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Background: Ulcerative colitis (UC) is a chronic inflammatory condition affecting the colon, with a global incidence that is rising. Despite the increasing prevalence, effective treatment options for UC remain limited. Methods: We utilized an NF-κB promoter dual fluorescence reporter system to screen for compounds that could inhibit p65 and IκBα phosphorylation. The anti-hypertension drug lacidipine was identified as a candidate. Its efficacy was further evaluated in a murine model of dextran sulfate sodium (DSS)-induced colitis. The analysis included the assessment of colon lesions, inflammation markers, and signal pathway activation, with a focus on NF-κB and Notch signaling. Results: Lacidipine effectively inhibited p65 and IκBα phosphorylation in the reporter system. In the DSS-induced colitis murine model, lacidipine treatment led to a reduction in colon lesions and inflammatory markers. Target analysis showed significant enrichment of the Notch signaling pathway. Additionally, lacidipine inhibited both NF-κB and Notch activation in DSS-stimulated colons. Conclusion: Lacidipine demonstrated a protective effect in UC, reducing inflammation and modulating key signaling pathways. These findings suggest that lacidipine could be a promising candidate for the treatment of UC. [ABSTRACT FROM AUTHOR]

Lacidipine, a calcium channel antagonist, is primarily used to treat hypertension. It is classified as a Biopharmaceutics Classification System Class II drug and exhibits an oral bioavailability of 10% due to its extensive hepatic first-pass metabolism. This research study focused on formulating lacidipine-loaded cubosomal nanovesicles developed into rapidly dissolving oral films as an alternative to overcome the downsides faced by conventional antihypertensive therapy. Lacidipine-loaded cubosomes were prepared utilizing a top-down technique using lipid and surfactant and were further developed into fast dissolving oral films. Box–Behnken design was used for the optimization of process variables to achieve minimum particle size and greater entrapment efficiency of the nanovesicles, and response data were statistically evaluated. The optimized cubosomal dispersions upon characterization reported particle size within nanorange (116.8–341 nm) and an entrapment efficiency of 88.15%–97.1%, with 91.72% of total drug content. Morphological studies revealed uniformly dispersed vesicles with cubic to spherical shape. Oral rapidly dissolving films, after evaluation, were reported to have transparent to opaque appearance with a highly porous nature, which was confirmed by scanning electron microscopic imaging and displayed uniformity in weight and thickness and reported optimum mechanical strength and considerable flexibility, with disintegration time of 37.67 ± 3.68 s and exhibited 91.44% ± 1.65% in vitro drug release after 6 min. Short-term stability studies conducted on films at 25°C ± 2°C and 60% ± 5% relative humidity for 3 months demonstrated no significant variation in morphological and mechanical properties. Therefore, lacidipine-loaded cubosomal rapid dissolving oral films may be a promising formulation approach for the management of hypertension. [ABSTRACT FROM AUTHOR]

The research work was aimed to formulate and evaluate gastroretentive mucoadhesive film of calcium channel blocker, Lacidipine for treatment of gastroparesis. Box–Behnken design was used for preparation of optimized formulation using solvent casting method. In this design, different concentrations of mucoadhesive polymers HPMC E15, Eudragit RL100, and Eudragit RS100 were considered as independent variables and its effect on responses like percent drug release, swelling index at 12 h, and folding endurance of the film were examined. Drug and polymer compatibility studies were performed using Fourier transform infrared spectroscopy and differential scanning calorimetry. Optimized formulation was evaluated for organoleptic properties, weight variation, thickness, swelling index, folding endurance, drug content, tensile strength, percent elongation, drug release, and percent moisture loss. The results revealed that the film possessed considerable flexibility and smoothness, and in vitro drug release was found to be 95.22% ± 0.93% at the end of 12 h. Scanning electron microscopy imaging of film displayed smooth, uniform, and porous surface texture. The dissolution followed Higuchi's model and Hixson Crowell model displayed non-Fickian drug release mechanism. Furthermore, the film was incorporated in capsule and the presence of capsule showed no effect on the drug release profile. In addition, no change was observed in the appearance, drug content, swelling index, folding endurance, and drug release upon storage at 25°C ± 2°C and 60% ± 5% relative humidity for 3 months. Collectively, the study revealed that gastroretentive mucoadhesive film of Lacidipine could serve as an effective and alternate site-specific targeted delivery in the management of gastroparesis. [ABSTRACT FROM AUTHOR]

Angiogenesis is a critical cellular process toward establishing a functional circulatory system capable of delivering oxygen and nutrients to the tissue in demand. In vitro angiogenesis assays represent an important tool for elucidating the biology of blood vessel formation and for drug discovery applications. Herein, we developed a novel, high content 2D angiogenesis assay that captures endothelial morphogenesis's cellular processes, including lumen formation. In this assay, endothelial cells form luminized vascular-like structures in 48 h. The assay was validated for its specificity and performance. Using the optimized assay, we conducted a phenotypic screen of a library containing 150 FDA-approved cardiovascular drugs to identify modulators of lumen formation. The screening resulted in several L-type calcium channel blockers being able to expand the lumen space compared to controls. Among these blockers, Lacidipine was selected for follow-up studies. We found that the endothelial cells treated with Lacidipine showed enhanced activity of caspase-3 in the luminal space. Pharmacological inhibition of caspase activity abolished the Lacidipine-enhancing effect on lumen formation, suggesting the involvement of apoptosis. Using a Ca2+ biosensor, we found that Lacipidine reduces the intracellular Ca2+ oscillations amplitude in the endothelial cells at the early stage, whereas Lacidipine blocks these Ca2+ oscillations completely at the late stage. The inhibition of MLCK exhibits a phenotype of lumen expansion similar to that of Lacidipine. In conclusion, this study describes a novel high-throughput phenotypic assay to study angiogenesis. Our findings suggest that calcium signalling plays an essential role during lumen morphogenesis. L-type Ca2+ channel blockers could be used for more efficient angiogenesis-mediated therapies. [ABSTRACT FROM AUTHOR]

The present research work was aimed to develop and optimize the nanostructured lipid carrier (NLCs) of the antihypertensive drug lacidipine (LAC) for the improvement of oral bioavailability and antihypertensive activity. LAC-NLCs were successfully developed by the preemulsion probe sonication technique. The formulations were optimized by Box-Behnken design and assessed for particle size (PS), polydispersity index (PDI), entrapment efficiency (EE), drug loading (DL), drug release, ex vivo permeation, and in vivo study. The optimized LAC-NLCs showed nanometric PS (191.0 ± 5.89 nm), high EE (90% ± 3.69%) and DL (9.26% ± 1.89%), negative zeta potential (−28.9 ± 0.99 mV), and narrow size distribution (PDI of 0.074 ± 0.013) with spherical morphology. The drug release study revealed that a significantly (p < 0.05) higher LAC release (88.49% ± 3.01%) was achieved from the optimized LAC-NLCs compared to LAC-dispersion (34.27% ± 3.01%). Moreover, the optimized LAC-NLCs showed significantly (p < 0.05) higher intestinal permeation (692.04 ± 19.76 μg) than LAC-dispersion (23.83 ± 5.08 μg). After oral administration of a single dose of LAC, the optimized LAC-NLCs exhibited 3.45-fold higher relative oral bioavailability as well as a more prominent antihypertensive effect than LAC-dispersion. This might be due to the high penetration and absorption of the drug. Hence, NLCs might provide an efficient nano delivery for the management of hypertension and promising drug delivery systems for the bioavailability enhancement of LAC. [ABSTRACT FROM AUTHOR]

Nicotine-withdrawal after daily exposure manifests somatic and affective symptom including a range of cognitive deficits. Earlier studies suggested participation of L-type calcium channels (LTCCs) in development of nicotine dependence and expression of withdrawal signs. An upsurge in Ca2+-induced oxidative stress in brain underlies the biochemical events and behavioral signs of nicotine-withdrawal. The present study is aimed to explore the effects of lacidipine (LTCC antagonist) against nicotine-withdrawal. Swiss albino mice were administered (−)-nicotine hydrogen tartrate (3.35 mg/kg, t.i.d.) from days 1 to 7 and alongside lacidipine (0.3, 1, and 3 mg/kg, i.p.) given from days 1 to 14. Somatic withdrawal signs were noted 48 h after last dose of nicotine. Bay-K8644 (LTCC agonist) was administered in mice subjected to nicotine-withdrawal and lacidipine (3 mg/kg) treatments. Behavioral tests of memory, anxiety, and depression were conducted on days 13 and 14 to assess the effects of lacidipine on affective symptoms of nicotine-withdrawal. Biomarkers of oxido-nitrosative were quantified in the whole brain. Nicotine-withdrawal significantly enhanced somatic signs and symptoms of anxiety, depression, and memory impairment in mice. Lacidipine (1 and 3 mg/kg) attenuated nicotine-withdrawal induced somatic symptoms and also ameliorated behavioral abnormalities. Nicotine-withdrawal triggered an upsurge in brain lipid peroxidation, total nitrite content, and decline in antioxidants, and these effects were attenuated by lacidipine. Bay-K8644 significantly abolished improvement in somatic and affective symptoms, and antioxidant effects by lacidipine in mice subjected to nicotine-withdrawal. Lacidipine mitigated nicotine-withdrawal triggered somatic and affective symptoms owing to decrease in brain oxido-nitrosative stress. [ABSTRACT FROM AUTHOR]

Cholinergic deficits and oxido-nitrosative stress are consistently associated with Alzheimer's disease (AD). Previous findings indicate that acetylcholine subdues Ca2+ current in the brain. Cholinergic antagonists (e.g., scopolamine) can instigate Ca2+-induced redox imbalance, inflammation, and cell-death pathways leading to AD-type memory impairment. Earlier, several Ca2+-channel blockers (CCB, e.g., dihydropyridine type) or cholinergic enhancers showed promising results in animal models of AD. In the present research, pretreatment effects of lacidipine (L-type CCB) on learning and memory functions were investigated using the scopolamine mouse model of AD. Swiss albino mice (20–25 g) were administered lacidipine (1 and 3 mg/kg) for 14 days. Scopolamine, an anti-muscarinic drug, was given (1 mg/kg) from days 8 to 14. The mice were subjected to elevated plus maze (EPM) and passive-avoidance (PA) paradigms. Bay-K8644 (a Ca2+-channel agonist) was administered before behavioral studies on days 13 and 14. Biochemical parameters of oxidative stress and acetylcholinesterase (AChE) activity were quantified using the whole brain. Behavioral studies showed an increase in transfer latency (TL) in the EPM test and a decrease in step-through latency (STL) in the PA test in scopolamine-administered mice. Scopolamine enhanced the AChE activity and oxidative stress in the brain of mice which resulted in memory impairment. Lacidipine prevented the amnesia against scopolamine and reduced the oxidative stress and AChE activity in the brain of mice. Bay-K8644 attenuated the lacidipine-induced improvement in memory and redox balance in scopolamine-administered mice. Lacidipine can prevent the oxidative stress and improve the cholinergic function in the brain. These properties of lacidipine can mitigate the pathogenesis of AD-type dementia. [ABSTRACT FROM AUTHOR]

Depression is a serious medical illness displaying high lifetime prevalence, early-age onset that adversely affects socio-economic status. The bidirectional association between oxidative stress and calcium-signaling adversely affects the monoaminergic neuron functions that instigate the pathogenesis of depression. The present study investigates the effect of lacidipine (LCD), L-type Ca2+-channel blocker, on reserpine-induced depression in mice. Separate groups of mice (Swiss albino, 18–25 g) were administered lacidipine (0.3, 1 and 3 mg/kg, i.p.) daily for 14 days and reserpine (5 mg/kg, i.p.) was injected on day 14. Rectal temperature, catalepsy, and tail-suspension test (TST) were performed 18 h and ptosis scores at 60, 120, 240, 360 min post-reserpine treatment. Whole-brain TBARS, GSH, nitrite, and superoxide dismutase (SOD) and catalase activities were estimated. Reserpine elevated the catalepsy, ptosis, hypothermia, and immobility period in TST owing to the marked increase in oxidative-nitrosative stress in the brain of mice. LCD attenuated the reserpine triggered the rise in catalepsy, ptosis scores, hypothermia, and immobility period in mice. LCD pretreatment attenuated the increase in TBARS and nitrite levels, and the decline of GSH, SOD, and catalase activities in the brain of reserpine injected mice. Bay-K8644 (0.5 mg/kg, i.p.), Ca2+-channel agonist, attenuated these effects of LCD (3 mg/kg) in reserpine-treated mice. It can be inferred that lacidipine (Ca2+ channel antagonist) attenuates depression-like symptoms in reserpine-treated mice. Furthermore, the abrogation of antidepressant-like effects of LCD by Bay-K8644 revealed that modulation of Ca2+-channels might present a potential strategy in the management of depression. [ABSTRACT FROM AUTHOR]

Co-amorphous solid dispersion (C-ASD) systems have attracted great attention to improve the solubility of poorly soluble drugs, but the selection of an appropriate stabilizer to stabilize amorphous forms is still a huge challenge. Herein, C-ASD system of two clinical combined used drugs (lacidipine (LCDP) and spironolactone (SPL)) as stabilizers to each other, was prepared by solvent evaporation method. The effects of variation in molar ratio of LCDP and SPL (3:1, 1:1, 1:3, 1:6, and 1:9) on the drug release characteristics were explored. Polarized light microscopy (PLM), powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) were employed to evaluate the solid states. Prepared C-ASDs were further studied for their stability under the high humidity (RH 92.5%). Further analysis of C-ASDs via Fourier-transform infrared spectroscopy (FTIR) and Raman spectroscopy confirmed that hydrogen bond interactions between the two drugs played a significant role in maintaining the stability of the C-ASDs systems. Moreover, molecular dynamic (MD) simulations provided a clear insight into the stability mechanism at the molecular level. This study demonstrated the novel drug-drug C-ASDs systems is a promising formulation strategy for improved dissolution rate and enhanced physical stability of poorly soluble drugs. [ABSTRACT FROM AUTHOR]

Lack of quality analytical methods with assured robustness and reliability has always been a serious concern for drug regulatory agencies. In the present study, a contemporary approach of analytical life‐cycle management resulted in the robust and reliable chromatographic analysis of lacidipine at a retention time of 5.1 min on a C‐18 column. Method variables such as %acetonitrile, flow rate, and pH were optimized using the design of experiment approach and their effect on critical quality attributes was studied. The attributes of the present study were significantly influenced by %acetonitrile and flow of the mobile phase. The newly optimized method was validated for various parameters with values in accordance with federal guidance. The lifecycle approach proved to be beneficial for routine application with a potential of future bio‐analytical utility. [ABSTRACT FROM AUTHOR]

This study aims at preparing and optimizing lacidipine (LCDP) polymeric micelles using thin film hydration technique in order to overcome LCDP solubility-limited oral bioavailability. A two-factor three-level central composite face-centered design (CCFD) was employed to optimize the formulation variables to obtain LCDP polymeric micelles of high entrapment efficiency and small and uniform particle size (PS). Formulation variables were: Pluronic to drug ratio (A) and Pluronic P123 percentage (B). LCDP polymeric micelles were assessed for entrapment efficiency (EE%), PS and polydispersity index (PDI). The formula with the highest desirability (0.959) was chosen as the optimized formula. The values of the formulation variables (A and B) in the optimized polymeric micelles formula were 45% and 80%, respectively. Optimum LCDP polymeric micelles had entrapment efficiency of 99.23%, PS of 21.08 nm and PDI of 0.11. Optimum LCDP polymeric micelles formula was physically characterized using transmission electron microscopy. LCDP polymeric micelles showed saturation solubility approximately 450 times that of raw LCDP in addition to significantly enhanced dissolution rate. Bioavailability study of optimum LCDP polymeric micelles formula in rabbits revealed a 6.85-fold increase in LCDP bioavailability compared to LCDP oral suspension. [ABSTRACT FROM AUTHOR]

The present study aimed to increase the in vitro dissolution rate of lacidipine, a poorly water-soluble drug, by formulating amorphous solid dispersions (ASDs) using hot-melt extrusion (HME). Differential scanning calorimetry, powder X-ray diffraction, polarized light microscopy, and Fourier transform infrared were used to characterize the optimal formulations and evaluate the physical stability for the stress test. Film-casting method and hot-stage microscopy were applied to study the miscibility of lacidipine and the drug carriers. In vitro dissolution tests were conducted as the final evaluation index. The optimal formulations were successfully obtained with Soluplus and PVP VA64 at a drug/carrier ratio of 1:10 (w/w), Fourier transform infrared studies revealed the hydrogen bonding between drug and polymers, and in vitro dissolution rates of the optimal formulations were extremely enhanced compared to bulk lacidipine and physical mixtures, similar with that of the commercial tablet. The ASD formulated with Soluplus showed better physical stability than that with PVP VA64. A strong hydrogen bonding and good drug-polymer miscibility were essential to hinder the recrystallization of lacidipine ASDs. In conclusion, the lacidipine ASD formulated with Soluplus showed a significant increase in in vitro dissolution rate and favorable physical stability in the stress test. [ABSTRACT FROM AUTHOR]

This study aims at preparing and optimizing lacidipine (LCDP) polymeric micelles using thin film hydration technique in order to overcome LCDP solubility-limited oral bioavailability. A two-factor three-level central composite face-centered design (CCFD) was employed to optimize the formulation variables to obtain LCDP polymeric micelles of high entrapment efficiency and small and uniform particle size (PS). Formulation variables were: Pluronic to drug ratio (A) and Pluronic P123 percentage (B). LCDP polymeric micelles were assessed for entrapment efficiency (EE%), PS and polydispersity index (PDI). The formula with the highest desirability (0.959) was chosen as the optimized formula. The values of the formulation variables (A and B) in the optimized polymeric micelles formula were 45% and 80%, respectively. Optimum LCDP polymeric micelles had entrapment efficiency of 99.23%, PS of 21.08 nm and PDI of 0.11. Optimum LCDP polymeric micelles formula was physically characterized using transmission electron microscopy. LCDP polymeric micelles showed saturation solubility approximately 450 times that of raw LCDP in addition to significantly enhanced dissolution rate. Bioavailability study of optimum LCDP polymeric micelles formula in rabbits revealed a 6.85-fold increase in LCDP bioavailability compared to LCDP oral suspension. [ABSTRACT FROM AUTHOR]

Lacidipine (LCDP) is a highly lipophilic calcium channel blocker of poor aqueous solubility leading to poor oral absorption. This study aims to prepare and optimize LCDP nanosuspensions using antisolvent sonoprecipitation technique to enhance the solubility and dissolution of LCDP. A three-factor, three-level Box-Behnken design was employed to optimize the formulation variables to obtain LCDP nanosuspension of small and uniform particle size. Formulation variables were as follows: stabilizer to drug ratio ( A), sodium deoxycholate percentage ( B), and sonication time ( C). LCDP nanosuspensions were assessed for particle size, zeta potential, and polydispersity index. The formula with the highest desirability (0.969) was chosen as the optimized formula. The values of the formulation variables ( A, B, and C) in the optimized nanosuspension were 1.5, 100%, and 8 min, respectively. Optimal LCDP nanosuspension had particle size (PS) of 273.21 nm, zeta potential (ZP) of −32.68 mV and polydispersity index (PDI) of 0.098. LCDP nanosuspension was characterized using x-ray powder diffraction, differential scanning calorimetry, and transmission electron microscopy. LCDP nanosuspension showed saturation solubility 70 times that of raw LCDP in addition to significantly enhanced dissolution rate due to particle size reduction and decreased crystallinity. These results suggest that the optimized LCDP nanosuspension could be promising to improve oral absorption of LCDP. [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate virtual population pharmacokinetic using physiologically based pharmacokinetic (PBPK) model for evaluating bioequivalence of oral lacidipine formulations in dogs. The dissolution behaviors of three lacidipine formulations including one commercial product and two self-made amorphous solid dispersions (ASDs) capsules were determined in 0.07% Tween 80 media.A randomized 3-period crossover design in 6 healthy beagle dogs after oral administration of the three formulations at a single dose of 4 mg was conducted. The PBPK modeling was utilized for the virtual bioequivalence study. In vitro dissolution experiment showed that the dissolution behaviors of lacidipine amorphous solid dispersions (ASDs) capsules, which was respectively prepared by HPMC-E5 or Soluplus, as polymer displayed similar curves compared with the reference formulation in 0.07% Tween 80 media. In vivo pharmacokinetics experiments showed that three formulations had comparable maximum plasma drug concentration (Cmax), and the time (Tmax) to reach Cmax of lacidipine tablet, which was prepared by Soluplus, as polymer was slower than other two formulations in consistency with the in vitro dissolution rate. The 90% confidence interval (CI) for the Cmax,AUC0-24 h and AUC0-∞ of the ratio of the test drug to the reference drug exceeded the acceptable bioequivalence (BE) limits (0.80-1.25). However, the 90% CI of the AUC0-24 h, AUC0-∞ and Cmax of the ratio of test to reference drug were within the BE limit, calculated using PBPK modeling when the virtual subjects reached 24 dogs. The results all demonstrated that virtual bioequivalence study can overcome the inequivalence caused by inter-subject variability of the 6 beagle dogs involved in in vivo experiments. [ABSTRACT FROM AUTHOR]

Solubilities of two calcium channel blockers, nifedipine and lacidipine, were measured in supercritical carbon dioxide at T = (313, 323, and 333) K over the pressure range (12.0-36.0) MPa using a dynamic-analytical apparatus. The solubility values obtained are in the range of (0.18-7.05) × 10 mol·mol. The solubilities of the two solids show similar trends with a crossover region of the respective isotherms in the range 18.0-21.0 MPa. The experimental solubility data were correlated with several different models. The semi-empirical density-based models provided satisfactory correlation results with AARD values lower than 10%. According to the results of the Méndez-Santiago and Teja models, the measured solid solubility data are quite consistent at all experimental conditions, which indicates the reliability of the data. The compressed gas model of the Peng-Robinson equation of state, combined with the two parameter van der Waals mixing rule (PR-EoS-VDW2) model, gives better correlation results than the PR-EoS-VDW1 model. The expanded liquid model based on Scatchard-Hildebrand regular solution theory can be used for solubility prediction, but the correlation results for nifedipine and lacidipine by the model are inferior to the compressed gas models in this work. [ABSTRACT FROM AUTHOR]

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Context: Proniosomes offer a versatile vesicle drug delivery concept with potential for delivery of drugs via transdermal route. Objectives: To develop proniosomal gel using cremophor RH 40 as non-ionic surfactant containing the antihypertensive drug lacidipine for transdermal delivery so as to avoid its extensive first pass metabolism and to improve its permeation through the skin. Materials and methods: Proniosomes containing 1% lacidipine were prepared by the coacervation phase separation method, characterized, and optimized using a 23full factorial design to define the optimum conditions to produce proniosomes with high entrapment efficiency, minimal vesicle size, and high-percentage release efficiency. The amount of cholesterol (X1), the amount of soya lecithin (X2), and the amount of cremophor RH 40 (X3) were selected as three independent variables. Results and discussion: The system F4 was found to fulfill the maximum requisite of an optimum system because it had minimum vesicle size, maximum EE, maximum release efficiency, and maximum desirability. The optimized system (F4) was then converted to proniosomal gel using carbopol 940 (1% w/w).In vitropermeation through excised rabbit skin study revealed higher flux (6.48 ± 0.45) for lacidipine from the optimized proniosomal gel when compared with the corresponding emulgel (3.04 ± 0.13) mg/cm2/h. The optimized formulation was evaluated for its bioavailability compared with commercial product. Statistical analysis revealed significant increase in AUC (0 − α) 464.17 ± 113.15 ng h/ml compared with 209.02 ± 47.35 ng h/ml for commercial tablet. Skin irritancy and histopathological investigation of rat skin revealed its safety. Conclusions: Cremophor RH 40 proniosomal gel could be considered as very promising nanocarriers for transdermal delivery of lacidipine. [ABSTRACT FROM PUBLISHER]

Low bioavailability of Lacidipine (LD), an calcium channel blocker pose many challenges in the treatment of hypertension. The objective of this study was to formulate and characterize LD self-nanoemulsifying drug delivery systems (SNEDDS) to improve oral bioavailability of the drug. Formulations were evaluated for globule size, surface morphology, emulsification time, cloud point, drug content, in vitro dissolution, ex vivo permeation, stability and oral bioavailability studies. Captex 810D, TPGS, Tween-60, Transcutol P and PEG 400 was selected based on the solubility study results. The optimized SNEDDS readily gets nanoemulsified at 37 °C with droplet size of 41 nm when mixed with 200 times of its water. Transmission electron microscope photographs confirmed the spherical shape of the globules. In vitro dissolution of SNEDDS showed more than 80 % of drug release within 15 min. The ex vivo permeation of LD from SNEDDS is 4.8- and 9-fold higher compared to pure drug in the absence and presence of verapamil respectively. The stability study of the SNEDDS confirmed no environmental effect on the physical nature and drug content. Oral bioavailability of SNEDDS is 2.5 times higher than marketed tablet. The results suggest that, the SNEDDS formulation can be used as a possible alternative for the traditional oral formulations of LD to improve its oral bioavailability. [ABSTRACT FROM AUTHOR]

The objective of the study was to explore the possible formation of the inclusion complex of lacidipine (LCDP), a class II drug under biopharmaceutics classification system (BCS) with beta-cyclodextrin (β-CD) and modified β-CDs: hydroxy propyl- beta-cyclodextrin (HP-β-CD) and sulfobutyl ether-beta-cyclodextrin (SBE-β-CD) in order to enhance the solubility and the dissolution rate of the drug with an intention to improve its bioavailability. The stability constants found using phase solubility studies showed that SBE-β-CD formed the most stable inclusion complex with the drug (K = 348 ± 4 M) compared to the other cyclodextrins (CDs). The thermal analysis confirmed this finding. IR spectral analysis indicated the involvement of the hydroxyl function of CDs with the COOH of the drug. H NMR and 13C NMR spectral analysis indicated that the aromatic ring of drug included deeply in the CD cavity leaving the side chain protruding outside the CD cage and hydrogen bonds are formed which stabilizes the complex formation. The dissolution of the drug was improved on complexation with SBE-β-CD more effectively compared to the other CDs. The in vivo pharmacokinetic study of the complexes in Wistar rats showed an increase in AUC value by 1.5-2 times in case of (HP-β-CD) and SBE-β-CD compared to the plain drug and maximum with SBE-β-CD complex (C = 242 ± 150 ng/ml, AUC = 1506.95 ± 0.505 ng/ml h). [ABSTRACT FROM AUTHOR]

This study was performed to evaluate the possible protective effect of two calcium channel blocker's 'lacidipine (LAC) and amlodipine (AML)' on bone metabolism in an experimental ovariectomized and inflammation-induced osteoporosis rat model (OVXinf). For the purpose of this study, the rats were divided into eight groups, each containing eight rats: sham-operated control (group 1, SH), sham + inflammation (group 2, SHinf), ovariectomy (group 3, OVX), ovariectomy + inflammation (group 4, OVXinf), ovariectomy + LAC 4 mg/kg (group 5, OVX + LAC), ovariectomy + inflammation + LAC 4 mg/kg (group 6, OVXinf + LAC), ovariectomy + AML 5 mg/kg (group 7, OVX + AML), ovariectomy + inflammation + AML 5 mg/kg (group 8, OVXinf + AML). The levels of osteocalcin and osteopontin decreased in OVXinf + LAC and OVXinf + AML groups. The serum levels of TNF-α, IL-1β, and IL-6 were increased significantly in the OVXinf rats compared with the SH group. Gene expression levels of the osteogenic factor runt-related transcription factor 2 (Runx2) and type I collagen 1A1 (Col1A1) significantly decreased in the OVXinf group, when compared with the control group. AML or LAC administrations increased the levels of Runx2 and Col1A1. These results suggest that amlodipine and lacidipine may be a novel therapeutic target for radical osteoporosis treatment in hypertensive patients. [ABSTRACT FROM AUTHOR]

A highly sensitive, simple and rapid spectrofluorimetric method was developed for the determination of lacidipine (LCP) in tablets. The proposed method is based on the investigation of the fluorescence spectral behavior of LCP in both sodium dodecyl sulphate (SDS) and the tween-80 micellar system. In aqueous solutions of acetate buffer (pH 4.5), the fluorescence intensities of LCP were greatly enhanced (ca. 2.4 and 4.3 folds) in the presence of either SDS or tween-80, respectively. The fluorescence intensity was measured at 444 nm after excitation at 277 nm using either SDS or tween-80 as a surfactant. The fluorescence-concentration plots were rectilinear over the ranges of 50.0-500.0 ng/ml and 5.0-200.0 ng/ml with lower detection limits of 5.11 and 2.06 ng/ml and lower quantification limits of 17 and 6.87 ng/ml using SDS and tween-80, respectively. The method was successfully applied to the analysis of LCP in commercial tablets and the results were in good agreement with those obtained with the comparison method. Furthermore, content uniformity testing of pharmaceutical tablets was also conducted. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The present study was aimed at investigating the safety of Lacidipine (LCDP) loaded nanostructured lipid carriers (NLCs) in Wistar rats. NLCs were formulated using ultrasound dispersion technique. Animals were orally treated once daily with NLCs containing 0.140 mg, 0.350 mg, and 0.875 mg of LCDP as low, medium, and high dose per kg body weight, respectively, during 28 days along with blank formulation and pure LCDP. Control rats were fed with water. Animals were observed throughout experiment period and their body weight was recorded once weekly. Overnight fasted rats were sacrificed on the 29th day. Study revealed no signs or symptoms of toxicity or morbidity. No significant changes in the body weight were observed between treated and control group. Significant increase in left testis weight and liver weight was observed in male and female rats, respectively. Haematological estimation revealed significant decrease in haemoglobin count in male rats while female rats showed significant increase in granulocyte count. All the serum clinical parameters were within the normal range and no gross histopathological changes were observed. No delayed effect was noted in satellite group. The results indicate that developed LCDP loaded NLCs are safe when administered orally in rats. [ABSTRACT FROM AUTHOR]

The article presents a comparison of the efficacy of dietary antioxidants and calcium channel blockers (CCB) in patients with cardiovascular diseases (CVD). Topics discussed include the role of reactive oxygen species (ROS) in the development of diseases, the antioxidant effect of enzymes and scavenger agents, and the therapeutic effect of superoxide dismutase (SOD). The protective role of CCB in as antioxidants in stroke and CVD.

Background: Acute kidney injury (AKI) is common in hospitalised patients and has a poor prognosis. Therefore, new therapeutic strategies are anticipated. Lacidipine, a novel third-generation dihydropyridine calcium channel blocker, has been demonstrated effective for hypertension. However, its potential effect on renal injury remains unknown. In the present study, an in vitro model of renal ischemia reperfusion (I/R) injury was used to investigate the protective effect and underlying mechanisms of lacidipine on human kidney cell (HKC) apoptosis. Methods: HKCs were subjected to adenosine triphosphate (ATP) depletion and recovery (0.01 µM AA, depletion for 2 h and recovery for 30 min), with or without lacidipine (1 µM and 10 µM, 24 h), then cell viability and apoptosis were determined using the cell counting kit-8 (CCK-8) assay and Annexin V flow cytometry. The expression of Bcl-2, Bax, and cytochrome c (cyt c) was examined by western blot. Results: Antimycin A (AA) was found to induce apoptosis of HKCs. The proportion of early apoptosis and activity of caspase-3 peaked at 30 min after ATP depletion and recovery and were attenuated by lacidipine. The expression of cyt c and Bax was decreased, while that of Bcl-2 was increased significantly in lacidipine treated group. Conclusion: We conclude that lacidipine protects HKCs against apoptosis induced by ATP depletion and recovery by regulating the caspase-3 pathway. © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

ABSTRACT A robust, specific and fully validated LC-MS/MS method as per general practices of industry has been developed for estimation of lacidipine (LAC) with 100 μL of human plasma using lacidipine-13C8 as an internal standard (IS). The API-4000 LC-MS/MS was operated under the multiple reaction-monitoring mode. A simple liquid-liquid extraction process was used to extract LAC and IS from human plasma. The total run time was 3.0 min and the elution of LAC and IS occurred at 1.96 and 1.97 min; this was achieved with a mobile phase consisting of 5 m m ammonium acetate buffer-acetontrile (15:85 v/v) at a flow rate of 0.60 mL/min on a Zorbax SB C18 (50 × 4.6 mm, 5 µm) column. A linear response function was established for the range of concentrations 50-15,000 pg/mL ( r > 0.998) for LAC. The current developed method has negligible matrix effect and is free from unwanted adducts and clusters which are formed owing to system such as solvent or mobile phase. The developed assay method was applied to an oral pharmacokinetic study in humans and successfully characterized the pharmacokinetic data up to 72 h. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Introduction: Lacidipine (LCDP) is chemically a "1, 4-dihydropyridine derivative" Ca+² channel blocker used as an antihypertensive. Type and extent of packaging have a strong influence on the photo-stability of the 1,4-dihydropyridine derivatives. In standard, light protection of drug substance/drug product can be obtained either by use of an opaque additive in the formulation that competitively absorbs or reflects light reaching the sample and/or by blocking the access of light to the drug through external protection by packaging. Materials and Methods: External protection by covering tablets with an opaque film coating involving a light-reflecting inorganic pigment such as titanium dioxide and/or by using an opaque impermeable packaging material was an appropriate suitable option for establishing photo-stability. Thus, the main objective of the present study was to optimize the % level of film coating in LCDP core tablets, and selection of a final packaging material and its respective extent, that is, primary, secondary and/or tertiary packaging, for LCDP tablets. Results and Conclusion: The main objective (% level of film coating) was optimized by directly exposing core tablets, 1% w/w, 2% w/w and 3% w/w film-coated tablets, to a light source as per Option-2 of ICH Q1B and its comparative analysis at the end of light exposure testing. The other objective (extent of drug product packaging) was established successfully by assessing whether or not an acceptable change has occurred at the end of the light exposure testing of the LCDP film-coated tablets in a direct exposure study or a primary immediate pack and/or secondary marketing pack. Key words: Alu-Alu blister, film coating, folding box board carton, immediate pack, lacidipine, marketing pack, oriented poly amide, photodegradation, photo-stability, polyvinyl chloride [ABSTRACT FROM AUTHOR]

Gaucher’s disease (GD) is characterized by loss of lysosomal glucocerebrosidase (GC) activity. Mutations in the gene encoding GC destabilize the protein’s native folding leading to ER-associated degradation (ERAD) of the misfolded enzyme. Enhancing the cellular folding capacity by remodeling the proteostasis network promotes native folding and lysosomal activity of mutated GC variants. However, proteostasis modulators reported so far, including ERAD inhibitors, trigger cellular stress and lead to induction of apoptosis. We show herein that lacidipine, an L-type Ca2+ channel blocker that also inhibits ryanodine receptors on the ER membrane, enhances folding, trafficking and lysosomal activity of the most severely destabilized GC variant achieved via ERAD inhibition in fibroblasts derived from patients with GD. Interestingly, reprogramming the proteostasis network by combining modulation of Ca2+ homeostasis and ERAD inhibition remodels the unfolded protein response and dramatically lowers apoptosis induction typically associated with ERAD inhibition. [ABSTRACT FROM AUTHOR]

Mesoporous material SBA-15 of hexagonal structure was synthesised and its usefulness as a carrier for a poorly soluble drug - lacidipine (LA) - was tested. The source of silica was tetraethyl orthosilicate (TEOS) and the structure ordering agent was non-ionic surfactant Pluronic P123. SBA-15 with encapsulated LA was characterised by X-ray diffraction (XRD), infrared spectroscopy (FTIR), thermogravimetry (TG), differential scanning calorimetry (DSC) and transmission electron microscopy (TEM). Adsorption of the therapeutically active substance was performed in anhydrous environment (chloroform). The content of the therapeutic substance in SBA-15 estimated from TG measurements reached 9%. The properties of the compound obtained were compared with those of a physical mixture of the components. [ABSTRACT FROM AUTHOR]

Introduction: Lacidipine (LCDP) is a very low soluble and highly biovariable calcium channel blocker used in the treatment of hypertension. To increase its apparent solubility and to reduce its biovariability, solid dispersion fluid bed processing technology was explored, as it produces highly dispersible granules with a characteristic porous structure that enhances dispersibility, wettability, blend uniformity (by dissolving and spraying a solution of actives), low ability and compressibility of granules for tableting and reducing variability by uniform drug-binder solution distribution on carrier molecules. Materials and Methods: Main object of this quality risk management (QRM) study is to provide a sophisticated "robust and rugged" Fluidized Bed Process (FBP) for the preparation of LCDP tablets with desired quality (stability) and performance (dissolution) by quality by design (QbD) concept. Results and Conclusion: This study is principally focusing on thorough mechanistic understanding of the FBP by which it is developed and scaled up with a knowledge of the critical risks involved in manufacturing process analyzed by risk assessment tools like: Qualitative Initial Risk-based Matrix Analysis (IRMA) and Quantitative Failure Mode Effective Analysis (FMEA) to identify and rank parameters with potential to have an impact on In Process/Finished Product Critical Quality Attributes (IP/FP CQAs). These Critical Process Parameters (CPPs) were further reined by DoE and MVDA to develop design space with Real Time Release Testing (RTRT) that leads to implementation of a control strategy to achieve consistent finished product quality at lab scale itself to prevent possible product failure at larger manufacturing scale. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the effects of metyrosine, lacidipine, clonidine, and moxonidine on the renal damage in rats with unilateral ureteral ligation by examining the histological evidence of parenchymal damage and tubular dilatation, as well as biochemical changes indicating cell membrane damage and DNA oxidation. Methods: Thirty-six albino Wistar rats were randomly divided into six equal groups: a healthy (intact) group, a unilateral ureteral ligation (control) group, and four drug treatment groups given metyrosine (50 mg/kg), lacidipine (2 mg/kg), clonidine (0.075 mg/kg), or moxonidine (0.2 mg/kg), respectively, for 10 days. The latter five groups underwent ligation of the left ureter. Ten days after the operation, we removed both kidneys from each rat in the control and drug treatment groups for renal pathological and biochemical [malondialdehyde (MDA), total glutathione, 8-hydroxy-2-deoxyguanine (8-OH-Gua)] examinations. Spectrophotometric assays were used to detect the malondialdehyde and total glutathione levels of the renal tissue. High-performance liquid chromatography was used to measure the 8-hydroxy-2-deoxyguanine levels. Results: When the drug treatment groups were compared with the control group, the drug treatment groups' total glutathione level was higher and their malondialdehyde level was lower than that of the control group ( P < 0.05), especially in the clonidine group ( P < 0.0001). The 8-hydroxy-2-deoxyguanine levels of the drug treatment groups, except the lacidipine group, were significantly lower than that of the control group ( P < 0.0001). There was no significant difference between the contralateral kidneys of the treatment groups and control group, according to the biochemical results. As revealed via light microscopy, clonidine and moxonidine treatment significantly reduced the tubular and glomerular damage, as well as the tubular dilation. The interstitial inflammation of the kidneys in the lacidipine group was higher than that of the other treatment groups. However, the apoptotic cell count was at a high level in both the lacidipine and metyrosine groups. The increase in the collagen content was most pronounced in the lacidipine and metyrosine groups. An examination of the contralateral kidneys showed no marked pathological findings. Conclusions: The use of a direct or indirect α2-adrenergic receptor agonist for the temporary treatment of unilateral ureteral obstruction-induced renal damage may be important for preventing renal structural injury. A more advanced study is necessary to determine the mechanisms underlying the protective effects of these drugs with regard to renal damage in ureteral obstruction. [ABSTRACT FROM AUTHOR]

In this study, a new discriminative dissolution condition for lacidipine tablets was developed by the established in vitro- in vivo relationship. Series of dissolution media of phosphate buffer solution (PBS) covering the pH range of 1-7.2 and pH 6.8 PBS containing different concentrations of sodium dodecyl sulfate (SDS), were prepared and used to investigate the dissolution behavior of lacidipine tablets. There was an obvious difference in the dissolution profiles of the both brands in pH 6.8 PBS medium containing 0.1% SDS. The pharmacokinetic study of the two lacidipine tablets was carried out in the healthy beagle dogs at a single dose of 4 mg. Statistical comparison of the AUC0-24, Cmax, and Tmax showed a significant difference in the two brand tablets, coinciding with the dissolution performance with pH 6.8 PBS containing 0.1% SDS. The superiority of the proposed system, pH 6.8 PBS containing 0.1% SDS, could serve as a dissolution medium for lacidipine tablets, and more important it could discriminate the in vivo pharmacokinetic behavior for different brands of products. In summary, in vivo pharmacokinetic evaluation is essential to develop an appropriate in vitro dissolution condition for oral solid dosage forms of poorly soluble drugs. [ABSTRACT FROM AUTHOR]

In this study, the effects of lacidipine (LAC), ramipril (RAM), and valsartan (VAL) on biochemical and histopathologic changes in heart tissue were studied in rats with isoproterenol-induced (ISO-induced) myocardial infarction (MI). LAC, RAM, and VAL had been administered via oral gavage at 3, 3, and 30 mg/kg doses, respectively, once per day during a 30-day time period. On days 29 and 30, the drug treatment group and the control group (with the exception of the intact control group, in which no medications were given, and ISO was not administered) were administered 180 mg/kg ISO subcutaneously over an interval of 24 h. After this period, the hearts of the rats were removed and processed for biochemical and histopathologic studies. The antioxidant parameters superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA) were estimated. A diagnosis of MI was confirmed with antioxidant parameters and histopathologic findings. In MI control groups, histopathologic indicators were found to be statistically higher than those in drug groups; an increase in histopathologic indicators of MI correlates with significant decreases in SOD and CAT levels, and an increase in MDA level. Histopathologic grades of MI indicators were significantly higher in MI group that did not receive any cardioprotective medications in comparison with MI groups that received LAC, RAM, and VAL. Each of the three medications favorably modulated most of the biochemical and histopathologic parameters observed. No significant difference existed with regard to any of the estimated parameters in the rat groups that received medications without MI induction. In conclusion, results indicate that LAC, RAM, and VAL significantly reduced myocardial injury and emphasize the cardioprotective nature of these agents. [ABSTRACT FROM AUTHOR]

Background: Lacidipine (LCDP) is a 1,4-dihydropyridine derivative categorized as an anti-hypertensive Ca2+ channel blocker having very low solubility, and thus very low oral bioavailability, which presents a challenge to the formulation scientists. Homogeneous distribution of poorly water-soluble drugs like LCDP in polyvinylpyrrolidone (PVP), a hydrophilic carrier, is definitely a suitable way to improve the bioavailability of such drugs. Materials and Methods: The aim of the study was to develop a combined thermal, imaging, and spectroscopic approach, and characterize physical state, dissolution behavior, and elucidation of drug--PVP interaction in LCDP/PVP solid dispersion (SD) using differential scanning calorimetry (DSC), X-ray diffractometry (XRD), fourier transform infrared (FTIR) spectroscopy, and hot stage microscopy (HSM), which is the prerequisite for the development of a useful drug product. Results: Dissolution studies of LCDP and its physical mixture with PVP showed less than 50% release even after 60 min, whereas SD of LCDP/ PVP ratio of 1:10% w/w showed complete dissolution within 45 min. DSC and powder XRD proved the absence of crystallinity in LCDP/PVP SD at a ratio of 1:10% w/w. The FTIR spectroscopy indicated formation of hydrogen bond between LCDP and PVP. In the SD FTIR spectra, the -NH stretching vibrations and the -C=O stretch in esteric groups of LCDP shift to free -NH and C=O regions, indicating the rupture of intermolecular hydrogen bond in the crystalline structure of LCDP. Conclusion: Solid-state characterization by HSM, DSC, XRD, and FTIR studies, in comparison with corresponding physical mixtures, revealed the changes in solid state during the formation of dispersion and justified the formation of high-energy amorphous phase. [ABSTRACT FROM AUTHOR]

Objective: The present study was planned to evaluate the effects of lacidipine on STZ induced diabetic neuropathy. Material and methods: Streptozotocin (STZ) induced diabetic neuropathy in rats was monitored by measuring blood sugar levels, motor nerve conduction velocity (MNCV), nociception and histopathology of tibial nerve. Forty rats were divided in to four groups of 10 each. Group I: Control (vehicle). Group II: STZ (50mg/kg, iv, single injection). Group III: Lacidipine (0.5 mg/kg, po, daily + STZ). Group IV: STZ + insulin (4 unit/kg, sc, bid). Similar protocol was used for other parameters also. Results: Lacidipine pre-treatment failed to reduce blood sugar levels in diabetic rats but prevented deterioration of motor nerve conduction velocity as compared to STZ diabetic rats. Hyperalgesia induced by STZ was antagonized by lacidipine. Histology of nerve showed less structural damage in lacidipine pre-treated group. Discussion and conclusion: Thus, lacidipine prevents the development of neuropathic changes induced by STZ in rats. [ABSTRACT FROM AUTHOR]

The cardiovascular drug lacidipine (Lc) is known to possess antibacterial activity. Further potentiation of action is possible by synergism between Lc and an antibiotic or a non-antibiotic. The minimum inhibitory concentration (MIC) of antibiotics, Lc and other non-antibiotics were detected by the agar dilution technique in different bacteria. Synergism was determined by disc diffusion assay, the fractional inhibitory concentration (FIC) index through checkerboard assessment and, also, the protective capacity of the combination by administering the drugs along with 50 × LD50 challenge dose of virulent Salmonella typhimurium in animal experiments. Synergism between Lc and penicillin was found to be statistically significant ( P ≤ 0.01) when compared with their individual effects. The FIC index of this combination was 0.375, confirming synergism. In vivo tests suggested the statistically significant protection of infected mice with this combination. Lc exhibited synergism when combined with non-antibiotics methdilazine and triflupromazine both in vitro and in vivo. Distinct antimicrobial action of Lc and its subsequent synergism with other drugs can open up the possibility of synthesising new molecules by the structural analyses of these compounds. [ABSTRACT FROM AUTHOR]

Aim: Gentamycin, a widely-used aminoglycoside antibiotic, is recognized as possessing significant nephrotoxic potential in human beings. Gentamycin-induced nephrotoxicity is suggested to be mediated via reactive oxygen species. The present study investigated the possible antioxidant nephroprotective effect of lacidipine as a calcium-channel blocker in a gentamycin-induced nephrotoxicity model in albino rats. Methods: Albino rats were divided into 3 groups. Group 1 received normal saline. Group 2 received gentamycin 80 mg/kg intraperitoneally for 14 days. Group 3 received lacidipine 1 mg/kg intraperitoneally 3 days before and 14 days concurrently with gentamycin. This dose does not affect the blood pressure of rats, as evidenced in the pilot study. Results: Gentamycin-induced nephrotoxicity was evidenced by a marked reduction in creatinine clearance. Treatment with lacidipine improved creatinine clearance compared to the gentamycin- treated group. In addition, it reduced thiobarbituric acid reactive substance, as an index of lipid peroxidation, with significant increases in superoxide dismutase enzyme in erythrocyte lysates and kidney catalase enzyme activities. Conclusion: This study recommends the use of lacidipine in prophylaxis against gentamycininduced nephrotoxicity. [ABSTRACT FROM AUTHOR]

The purpose of this research work was to formulate and systematically evaluate in vitro performance of mucoadhesive microspheres of lacidipine for treatment of pylorospasm. Lacidipine microspheres containing chitosan were prepared by chemical denaturation using glutaraldehyde as a cross-linking agent. The microspheres were evaluated for physical characteristics such as particle size, particle shape and surface morphology by scanning electron microscopy, drug entrapment efficiency and in vitro mucoadhesion. Results of preliminary trials indicated that the polymer concentration, cross-linking agent and stirring speed had a noticeable effect on size and surface morphology. A central composite design was employed to study the effect of independent variables, polymer concentration ( X1), volume of glutaraldehyde ( X2), stirring speed ( X3) and cross-linking time ( X4) on dependent variables, drug entrapment efficiency and percentage mucoadhesion. The entrapment efficiency varied from 14–40.82% depending upon the polymer concentration, volume of cross-linker and stirring speed. All batches of microspheres exhibited good mucoadhesive property (73–83%) in the in vitro wash-off test. It was observed that polymer concentration and glutaraldehyde volume had a more significant effect on the dependent variables. Maximum entrapment (36.53%) and mucoadhesion (81.33%) was predicted at 3.5% chitosan, 3 ml glutaraldehyde, 3000 rpm stirring speed and 75 min cross-linking time under optimized process condition. The selected formulation showed controlled release for more than 6 h. The release followed Higuchi kinetics via a Fickian diffusion. [ABSTRACT FROM AUTHOR]

Several diagrams showing the synthesis of BAPTA calcium chelators, solid phase synthesis of N-aryl succinimides and synthesis and spectral characterization of related substances of lacidipine.

Five related substances (impurities) were detected in lacidipine bulk drug substance by a simple high-performance liquid chromatographic method (HPLC) and were identified by liquid chromatography-mass spectrometry (LC-MS). These related substances were independently synthesized, characterized, and co-injected with the sample containing impurities. [ABSTRACT FROM AUTHOR]

A simple, stability-indicating, reversed-phase liquid chromatographic method was developed for the determination of lacidipine in the presence of its degradation products. The analysis was carried out using a 150 mm × 4.6 mm i.d., 5 μm particle size Nucleodur MN-C18 column. Mobile phase containing a mixture of acetonitrile and 0.02 M phosphate buffer (70:30) at pH = 5.0 was pumped at a flow rate of 1 mL min−1 with UV-detection at 254 nm. The method showed good linearity in the range of 0.06–15 μg mL−1 with a limit of detection ( S/ N = 3) of 0.016 μg mL−1 (3.5 × 10−8 M). The suggested method was successfully applied for the analysis of lacidipine in bulk and in commercial tablets with average recoveries of 100.19 ± 0.81% and 100.05 ± 0.69%, respectively. The results were favorably compared to those obtained by a reference method. The suggested method was utilized to investigate the kinetics of alkaline, acidic, peroxide and photo-induced degradation of the drug. The apparent first-order rate constant, half-life times and activation energies of the degradation process were calculated. The pH profile curve was derived. The proposed method was successfully applied to the content uniformity testing of tablets. [ABSTRACT FROM AUTHOR]

Inflammation and increased capillary permeability is a significant aspect of the pathogenesis of many diseases including atherosclerosis. L-type calcium channel blockers (CCB) are commonly used as cardiovascular drugs. Amlodipine, lacidipine, and nicardipine were evaluated for anti-inflammatory activity on the paw oedema produced by carrageenan. The effect of these drugs was compared with the activity of indomethacin. Their effects on vascular permeability were also tested by hyaluronidase-induced capillary permeability. In our animal experiments, amlodipine decreased the carrageenan-induced paw oedema at doses of 1, 3, and 6 mg kg−1 by 27.3%, 43.7%, and 67.3% four hour after carrageenan administration; the same doses of lacidipine and nicardipine decreased paw oedema by 37.1%, 55.6%, 76.4%, 11.2%, 31.0%, 91%; and indomethacin decreased oedema by 38.2% at a dose of 6 mg kg−1. Lacidipine significantly inhibited the hyaluronidase-induced increase in capillary permeability at doses of 1, 3, and 6 mg kg−1 compared with the control group. However, amlodipine and nicardipine significantly inhibited the hyaluronidase-induced increase in capillary permeability at 3 and 6 mg kg−1 doses. A 6 mg kg−1 dose of indomethacin significantly decreased the capillary permeability which was increased by hyaluronidase. These results suggest that CCBs can be efficient anti-inflammatories, and can also significantly decrease capillary permeability. [ABSTRACT FROM AUTHOR]

Abstract  2,6-Dimethyl-5-(phenylcarbamoyl)-4-(3-nitrophenyl)-1,4-dihydropyridine-2-carboxylate was synthesized in two steps and was characterized spectroscopically and confirmed by X-ray diffraction studies. The molecule crystallizes in the monoclinic crystal class in the spacegroup P21/c with cell parameters a = 10.5960(6) Å, b = 10.2450(7) Å, c = 19.5790(11) Å, β = 107.448(3)° and Z = 4. The 1,4-dihydropyridine ring in the structure adopts a flattened boat conformation. Graphical Abstract  2,6-Dimethyl-5-(phenylcarbamoyl)-4-(3-nitrophenyl)-1,4-dihydropyridine-2-carboxylate was synthesized in two steps and was characterized spectroscopically and confirmed by X-ray diffraction studies. The molecule crystallizes in the monoclinic crystal class in the spacegroup P21/c with cell parameters a = 10.5960(6) Å, b = 10.2450(7) Å, c = 19.5790(11) Å, β = 107.448(3)° and Z = 4. The 1,4-dihydropyridine ring in the structure adopts a flattened boat conformation. [ABSTRACT FROM AUTHOR]

Confocal laser scanning microscopy (CLSM) was applied to detect the intracellular [Ca2+] variety of fluorescent intension, with Fluo-3/AM fluorescence loaded in SFSMC. The results show that 10 μmol/L Lacidipine can reduce the frequence which 10 μmol/L 5-HT induced [Ca2+] spark in SFSMC of calcium over loading to 50%, and amplitude to 50% or so. We can draw a conclusion that dihydropyridines calcium antagonists lacidipine can antagonize the release of intracellular [Ca2+] which 5-HT-induced in dose dependent manner. [ABSTRACT FROM AUTHOR]

It has been postulated that the loss of arterial compliance may precede cardiovascular diseases, and that arterial compliance is an important parameter to consider when evaluating arterial diseases such as essential hypertension (EH) and the effects of antihypertensive treatment. In all, 133 EH patients and 147 healthy subjects were enrolled in this study. Large arterial compliance (C1) and small arterial compliance (C2) were measured by the CVProfilor™ DO-2020 CardioVascular Profiling System. Thirty-five patients randomly received magnesium potassium supplementation (magnesium, 70.8 mg/d; potassium, 217.2 mg/d) for four weeks, and 32 patients received lacidipin (4mg/d) as a control. Before and after the four weeks, blood pressure, C1, and C2 were measured. It was found that arterial compliance was significantly lower in EH patients compared with healthy subjects (C1: 12.53 ± 0.33 vs. 15.63 ± 0.30 ml/mmHg × 10, p + and Mg 2+ supplementation, systolic and diastolic BP decreased 7.83 ± 1.87 mm Hg and 3.67 ± 1.03 mm Hg, and C1 and C2 compliance values increased 12.44% ± 4.43% and 45.25% ± 6.67%, respectively. Decreases in systemic vascular resistance (mean arterial pressure divided by cardiac output) by 11.9% and 16.6 % (p [ABSTRACT FROM AUTHOR]

Cyclocondensation of cyclohexene-4-carbaldehyde in the presence of morpholine with CH acids [malonodinitrile, dimedone, 1,3-cyclohexanedione, ethyl acetoacetate, cyanothioacetamide, β-aminophenol, resorcinol, and 4-(cyclopent-1-enyl)morpholine] yields the corresponding 4-(cyclohex-3-enyl)-substituted 4 H-chromenes, 4 H-thiopyrans, 1,4,5,6,7,8-hexahydroquinolines, 1,4-dihydropyridines, and 6,7-dihydro-5 H-[1]pyrindines. [ABSTRACT FROM AUTHOR]

A study has been carried out in the apolipoprotein (apo) E-deficient mouse to investigate the activity of lacidipine (a calcium antagonist with antioxidant properties) in inhibiting the development of atherosclerotic lesions; of particular interest were changes in the susceptibility of low-density lipoproteins (LDL) to oxidation. Mice receiving a Western-type diet to accelerate the development of atherosclerosis were treated orally with vehicle or lacidipine at 3 or 10 mg/kg/day for 8 weeks. Lacidipine treatment (at 3 or 10 mg/kg) had no effect on the plasma lipid profile. However, a significant ( P < 0.01) dose-related reduction of 43 and 50% of the aortic lesion area in respect to vehicle-treated mice was observed. Moreover, the resistance of mouse plasma LDL to undergo lipid peroxidation was significantly ( P < 0.01) increased in apo E-deficient mice treated with lacidipine. The native LDL-like particle, derived from apo E-deficient mice treated with lacidipine, contained significantly lower concentrations of malonyldialdehyde than the vehicle-treated control group ( P < 0.01). After exposure to human umbilical vein endothelial cells, LDL-like particle vitamin E levels (expressed as area under the curve; AUC), were significantly higher ( P < 0.01) in both the 3 and 10 mg/kg lacidipine-treated groups, in comparison with the vehicle-treated control animals. We conclude that lacidipine reduced the extent of the atherosclerotic area in hypercholesterolaemic apo E-deficient mice, and that this reduction may be associated with the capacity of the drug to decrease the susceptibility of LDL to oxidation. [ABSTRACT FROM AUTHOR]

This randomised, double-blind, double-dummy, parallel group, multicentre study compared the efficacy and tolerability of lercanidipine with lacidipine. Elderly patients with isolated systolic hypertension (supine blood pressure ?160/<95?mmHg) were enrolled and underwent a placebo run-in period of 14-27 days before random allocation to lercanidipine tablets 10?mg once daily (n=111) or lacidipine tablets 2?mg once daily (n=111) for the assessment period (112-160 days). Titration to lercanidipine 20?mg once daily (two 10?mg tablets) or lacidipine 4?mg once daily (two 2?mg tablets) was allowed after 8 weeks, if required. Both treatments decreased supine and standing systolic and diastolic blood pressure between the end of the run-in period and the end of the assessment period (P<0.0001). At the end of the assessment period, the estimated mean treatment difference (95% confidence intervals) in supine systolic blood pressure was -0.81 (-4.45, 2.84)?mmHg. These confidence intervals were within the limits specified for equivalence, that is, (-5, 5) mmHg. Ambulatory blood pressure monitoring showed that the antihypertensive effects of both drugs lasted for the full 24-h dosing period and followed a circadian pattern. Both treatments were well tolerated with a low incidence of adverse drug reactions and a low withdrawal rate. Significantly fewer patients withdrew from treatment with lercanidipine (P=0.015). Neither treatment had any clinically significant effect on pulse rate or cardiac conduction. In conclusion, both treatments were equally effective in controlling supine systolic blood pressure in patients with isolated systolic hypertension.Journal of Human Hypertension (2003) 17, 799-806. doi:10.1038/sj.jhh.1001614 [ABSTRACT FROM AUTHOR]

Objective: To assess the dose proportionality of lacidipine after single and repeated oral doses, and to obtain new information on the pharmacokinetics of the compound since improvement of the plasma assay method.Design: Open, randomised, four-way cross-over trial.Participants: 24 healthy male and female volunteers, aged 18-46 years.Methods: Lacidipine was administered as single doses of 2, 4, 6 and 8 mg, and as multiple doses of 2, 4 and 6 mg for 8 days. Pharmacokinetic evaluations were performed on study days 1 and 8. Plasma concentrations of lacidipine were determined by a validated high-performance liquid chromatography-radioimmunoassay method. The ratios of dose-normalised peak plasma concentration (C(max)) and area under the concentration-time curve (AUC) were calculated and then compared across dose groups by analysis of variance to assess dose linearity against a 4 mg reference dose. A power model was also applied as an alternative method for the evaluation of linearity.Results: After repeated 2, 4 and 6 mg doses of lacidipine, geometric least square mean values (95% CI) were 1.76 (1.46-2.12), 3.56 (2.96-4.29) and 5.23 (4.34--6.30) microg/L for C(max) and 5.29 (4.57-6.11), 11.42 (9.87-13.20) and 17.55 (15.18-20.29) microg x h/L for AUC over the administration interval at steady state (AUC(tau)), respectively. Mean half-life ranged between 13.2 hours and 18.7 hours. Precision of these estimates was limited by the small number of sampling timepoints collected in the final part of the curve. After administration of single doses, no statistically significant deviation from linearity was found except for the 8 mg dose, but a trend of greater than proportional exposure was evident with increasing dose. Following repeated administration, dose linearity over the therapeutic range was observed. No statistically significant difference was observed between AUC to infinity (AUC( infinity)) on day 1 and AUC(tau) on day 8, suggesting time-invariance of pharmacokinetics.Conclusions: Lacidipine exhibited linear kinetics after repeated doses in the therapeutic range of 2-6 mg once daily. The two different methodologies for assessing linearity gave consistent results. Only the single 8 mg dose, which is outside the recommended therapeutic range, resulted in greater than predicted exposure. After low doses, the analytical method still does not allow complete characterisation of kinetics. Time-invariance of lacidipine kinetics is suggested. [ABSTRACT FROM AUTHOR]