.The Analytical eco scale (AES), National environmental method index (NEMI), Green analytical procedure index (GAPI), and software-based Analytical greenness metric (AGREE) tools were used to assess the ecological impact of the new UV spectrophotometric technique and HPLC method. This assessment confirmed the method's environmental friendliness in terms of solvent usage, chemical compounds, energy consumption, and trash creation. Both methods can be used to successfully analyze Azelnidipine and Metoprolol succinate in combination dose form without interference from excipients. There were no spectral or chromatographic interferences from formulation excipients discovered. Because the proposed procedures are simple, quick, precise, and accurate, they were effectively used to determine Azelnidipine and Metoprolol succinate in their dose forms. To evaluate the greenness and whiteness of an analytical method, a reliable assessment of the health and environmental risk associated with chemical use is essential. An objective and useful way of risk assessment should consider all pertinent characteristics of substances utilized, the actual quantities required for method implementation, and the result of the assessment should be quantified using a standard unit.

Nimodipine Attenuates Early Brain Injury by Protecting the Glymphatic System After Subarachnoid Hemorrhage in Mice.

The glymphatic system (GS) plays an important role in subarachnoid hemorrhage (SAH). Nimodipine treatment provides SAH patients with short-term neurological benefits. However, no trials have been conducted to quantify the relationship between nimodipine and GS. We hypothesized that nimodipine could attenuate early brain injury (EBI) after SAH by affecting the function of the GS. In this study, we assessed the effects of nimodipine, a dihydropyridine calcium channel antagonist, on mice 3days after SAH. The functions of GS were assessed by immunofluorescence and western blot. The effects of nimodipine were assessed behaviorally. Concurrently, correlation analysis was performed for the functions of GS, immunofluorescence and behavioral function. Our results indicated that nimodipine improved GS function and attenuated neurological deficits and brain edema in mice with SAH. Activation of the cAMP/PKA pathway was involved in this process. GS function was closely associated with perivascular AQP4 polarization, cortical GFAP/AQP4 expression, brain edema and neurobehavioral function. In conclusion, this study shows for the first time that nimodipine plays a neuroprotective role in the period of EBI after SAH in mice through the GS.

Study on pharmacokinetics of nimodipine nano-controlled release agent modified by host-guest reaction of β-cyclodextrin in rats

Nimodipine (NIMO) has been identified as a second-generation dihydropyridine calcium channel antagonist. NIMO’s specificity for the cerebrovascular smooth muscle contributes to its broad usage in treating ischemic cerebrovascular diseases in the elderly. Therefore, enhancing NIMO’s therapeutic effect and reducing its adverse reactions caused by short-term repeated use have become a focus of research. As a result, a new controlled-release preparation of NIMO, the carboxymethyl chitosan/nimodipine-hydroxypropyl-β-cyclodextrin nanoparticle (Nano-NIMO), was constructed based on hydroxypropyl-β-cyclodextrin. The novel composite Nano-NIMO preparation could significantly improve the stability of NIMO in rat plasma, achieving an absolute bioavailability as high as 62.3%, which is three times that of the traditional NIMO oral preparation. Therefore, Nano-NIMO is expected to provide a new direction for the preparation of modified controlled-release Nano- NIMO agents.

Nicardipine sensitizes temozolomide by inhibiting autophagy and promoting cell apoptosis in glioma stem cells.

Glioblastoma multiforme (GBM) is the most invasive malignant central nervous system tumor with poor prognosis. Nicardipine, a dihydropyridine calcium channel antagonist, has been used as an adjuvant to enhance sensitivity to chemotherapeutic drugs. However, whether glioma stem cells (GSCs) can be sensitized to chemotherapy via combined treatment with temozolomide (TMZ) and nicardipine is unclear. In this study, surgical specimen derived GSCs SU4 and SU5 were applied to explore the sensitization effect of nicardipine on temozolomide against GSCs, and further explore the relevant molecular mechanisms. Our results showed that nicardipine can enhance the toxic effect of temozolomide against GSCs, promote apoptosis of GSCs, and inhibit autophagy of GSCs. The relevant mechanisms were related to activation of mTOR, and selective inhibition of mTOR by rapamycin could weaken the sensitization of nicardipine to temozolomide, which suggest that nicardipine can be applied as an adjuvant to inhibit autophagy in GSCs, and enhance apoptosis-promoting effect of temozolomide in GSCs as well. Nicardipine can inhibit autophagy by activating expression of mTOR, thus play tumor inhibition roles both in vitro and in vivo. Repurposing of nicardipine can help to improving therapeutic effect of TMZ against GBM, which deserves further clinical investigations.

Nanosuspensions by Solid Lipid Nanoparticles method for the Formulation and In vitro/in vivo, characterization of Nifedipine

Nifedipine is a dihydropyridine calcium channel antagonist initially prescribed for treatment of angina pectoris and hypertension. The drug belongs to BCS Class-2 drug, is poorly water soluble drug, it suffers from a poor aqueous solubility, hence the delays its onset of action. Therefore, the purpose of the research study is to adopt the nanotechnology to formulate nanoparticles that improve the rate of dissolution of drug and to get desired bioavailability of nifedipine. Nanosuspensions were prepared by Solid Lipid Nano Particles method in the presence of selected stabilizers at different concentrations. The nanosuspensions were determined for their particle size of drug, zeta potential of drug, drug content and drug dissolution. The selected formula was freeze dried and illustrated by scanning electron microscopy (SEM), FT-IR, differential scanning calorimetry (DSC), and pharmacokinetic study. The in vitro dissolution confirmed the rate of drug release greater compared to the pure drug. The optimum formula has a typical particle size of 225.56±4.65nm and zeta potential of -17.84±2.17 mV. The bioavailability parameters in the rabbits were enhanced by 2 folds when compared with the marketed tablets (Calcigard®). Solid lipid nanoparticles method was successfully employed to produce stable Nifedipine nanosuspension by using the suitable concentration of stabilizer (PVA, Tween 80, PVP and HPMC). From this study, it is concluded that formulation of Nifedipine nanosuspension may be a competent approach that boost the rate of dissolution and hence oral bioavailability of drug.

Nadciśnienie tętnicze po przeszczepieniu narządów unaczynionych

W ostatnich latach można zaobserwować dynamiczny rozwój transplantologii klinicznej. Dzięki udoskonaleniu technik chirurgicznych oraz wprowadzeniu bardziej skutecznych i bezpiecznych leków immunosupresyjnych rokowanie u chorych po przeszczepieniu narządów znacznie się poprawiło. Biorąc jednak pod uwagę rzadsze występowanie powikłań chirurgicznych oraz immunologicznych, a co za tym idzie — dłuższe przeżycie, obecnie to choroby układu krążenia są jedną z głównych przyczyn śmierci u tych chorych. Częstość występowania nadciśnienia tętniczego po przeszczepieniu narządów jest większa niż w populacji ogólnej. Ponadto w wielu badaniach wykazano, że u chorych po transplantacji narządów często nie występuje fizjologiczne obniżenie ciśnienia tętniczego w godzinach nocnych, co jest niekorzystnym czynnikiem rokowniczym. Niektóre leki immunosupresyjne stosowane po przeszczepieniu narządów unaczynionych mają właściwości hipertensynogenne. Niekorzystny mechanizm działania glukokortykosteroidów polega przede wszystkim na retencji sodu i wody. Hipertensynogenne właściwości inhibitorów kalcyneuryny wynikają z ich działania naczyniokurczącego. Efekt hipertensynogenny obu tych grup leków zależy od dawki. Drugą główną przyczyną nadciśnienia tętniczego u chorych po przeszczepieniu narządów unaczynionych, oprócz stosowania leków immunosupresyjnych, jest upośledzenie czynności nerek. Patogeneza nadciśnienia tętniczego u chorych po transplantacji nerki pozostaje złożona. Najczęściej wysokie wartości ciśnienia tętniczego wynikają z pogorszenia czynności przeszczepionej nerki. W diagnostyce różnicowej należy jednak uwzględnić również zaburzenia w obrębie nerek własnych i zaburzenia unaczynienia nerki przeszczepionej. W leczeniu nadciśnienia tętniczego po przeszczepieniu narządów unaczynionych w pierwszej kolejności należy wdrożyć postępowanie niefarmakologiczne — dietę, codzienną aktywność fizyczną, zmniejszenie masy ciała oraz zaprzestanie palenia papierosów. W farmakoterapii przeciwnadciśnieniowej można stosować leki ze wszystkich grup. Natomiast w farmakoterapii nadciśnienia tętniczego wywołanego inhibitorami kalcyneuryny należy preferować stosowanie dihydropirydynowych antagonistów wapnia (z wyjątkiem lerkanidipiny).

Rapidly dissolving Felodipine nanoparticle strips -Formulation using Design of Experiment and Characterisation

Felodipine (FDP), a dihydropyridine calcium-channel antagonist is used for the treatment of hypertension and angina pectoris. FDP is poorly soluble drug and upon oral administration, it undergoes first pass metabolism, resulting in bioavailability of 15%. The present work was aimed to formulate rapidly dissolving strips containing FDP nanoparticles for transbuccal administration. Such formulations are absorbed through buccal mucosa resulting in increase in oral bioavailability by circumventing first pass metabolism. Nanosuspension was formulated using solvent-antisolvent sonoprecipitation technique. An ordinary 23 factorial design was applied using Design Expert® 12 software. Formulated nanosuspensions were characterized for particle size, polydispersity index, zeta potential and saturation solubility. Surface morphology was studied using high resolution transmission electron microscopy, atomic force microscopy and field emission scanning electron microscopy. The optimised nanosuspension D1 formulated with PVP-K30 as stabiliser was selected for further incorporation into the film. Central composite design was applied to select film composition with desirable properties. X-ray diffraction studies were performed to assess the solid-state characteristic of the drug in the formulation. Rapidly dissolving strips were evaluated for weight variation, folding endurance, disintegration time, thickness and surface pH. Scanning electron microscopy image of the optimised film revealed almost granular-shaped nanoparticles dispersed in the polymeric network. Drug release kinetics data of optimised film F5 showed 82 ± 0.47% release within 4 min and release pattern was non-fickian diffusion controlled. Stability studies were conducted at 25 ± 2 °C/60 ± 5% RH for 90 days. Collectively, the developed film demonstrated to possess optimum physical and mechanical properties along with rapid drug release and good stability.

Abstract P177: Treatment Of Resistant Hypertension In Hypertrophic Cardiomyopathy And Left Ventricular Outflow Tract Obstruction

Background: Lowering blood pressure (BP) in patients with resistant hypertension (RH) is challenging. When RH co-exists with hypertrophic cardiomyopathy (HCM) and left ventricular outflow tract (LVOT) obstruction, nuanced management is required. Diuretics and medications with vasodilating effects are commonly used for the treatment of hypertension; however they can worsen LVOT obstruction, leading to harm in patients with HCM. There is limited data for the treatment of RH in this patient population. Methods: Seven patients were referred to a RH clinic with uncontrolled BP and HCM with LVOT obstruction. Antihypertensive medications and BP were assessed at initial (T 0 ) and follow up (T 1 ) visits. Change in LVOT gradients - both at rest and provoked - were reviewed from echocardiographic data before and after adjustment of medications. Results: Medication regimens were personalized to eliminate dihydropyridine calcium-channel antagonists and renin-angiotensin system antagonists. When required, they were dosed once nightly. Beta blocker and non-dihydropyridine calcium channel antagonist dosages were optimized. Thiazides were prescribed at lowest dose possible and spironolactone was used in the majority of patients (Table 1). Patients experienced an average reduction of 21 mmHg in office systolic BP (4 - 57 mmHg) and 15 mmHg reduction in diastolic BP (3- 39 mmHg). LVOT gradient at rest decreased by an average of 23.8 mmHg, while provoked gradient decreased by 23 mmHg. Conclusions: Improved BP control and lower LVOT gradients were observed among HCM patients with RH through personalized adjustment of their medication regimen.

52-Year-Old Woman With Fever, Diaphoresis, and Abdominal Pain

52-Year-Old Woman With Fever, Diaphoresis, and Abdominal Pain

Comparison of short-acting versus extended-release nifedipine: Effects on hemodynamics and sympathetic activity in patients with stable coronary artery disease

We investigated the impact of short-acting and extended release nifedipine on sympathetic activity using radiotracer methodology in patients with stable coronary artery disease in order to more accurately document the response of the sympathetic nervous system to different formulations of this dihydropyridine calcium channel antagonist. Participants were randomized to placebo, short-acting or extended release nifedipine for 7–10 days. On the final day, systemic blood pressure, cardiac filling pressures, cardiac output, plasma norepinephrine (NE) and total body NE spillover were measured at baseline (time 0) and repeated at intervals for 6 hours. There were no differences in baseline measures between groups. Following the morning dose of study medication there were no changes in hemodynamics or sympathetic activity in the placebo group. However, there was a significant fall in blood pressure and a significant increase in total body NE spillover in both nifedipine groups. Importantly, the increase in sympathetic activity in response to short-acting nifedipine began earlier (30 minutes) and was much greater than that observed in the extended release group, which occurred later (270 minutes). These findings confirm that sustained therapy with nifedipine is associated with activation of the sympathetic nervous system which is dependent on the pharmacokinetics of the formulation.

Nimodipine Reappraised: An Old Drug With a Future.

Nimodipine is a dihydropyridine calcium channel antagonist that blocks the flux of extracellular calcium through L-type, voltage-gated calcium channels. While nimodipine is FDA-approved for the prevention and treatment of neurological deficits in patients with aneurysmal subarachnoid hemorrhage (aSAH), it affects myriad cell types throughout the body, and thus, likely has more complex mechanisms of action than simple inhibition of cerebral vasoconstriction. Newer understanding of the pathophysiology of delayed ischemic injury after a variety of acute neurologic injuries including aSAH, traumatic brain injury (TBI) and ischemic stroke, coupled with advances in the drug delivery method for nimodipine, have reignited interest in refining its potential therapeutic use. In this context, this review seeks to establish a firm understanding of current data on nimodipine’s role in the mechanisms of delayed injury in aSAH, TBI, and ischemic stroke, and assess the extensive clinical data evaluating its use in these conditions. In addition, we will review pivotal trials using locally administered, sustained release nimodipine and discuss why such an approach has evaded demonstration of efficacy, while seemingly having the potential to significantly improve clinical care.

Repurposing Approved Drugs as Inhibitors of Kv7.1 and Nav1.8 to Treat Pitt Hopkins Syndrome.

Pitt Hopkins Syndrome (PTHS) is a rare genetic disorder caused by mutations of a specific gene, transcription factor 4 (TCF4), located on chromosome 18. PTHS results in individuals that have moderate to severe intellectual disability, with most exhibiting psychomotor delay. PTHS also exhibits features of autistic spectrum disorders, which are characterized by the impaired ability to communicate and socialize. PTHS is comorbid with a higher prevalence of epileptic seizures which can be present from birth or which commonly develop in childhood. Attenuated or absent TCF4 expression results in increased translation of peripheral ion channels Kv7.1 and Nav1.8 which triggers an increase in after-hyperpolarization and altered firing properties. We now describe a high throughput screen (HTS) of 1280 approved drugs and machine learning models developed from this data. The ion channels were expressed in either CHO (KV7.1) or HEK293 (Nav1.8) cells and the HTS used either 86Rb+ efflux (KV7.1) or a FLIPR assay (Nav1.8). The HTS delivered 55 inhibitors of Kv7.1 (4.2% hit rate) and 93 inhibitors of Nav1.8 (7.2% hit rate) at a screening concentration of 10μM. These datasets also enabled us to generate and validate Bayesian machine learning models for these ion channels. We also describe a structure activity relationship for several dihydropyridine compounds as inhibitors of Nav1.8. This work could lead to the potential repurposing of nicardipine or other dihydropyridine calcium channel antagonists as potential treatments for PTHS acting via Nav1.8, as there are currently no approved treatments for this rare disorder.

The impact of dihydropyridine derivatives on the cerebral blood flow response to somatosensory stimulation and spreading depolarization.

A new class of dihydropyridine derivatives, which act as co-inducers of heat shock protein but are devoid of calcium channel antagonist and vasodilator effects, has recently been developed with the purpose of selectively targeting neurodegeneration. Here, we evaluated the action of one of these novel compounds LA1011 on neurovascular coupling in the ischaemic rat cerebral cortex. As a reference, we applied nimodipine, a vasodilator dihydropyridine and well-known calcium channel antagonist. Rats were treated with LA1011 or nimodipine, either by chronic, systemic (LA1011), or acute, local administration (LA1011 and nimodipine). In the latter treatment group, global forebrain ischaemia was induced in half of the animals by bilateral common carotid artery occlusion under isoflurane anaesthesia. Functional hyperaemia in the somatosensory cortex was created by mechanical stimulation of the contralateral whisker pad under α-chloralose anaesthesia. Spreading depolarization (SD) events were elicited subsequently by 1 M KCl. Local field potential and cerebral blood flow (CBF) in the parietal somatosensory cortex were monitored by electrophysiology and laser Doppler flowmetry. LA1011 did not alter CBF, but intensified SD, presumably indicating the co-induction of heat shock proteins, and, perhaps an anti-inflammatory effect. Nimodipine attenuated evoked potentials and SD. In addition to the elevation of baseline CBF, nimodipine augmented hyperaemia in response to both somatosensory stimulation and SD, particularly under ischaemia. In contrast to the CBF improvement achieved with nimodipine, LA1011 seems not to have discernible cerebrovascular effects but may up-regulate the stress response.

Augmented bioavailability of felodipine through an α-linolenic acid-based microemulsion.

The oral bioavailability of felodipine, a dihydropyridine calcium channel antagonist, is about 15%. This may be due to poor water solubility, and a lower intestinal permeability than a BCS class I drug, and hepatic first-pass metabolism of the drug. Many drugs are unpopular due to solubility issues. The goal of this study was to develop and optimize a felodipine-containing microemulsion to improve the intestinal permeability and bioavailability of the drug. The felodipine microemulsions were developed with the selected components, i.e., α-linolenic acid as the oil phase, Tween 80 as a surfactant, and isopropyl alcohol as co-surfactant using Box-Behnken design and characterized for in vitro release and particle size. The optimized felodipine-loaded microemulsion was investigated for physicochemical interaction, surface morphology, intestinal permeability, rheology, cytotoxicity, cellular uptake, pharmacodynamic (electrocardiogram and heart rate variability), and pharmacokinetic studies to explore its suitability as a promising oral drug delivery system for the treatment of hypertension. The optimized felodipine-loaded microemulsion showed significantly higher (P < 0.05) apparent permeability coefficients (Papp) at 7.918 × 10-5cm/s after 1h, when compared with conventional formulations that are marketed tablet, drug oily solution, and drug emulsion, which showed a maximum Papp of 3.013, 4.428, and 5.335 × 10-5cm/s, respectively. The optimized felodipine-loaded microemulsion showed biocompatibility and no cytotoxicity. Cellular uptake studies confirmed payload delivery to a cellular site on the J774.A1 cell line. The rheology study of the optimized felodipine-loaded microemulsion revealed Newtonian-type flow behavior and discontinuous microemulsion formation. In pharmacodynamic studies, significant differences in parameters were observed between the optimized felodipine-loaded microemulsion and marketed formulation. The optimized felodipine-loaded microemulsion showed significantly higher (p < 0.01) C max (7.12 ± 1.04μg/ml) than marketed tablets (2.44 ± 1.03μg/ml). It was found that AUClast obtained from the optimized felodipine-loaded microemulsion (84.53 ± 10.73μgh/ml) was significantly higher (p < 0.01) than the marketed tablet (27.41 ± 5.54μgh/ml). The relative bioavailability (Fr) of the optimized felodipine-loaded microemulsion was about 308.3% higher than that of the marketed formulation. The results demonstrate that the prepared microemulsion is an advanced and efficient oral delivery system of felodipine for the management of hypertension.

Studies on the competitive binding of cleviprex and flavonoids to plasma protein by multi-spectroscopic methods: A prediction of food-drug interaction

Cleviprex is a short-acting dihydropyridine calcium channel antagonist used as an antihypertensive drug. In this work, the binding characterization of cleviprex to human serum albumin (HSA) and the competitive binding to HSA between cleviprex and two flavonoids, baicalin and rutin, were studied using multi-spectroscopic techniques and molecular docking method. The fluorescence quenching of HSA by cleviprex was initiated by the formation of HSA-cleviprex complex, which was confirmed by UV–vis spectra measurements. The results of thermodynamic analysis and molecular docking revealed that the hydrophobic interactions and hydrogen bonding were the major acting forces in stabilizing HSA-cleviprex complex. The results of substitution experiments and molecular docking demonstrated that cleviprex was mainly situated within the site I of HSA. Baicalin and rutin could reduce the values of binding constant and enhance the values of binding distance of cleviprex binding to HSA because they bind to the same binding site. The results of synchronous fluorescence and CD spectra suggested that the binding reaction of cleviprex to HSA could give rise to the changes of protein conformation and the combined actions of cleviprex and flavonoids could cause further changes of HSA conformation. Consequently, the intakes of flavonoid-rich foods and beverages should be lessened under the treatment of cleviprex to avoid food-drug interactions.

HSA induced HCPT nanocrystal for high-performance antitumor therapy

The aim of this study was to prepare solid dispersion of nimodipine (NMD) by solvent evaporation method to overcome the poor water solubility of NMD, and to formulate controlled-release (CR) tablets containing the NMD solid dispersion. NMD is a dihydropyridine calcium-channel antagonist that is practically insoluble in water. Owing to the short half-life of the drug in the plasma, NMD immediate-release tablets should be administered frequently for the treatment and prevention of ischemic disorders following aneurysmal subarachnoid hemorrhage. In this study, solid dispersion technique was applied to increase the low solubility of NMD. Carriers for solid dispersions were prepared with different kinds of hydrophilic polymers. Kinetic solubility studies were performed for the prepared solid dispersions, using sodium acetate buffer (pH 4.5). Solid dispersions were then characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and Fourier transform infrared spectrometry (FT-IR). CR tablets containing the NMD-PVP K30 solid dispersions were designed to reduce the dosing interval and increase patient compliance. Hydroxypropyl methylcelluloses (HPMC) were used as release-modifiers, and lactose anhydrous as a diluent.

Amlodipine, an L-type calcium channel blocker, protects against chlorpromazine-induced neurobehavioural deficits in mice.

This study investigated the modulatory and chemopreventive benefit of amlodipine (AML), a dihydropyridine calcium channel antagonist, against neurobehavioural abnormalities (NAs) associated with chlorpromazine (CPZ) toxicity in mice. Adult mice were divided into five groups of six animals/group. Group 1 (control) was administered saline (10 mL/kg i.p.). Group 2 received CPZ (2 mg/kg i.p.). Groups 3 and 4 received bromocriptine (BMC, 2.5 mg/kg s.c.) and AML (1 mg/kg s.c.), respectively, while group 5 received their combination. Groups 3-5 later received CPZ 30 min after initial treatments. Animals were subjected to neurobehavioural tests and euthanized 18 h later. CPZ-induced NAs were characterized by significant increase (P < 0.001) in cataleptic behaviour and lowered (P < 0.05) spontaneous activity reaction time in mice. There were also significant (P < 0.001) increases in malondialdehyde levels and decreased locomotion plus learning and memory parameters (P < 0.05-0.001). AML pretreatment alone did not alleviate CPZ-induced motor deficits in the mice. While pretreatment with BMC alone attenuated CPZ-associated catalepsy, its combination with AML further protected mice against NAs. Furthermore, BMC pretreatment did not affect CPZ-induced increase in malondialdehyde level, but AML or BMC+AML significantly (P < 0.05) decreased malondialdehyde in the CPZ-treated rats. Reduced glutathione levels and activities of superoxide dismutase and catalase remained elevated in all treatment groups. In conclusion, data from this study suggest possible chemopreventive benefit of AML alone or in combination with BMC against CPZ-associated neurobehavioural deficits. The ameliorative effect of AML may be related to its antioxidant and/or calcium channel blocking property.

Controlled-release oral dosage forms containing nimodipine solid dispersion and hydrophilic carriers

The aim of this study was to prepare solid dispersion of nimodipine (NMD) by solvent evaporation method to overcome the poor water solubility of NMD, and to formulate controlled-release (CR) tablets containing the NMD solid dispersion. NMD is a dihydropyridine calcium-channel antagonist that is practically insoluble in water. Owing to the short half-life of the drug in the plasma, NMD immediate-release tablets should be administered frequently for the treatment and prevention of ischemic disorders following aneurysmal subarachnoid hemorrhage. In this study, solid dispersion technique was applied to increase the low solubility of NMD. Carriers for solid dispersions were prepared with different kinds of hydrophilic polymers. Kinetic solubility studies were performed for the prepared solid dispersions, using sodium acetate buffer (pH 4.5). Solid dispersions were then characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and Fourier transform infrared spectrometry (FT-IR). CR tablets containing the NMD-PVP K30 solid dispersions were designed to reduce the dosing interval and increase patient compliance. Hydroxypropyl methylcelluloses (HPMC) were used as release-modifiers, and lactose anhydrous as a diluent.