Clopidogrel Research Articles

Analysis of the Therapeutic Effect of Clopidogrel Bisulfate Tablets + Aspirin Enteric-Coated Tablets on Acute Myocardial Infarction

Analysis of the Therapeutic Effect of Clopidogrel Bisulfate Tablets + Aspirin Enteric-Coated Tablets on Acute Myocardial Infarction

Integrating Clopidogrel's First-Pass Effect in a Joint Semi-Physiological Population Pharmacokinetic Model of the Drug and Its Inactive Carboxylic Acid Metabolite.

Clopidogrel (CLO), a pro-drug for preventing thrombotic events, undergoes rapid absorption and extensive metabolism, with approximately 85-90% converted to an inactive carboxylic acid metabolite (CLO-CA) and the remaining to an active thiol (CLO-TH). Few pharmacokinetic models for the drug and its metabolites exist, with most focusing on CLO-TH. Although CLO-CA is inactive, its predominant (compared to its parent drug and metabolites) presence in plasma underscores the importance of characterizing its formation and pharmacokinetic profile. This study aimed to characterize the process of the absorption of CLO and its conversion to CLO-CA via developing a population pharmacokinetic model. Individual participants' data from two bioequivalence studies were utilized. Extensive blood samples were collected at predetermined intervals, including 841 concentrations of CLO and 1149 of CLO-CA. A nonlinear, mixed-effects modelling approach using NONMEM® software (v 7.5) was applied. A one-compartment model was chosen for CLO, while a two-compartment proved optimal for CLO-CA. Absorption from the depot compartment was modeled via two transit compartments, incorporating transit rate constants (Ktr). A semi-physiological model explained the first-pass effect of CLO, integrating a liver compartment. The estimated mean transit times (MTTs) for the studies were 0.470 and 0.410 h, respectively. The relative bioavailability for each study's generic medicine compared to the reference were 1.08 and 0.960, respectively. Based on the estimated parameters, the fractions metabolized to inactive metabolites (FiaM_st1 and FiaM_st2) were determined to be 87.27% and 86.87% for the two studies, respectively. The appropriateness of the final model was confirmed. Our model offers a robust framework for elucidating the pharmacokinetic profiles of CLO and CLO-CA.

Huanglian Jiedu decoction inhibits vascular smooth muscle cell-derived foam cell formation by activating autophagy via suppressing P2RY12

Ethnopharmacological relevanceHuanglian Jiedu Decoction (HLJDD) is a Chinese medicine with a long history of therapeutic application. It is widely used in treating atherosclerosis (AS) in Chinese medicine theory and clinical practice. However, the mechanism of HLJDD in treating AS remains unclear. Aim of the studyTo investigate the efficacy and mechanism of HLJDD in treating AS. Materials and methodsAS was induced on high-fat diet-fed ApoE−/− mice, with the aorta pathological changes evaluated with lipid content and plaque progression. In vitro, foam cells were induced by subjecting primary mouse aortic vascular smooth muscle cells (VSMCs) to oxLDL incubation. After HLJDD intervention, VSMCs were assessed with lipid stack, apoptosis, oxidative stress, and the expression of foam cell markers. The effects of P2RY12 were tested by adopting clopidogrel hydrogen sulfate (CDL) in vivo and transfecting P2RY12 over-expressive plasmid in vitro. Autophagy was inhibited by Chloroquine or transfecting siRNA targeting ATG7 (siATG7). The mechanism of HLJDD treating atherosclerosis was explored using network pharmacology and validated with molecular docking and co-immunoprecipitation. ResultsHLJDD exhibited a dose-dependent reduction in lipid deposition, collagen loss, and necrosis within plaques. It also reversed lipid accumulation and down-regulated the expression of foam cell markers. P2RY12 inhibition alleviated AS, while P2RY12 overexpression enhanced foam cell formation and blocked the therapeutic effects of HLJDD. Network pharmacological analysis suggested that HLJDD might mediate PI3K/AKT signaling pathway-induced autophagy. P2RY12 overexpression also impaired autophagy. Similarly, inhibiting autophagy counteracted the effect of CDL, exacerbated AS in vivo, and promoted foam cell formation in vitro. However, HLJDD treatment mitigated these detrimental effects by suppressing the PI3K/AKT signaling pathway. Immunofluorescence and molecular docking revealed a high affinity between P2RY12 and PIK3CB, while co-immunoprecipitation assays illustrated their interaction. ConclusionsHLJDD inhibited AS in vivo and foam cell formation in vitro by restoring P2RY12/PI3K/AKT signaling pathway-suppressed autophagy. This study is the first to reveal an interaction between P2RY12 and PI3K3CB.

Analysis of the Effectiveness of Clopidogrel Combined with Aspirin in the Treatment of Coronary Heart Disease in Community-Dwelling Elderly

Objective: To analyze the combined therapeutic effect of clopidogrel (CLO) and aspirin (ASP) on coronary heart disease (CHD) in community-dwelling elderly. Methods: Thirty elderly patients with CHD who were admitted to the Xinxin Community Health Service Station, Pangzhuang Street, Quanshan District, Xuzhou City, from November 2020 to November 2022 were selected and randomly grouped into an observation group and a control group, with 15 cases in each group. The observation group was given the combination of CLO and ASP and the reference group was given only ASP. The total effective rate and other treatment indicators between the two groups were compared. Results: The total effective rate of the observation group (93.33%) was higher than that of the reference group (60.00%) (P < 0.05). The adverse drug reaction rate (13.33%) and long-term cardiovascular adverse event rate (6.67%) of the observation group were lower than those of the reference group at 46.67% and 40.00% respectively, (P < 0.05). Before treatment, the two groups had no difference in the quality-of-life scores (P > 0.05). After treatment, the quality-of-life scores of the observation group were higher than those of the reference group (P < 0.05). Conclusion: CLO combined with ASP improved the therapeutic effect of community-dwelling elderly patients with CHD, reduced adverse reactions during medication, prevented adverse cardiovascular events, and comprehensively improved the patient’s quality of life.

Assessment of Aspirin and Clopidogrel Resistance in Patients Undergoing Cardiovascular Surgery: A Single-Center Cross-Sectional Study

We aimed to investigate antiplatelet drug resistance utilizing light transmission-lumiaggregometry (LT-LA) and the Platelet Function Analyzer-100 (PFA-100) in patients undergoing cardiovascular surgery. The study included 60 patients diagnosed with stable coronary artery disease and peripheral vascular diseases that required surgery. Participants were divided into three groups: patients receiving aspirin (ASA) (n=21), patients receiving clopidogrel (CLO) (n=19), and patients receiving dual therapy (ASA+CLO) (n=20). Aggregation and secretion tests by LT-LA and closure time by the PFA-100 were used to measure antiplatelet drug resistance. Based on the adenosine diphosphate (ADP)-induced aggregation test, 43% of patients were resistant to ASA, 22% to CLO, and 15% to dual therapy. Diabetes, hypertension, and hyperlipidemia were the most commonly identified comorbid disorders. In patients with comorbid risk factors, the median value of platelet aggregation response to ADP was significantly higher in the ASA group than in the CLO and dual therapy groups (p=0.0001). In patients receiving ASA monotherapy, the maximum amplitude of aggregation response to platelet agonists was ≥70% in 43% of patients for ADP and 28% for collagen by LT-LA. Elevated ADP (≥0.29 nmol) and collagen (≥0.41 nmol)-induced adenosine triphosphate release were found by LT-LA in 66% of patients utilizing an ADP agonist and 80% of patients using a collagen agonist undergoing ASA therapy. Closure times obtained with the PFA-100 were normal in 28% of patients using collagen-ADP cartridges and 62% of patients using collagen-epinephrine (CEPI) cartridges who received ASA. Recurrent thrombosis and bleeding were observed in 12 (20%) patients with cardiovascular disease. Three of these individuals (25%) showed ASA resistance with normal responses to ADP-induced aggregation (≥70%) and secretion (≥0.29 nmol), as well as normal CEPI closure times. Our findings suggest that antiplatelet drug monitoring by LT-LA and PFA-100 may be useful for high-risk and complicated cardiovascular patients.

The Effect of Clopidogrel and Ticagrelor on Human Adipose Mesenchymal Stem Cell Osteogenic Differentiation Potential: In Vitro Comparative Study.

Ticagrelor (TICA) and clopidogrel (CLP) are extensively used antiplatelet drugs that act by antagonizing the P2Y12 receptors that are found on platelets in addition to bone cells. Aim. The purpose of this study was to investigate the effect of clopidogrel and ticagrelor on stem cells osteogenic differentiation in vitro. Methods. Human adipose-derived mesenchymal stem cells (hAd-MSCs) were divided into (1) control group, (2) osteogenic group (osteo group), (3) clopidogrel group (CLP group), and (4) ticagrelor group (TICA group). The osteogenic differentiation potential was determined by mineralization nodule formation using Alizarin Red S staining, measuring ALP enzyme activity by alkaline phosphatase assay. Quantitative determination for osteogenic markers included osteocalcin (OC); runt-related transcription factor 2 (RUNX2) performed using western blot; osteoprotegerin (OPG) using enzyme-linked immunosorbent assay (ELISA) and inflammatory markers; and tumor necrosis factor (TNF-α) and interleukin-6 (IL-6) measured using real-time polymerase chain reaction quantitative (RT-PCR) and ELISA. Results. In comparison to all study groups, the TICA group showed significant increase in the mineralized extracellular matrix, ALP enzyme activity, and bone markers expression as RUNX2 (P < 0.0001), OC, and OPG (P < 0.05). The expression of IL-6 and TNF-α was determined by RT-qPCR and ELISA techniques. TICA and CLP significantly decreased both markers compared to the control group. The TICA group showed statistically significant lower levels of both markers (P < 0.0001) than the CLP and control groups via the ELISA technique. Conclusion. TICA may possess a positive effect on hAd-MSCs osteogenic differentiation compared to CLP.

HPLC Method Development and Validation for the Determination of Apixaban and Clopidogrel in Novel Fixed-Dose Combination Tablets

A simple, fast, and accurate high-performance liquid chromatographic (HPLC) method is developed, optimized, and validated for a fixed-dose combination of apixaban (APX) and clopidogrel (CLOP) tablets according to ICH guidelines. Chromatographic separation of the drugs was performed on a BDS Hypersil C18 (4.6 ∗ 150 mm, 5 μm), with acetonitrile (ACN) and trifluoroacetic acid (TFA) in the ratio 48 : 52 (v/v) as a mobile phase, at a flow rate of 0.9 ml/min., injection volume of 5 μL, and column temperature 45°C. The proposed method was linear over the level 25–200% for a concentration of APX 5 μg/ml and CLOP 75 μg/ml (R2 &gt; 0.999). The detection limit for APX and CLOP was found to be 0.3465 and 3.8496 μg/ml, whereas the quantification limit was 1.0499 and 11.6656 μg/ml, respectively. The recovery was more than 99% using the standard addition method. The developed method was found to be specific, accurate, precise, and robust against changes in column temperature (±5°C) and mobile phase composition (±5% ACN); hence, it can be used for the determination of APX and CLOP in the fixed-dose combination tablets.

QbD-based RP-HPLC method development for quantitative computation of phase III composition comprising apixaban and clopidogrel

The presented work highlights the use of the quality by design methodology in accordance with International Council on Harmonization (ICH) recommendations for developing an reverse phase high performance liquid chromatographic (RP-HPLC) method for apixaban (APX) and clopidogrel (CLP). An efficient approach based on a factorial design incorporating the essential method parameters of the RP-HPLC method such as flow rate, pH, and proportion of organic phase, is presented. The optimum conditions for analysis were derived by using Design Expert software 10.0 Version, i.e., Hypersil ODS C18 column (5.0 μ, 25 cm × 4.6 mm), methanol and 0.05M potassium dihydrogen phosphate buffer (63.5:36.5%v/v, pH 3) as mobile phase, and 0.8 ml/minute as the flow rate. The derived condition gave excellent resolution between APX and CLP with Rt of 4.89 and 14.35 minutes, respectively, with the best possible system suitability parameters. The developed method presented excellent linearity in the range of 1.25–3.75 μg/ml for APX and 37.5–112.5 μg/ml for CLP at 245 nm. The optimized method was further validated in accordance with ICH guidelines on analytical method validation. Finally, the approach was successful in determining APX and CLP from a binary combination.

Early vascular embolization improves neurological function in patients with intracranial aneurysm.

To investigate the effect of early vascular embolization for intracranial aneurysms and the effect of matrix metalloproteinase-9 (MMP-9) and nuclear factor-kappa B (NF-κB) on nerve function. This is a retrospective analysis study. A total of 90 patients with intracranial aneurysms admitted to our hospital from January 2017 to December 2021 were selected as research subjects. The patients were divided into a control group (n=47) and an observation group (n=43) according to different embolization timing. Both groups were treated with vascular embolization, the observation group received vascular embolization within 72 h after onset, while the control group received vascular embolization after 72 h. In addition, both groups were given clopidogrel bisulfate tablets and enteric-coated aspirin tablets from the day after operation for 3 months. The embolization at 3 months after operation, the occurrence of complications, the daily activities and neurological function before and 3 months after operation, serum levels of MMP-9 and NF-κB, the protein expression of MMP-9 and NF-κB, and the prognosis at 3 months after operation were compared between the two groups. The complete embolization rate (90.70%) in observation group was higher than that of the control group (72.34%) at 3 months after operation (P<0.05). The postoperative complications in the observation group (9.30%) were lower than those of the control group (27.66%) (P<0.05). The improvement in Modified Barthel index score, as well as serum levels of MMP-9 and NF-κB were better in the observation group than those of the control group 3 months after operation (P<0.05). The prognosis of patients in the observation group was better than those of the control group 3 months after operation (P<0.05). Early vascular embolization is an effective approach for intracranial aneurysm. It helps improve patients' neurological function, and reduce their serum and protein levels of both MMP-9 and NF-κB, thereby leading to favorable prognosis.

Periprocedural antiplatelet medication assessed by VerifyNow for neuroendovascular treatment: Comparison of prasugrel with clopidogrel

Objective The maintenance dose of prasugrel (PRAS) for neuroendovascular treatment requires much research. We report the antiplatelet effect of PRAS measured by VerifyNow P2Y12 reaction units (PRUs) in patients during the perioperative period of neuroendovascular treatment. Methods Between January 2017 and January 2023, 230 patients who underwent endovascular treatment for unruptured intracranial aneurysms or carotid artery stenosis at our institution were retrospectively identified. Patients received dual antiplatelet therapy with 100 mg aspirin (ASA) and 75 mg clopidogrel (CLP)/day (CLP group, n = 186) or 100 mg ASA and 3.75 mg PRAS/day (PRAS group, n = 44) 2 weeks before the procedures. The PRU value was compared between the CLP and PRAS groups. In the study, we defined 95≦PRU &lt; 208 as the optimal range. Perioperative complications within seven days of surgery were also analyzed. Results The mean value of PRU was significantly low in the PRAS group (179.13 ± 66.03 in CLP vs. 154.75 ± 54.01 in PRAS, p = 0.024). The proportion of the patients who exhibited 95≦PRU &lt; 208 was significantly higher in the PRAS group (55.4% vs. 72.7%, p = 0.036). Ischemic and hemorrhagic complication rates were not significantly different between the CLP and PRAS groups (7.6% vs. 0%, p = 0.076; 4.7% vs. 0%, p = 0.361). The ischemic complication rate was higher in patients with a PRU &gt; 208 than in those with PRU &lt; 208 (12.5% vs. 3.8%, p = 0.044). The hemorrhagic complication rate was not significantly different between the PRU &lt; 95 and 95≦PRU groups (8.4% vs. 3.2%, p = 0.224). Conclusions Maintenance dose PRAS further decreased the PRU value and reached the optimal range in more cases than CLP during the perioperative period of neuroendovascular treatment. Ischemic complications significantly increased in the 208 &lt; PRU group.

Clopidogrel-loaded vascular grafts prepared using digital light processing 3D printing

The leading cause of death worldwide and a significant factor in decreased quality of life are the cardiovascular diseases. Endovascular operations like angioplasty, stent placement, or atherectomy are often used in vascular surgery to either dilate a narrowed blood artery or remove a blockage. As an alternative, a vascular transplant may be utilised to replace or bypass a dysfunctional or blocked blood vessel. Despite the advancements in endovascular surgery and its popularisation over the past few decades, vascular bypass grafting remains prevalent and is considered the best option for patients in need of long-term revascularisation treatments. Consequently, the demand for synthetic vascular grafts composed of biocompatible materials persists. To address this need, biodegradable clopidogrel (CLOP)-loaded vascular grafts have been fabricated using the digital light processing (DLP) 3D printing technique. A mixture of polylactic acid-polyurethane acrylate (PLA-PUA), low molecular weight polycaprolactone (L-PCL), and CLOP was used to achieve the required mechanical and biological properties for vascular grafts. The 3D printing technology provides precise detail in terms of shape and size, which lead to the fabrication of customised vascular grafts. The fabricated vascular grafts were fully characterised using different techniques, and finally, the drug release was evaluated. Results suggested that the performed 3D-printed small-diameter vascular grafts containing the highest CLOP cargo (20% w/w) were able to provide a sustained drug release for up to 27 days. Furthermore, all the CLOP-loaded 3D-printed materials resulted in a substantial reduction of the platelet deposition across their surface compared to the blank materials containing no drug. Haemolysis percentage for all the 3D-printed samples was lower than 5%. Moreover, 3D-printed materials were able to provide a supportive environment for cellular attachment, viability, and growth. A substantial increase in cell growth was detected between the blank and drug-loaded grafts.Graphical

An innovative combination of Box-Behnken design and ecofriendly approaches for the simultaneous determination of aspirin, clopidogrel, atorvastatin and rosuvastatin in their fixed-dose combination tablets

Three-levels Box-Behnken design was used in the experimental design approach for the optimization of chromatographic parameters to achieve the optimum resolution and sharp peak shape within a reasonable run time. A method that is sensitive, reliable, and selective was constructed and validated for the simultaneous measurement of a combination therapy that contains blood-thinning and cholesterol-lowering compounds. The four cited drugs namely, aspirin (ASP), clopidogrel (CLP), atorvastatin (ATV) and rosuvastatin (ROS) were estimated in bulk and in pharmaceutical dosage forms in line with International Council for Harmonization guidelines. The separation was done utilizing Kinetex 2.6 C18 column (100 mm, 4.6 mm, 5 m) and RP-HPLC with diode array detector. The separation of the cited drugs and the degradation product of ASP was achieved with mobile phase composed of acetonitrile: KH2PO4 buffer in a gradient mode with pH 3.2 at room temperature. The four drugs were linear over the concentration range (0.05–50 µg/mL). The technique is feasible to be used in quality control laboratories. To picture the green profile of the developed method, four greenness assessment tools were applied. National environmental methods index (NEMI), analytical eco-scale assessment (ESA), green analytical procedure index (GAPI) and analytical greenness metric (AGREE) are the most widely used metrics. They were employed to evaluate the greenness profile of the proposed method and to perform a detailed greenness comparison between the developed method and some of the reported methods for the determination of the investigated drugs. The developed method was found to be relatively green with 0.54 AGREE score.

AGREE and ESA for Greenness Assessment of a Novel Validated RP-HPLC Method for Simultaneous Determination of Aspirin, Warfarin and Clopidogrel in Rat Plasma: Application to Pharmacokinetic Study of the Possible Interaction between the Three Drugs.

The green profile of the developed method is assessed and compared with previously reported methods. Percutaneous coronary intervention is a procedure where a catheter is utilized to place a stent in order to facilitate opening of the blood vessels in the heart. Triple antithrombotic therapy includes oral anticoagulation as warfarin and dual antiplatelet therapy (composed of aspirin and clopidogrel bisulfate). The aim of the current study was to evaluate the pharmacokinetic parameters of ASP, WAR and CLP and to investigate the possible interaction between the three drugs upon co-administration in rats. A selective and precise RP-HPLC method was developed for the simultaneous determination of ASP, WAR and CLP in rat plasma. Pharmacokinetic study was conducted in rats that received ASP, WAR and CLP as an application of the developed method. From the statistical evaluation of the pharmacokinetic parameters, it was observed that the co-administration of ASP, WAR and CLP significantly increased the ASP and CLP bioavailability in rats. A significant drug-drug interaction was confirmed in the current study. The elevated Cmax of ASP and CLP upon the co-administration of ASP, WAR and CLP may explain the reported bleeding.

HEMOCOMPATIBILITY STUDIES OF LAYER-BY-LAYER POLYELECTROLYTE COMPLEXES FOR BIO-BASED POLYMERS

Thrombogenesis is an important issue that causes blood-contacting biomedical device failure. This study focuses on hemocompatibility studies of novel blood-contacting polyelectrolyte complexes (PECs) for biomedical application designs. PEC films were fabricated from biobased polymers of silk fibroin (SF), chitosan (CH), and sodium alginate (AL) through the solvent casting method as well as Layer-by-Layer (LbL) technique. Characterization was carried out by Fourier-transform infrared spectroscopy (FTIR), Scanning electron microscopy (SEM), Atomic force microscopy (AFM), and Differential scanning calorimetry (DSC) analyses. FTIR spectra displayed all layers’ characteristic peaks of SF, CH, and AL. AFM images indicated that the addition of AL as an outer layer increased surface roughness. DSC analysis suggested that the best thermal stability has been observed with the CH outer layer of PECs. SEM micrograph analysis indicated that the morphologies of PECs were affected by the inclusion of the clopidogrel bisulfate (CLB). Hemocompatibility properties were investigated by complete blood count (CBC), prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin time (APTT), platelet adhesion, erythrocyte morphology analysis, in vitro cholesterol, and albumin level tests. These hemocompatibility analyses demonstrated that the PEC surfaces provide favourable principles to design and develop non-thrombogenic PECs for blood-contacting biomedical applications

Development and validation of a sensitive LC-MS/MS method for simultaneous analysis of clopidogrel and simvastatin and their main metabolites in beagles: Application to pharmacokinetic drug interactions.

Clopidogrel (CLP) and simvastatin (SV) are commonly used in combination therapies as anti-cardiovascular drugs. However, the effect of coadministration on the absorption and metabolism of the two drugs in vivo is not clear. This study developed and validated an LC-MS/MS method for the simultaneous determination of CLP, clopidogrel carboxylic acid (CLPCA), 2-oxo-clopidogrel (2-O-CLP), SV, and simvastatin hydroxy acid (SVA) in beagle plasma. Chromatographic separation was achieved on an InfinityLab Poroshell 120 SB-C8 column (2.1 × 100 mm, 2.7μm) using methanol and 0.1% formic acid in water as the mobile phase at a flow rate of 0.3mL/min in gradient mode. The lower limits of quantification are 0.1, 0.8, 0.05, 0.05, and 0.05 ng/mL for CLP, CLPCA, 2-O-CLP, SV, and SVA, respectively. The selectivity, linearity, accuracy, precision, extraction recovery, matrix effect, and stability were validated within acceptable criteria. This method was successfully applied to the pharmacokinetic drug interaction study between CLP and SV, and the results revealed that combined administration affected the metabolic rate of CLP, SV, and their metabolites. This study is the first to detect CLP, CLPCA, 2-O-CLP, SV, and SVA simultaneously.

PATHOGENETICALLY DIRECTED METHOD OF PREVENTION AND TREATMENT OF AGE-MACULAR DEGENERATION

Background. Age-related macular degeneration is one of the most common causes of blindness in developed countries, especially in people over 60 years old. The incidence of AMD is projected to increase to 288 million in 2040 compared to 196 million in 2020. Cardiovascular factors, smoking, alcohol consumption, overweight, genetic factors, and metabolic disorders are risk factors for the development of AMD. There are disorders of lipid metabolism, as well as hyperreactivity of platelet purine receptors may be associated with the progression of AMD. The AREDS2 formula is currently used to treat AMD. New therapeutic strategies aimed to correct metabolic disorders are needed to decrease the development of the late stages of AMD.&#x0D; Aim: to investigate the effectiveness of improving pathogenetically directed method of prevention and treatment of age-related macular degeneration.&#x0D; Materials and methods. We observed 40 patients (80 eyes), aged 50-85 years, with AMD of category 3 (intermediate AMD), who were divided into 2 groups. The main group included 20 patients (40 eyes), 14 women and 6 men, who have prescribed a complex drug according to the standard AREDS2 scheme, as well as fenofibrate (200 mg) and clopidogrel bisulfate (75 mg). The control group included 20 patients (40 eyes), 13 women and 7 men. These patients received AREDS2 standard treatment. Progression was evaluated according to the results of OCT of the macular area according to the AREDS classification and control of corrected visual acuity (CVA). The observation period was 2 years.&#x0D; Results. No signs of progression were noted in patients of both observation groups within 6 months from the start of the prescribed therapy. In the patients of the control group, the progression of the disease was recorded after 1 year of observation according to both defined criteria. Changes in OCT were observed in 7,5% of patients in the control group, and a decrease in CVA- in 5%. In the patients of the main group who used the extended therapeutic regimen, after 1 year of follow-up, progression according to OCT signs was noted in 2,5% of cases, but there was no worsening of CVA. After 2 years of observation, signs of progression according to OST were recorded in the main group by 50% less than in the control group. According to CVA, disease progression was detected in 15% of the main group and 30% of the control group.&#x0D; Conclusions. This study complemented already existing therapeutic strategies for the preventive treatment of AMD.

Human Serum Albumin-enriched Clopidogrel Bisulfate Nanoparticle Alleviates Cerebral Ischemia-Reperfusion Injury in Rats.

Cerebral ischemia-reperfusion (I/R) injury remains a leading cause of mobility and mortality among patients with ischemic stroke. This study aims to develop a human serum albumin (HSA)-enriched nanoparticle platform for solubilizing clopidogrel bisulfate (CLP) for intravenous administration, and to explore the protective effect of HSA-enriched nanoparticles loaded with CLP (CLP-ANPs) against cerebral I/R injury in transient middle cerebral artery occlusion (MCAO) rat model. CLP-ANPs were synthesized via a modified nanoparticle albumin-bound technology, lyophilized, and then characterized by morphology, particle size, zeta potential, drug loading capacity, encapsulation efficiency, stability and in vitro release kinetics. In vivo pharmacokinetic studies were conducted using Sprague-Dawley (SD) rats. Also, an MCAO rat model was established to explore the therapeutic effect of CLP-ANPs on cerebral I/R injury. CLP-ANPs remained spherical particles with a layer of proteins forming protein corona. Lyophilized CLP-ANPs after dispersion displayed an average size of about 235.6 ± 6.6nm (PDI = 0.16 ± 0.08) with a zeta potential of about - 13.5 ± 1.8mV. CLP-ANPs achieved sustained release for up to 168h in vitro. Next, a single injection of CLP-ANPs dose-dependently reversed the histopathological changes induced by cerebral I/R injury possibly via attenuating apoptosis and reducing oxidative damages in the brain tissues. CLP-ANPs represent a promising and translatable platform system for the management of cerebral I/R injury during ischemic stroke.

Effect of atmosphere and relative humidity on photodegradation of clopidogrel under artificial solar and indoor light irradiation

Knowledge of the chemical stability of active pharmaceutical ingredients (APIs) is an important issue in the drug development process. This work describes a methodical approach and a comprehensive protocol for forced photodegradation studies of solid clopidogrel hydrogen sulfate (Clp) under artificial sunlight and indoor irradiation at different relative humidities (RHs) and atmospheres. The results showed that, at low RHs (up to 21%), this API was relatively resistant to simulated sunlight as well as indoor light. However, at higher RHs (between 52% and 100%), more degradation products were formed, and the degradation rate increased with rising RH. The influence of oxygen on the degradation was relatively low, and most degradation reactions proceeded even in humid argon atmosphere. The photodegradation products (DP) were analyzed with two different HPLC systems (LC-UV, LC-UV-MS) and selected impurities were separated by a semi-preparative HPLC and identified by high resolution mass spectrometry (ESI-TOF-MS) and 1H NMR techniques. Based on the obtained results, a light induced degradation pathway could be proposed for Clp in solid state.

Evaluation of herb-drug interactions between compound Danshen dripping pills and clopidogrel based on the pharmacokinetics and pharmacodynamics in rats.

Compound Danshen dripping pills (CDDP), a well-known traditional Chinese medicine, is widely used to prevent and treat cardiovascular diseases. CDDP is usually prescribed in combination with clopidogrel (CLP), but the herb-drug interactions are rarely reported. This study evaluated the effects of CDDP on the pharmacokinetics and pharmacodynamics of coadministered CLP, and ensured the safety and efficacy of their usage. The trial design included a single-dose administration and multidose test for 7 consecutive days. Wistar rats received CLP alone or CLP combined with CDDP. After the final dose, plasma samples were collected at various time points, and the active metabolite H4 of CLP was analyzed by ultrafast liquid chromatography coupled with triple quadrupole tandem mass spectrometry. The main pharmacokinetic parameters of Cmax (maximum [or peak] serum concentration), Tmax (peak plasma time), t1/2 (half-time), AUC0-∞ (area under the concentration-time curve from dosing (time 0) to infinite time), and AUC0-t (area under the concentration-time curve from dosing [time 0] to time t) were calculated using the non-compartment model. In addition, prothrombin time, activated partial thromboplastin time, bleeding time, and adenosine diphosphate-induced platelet aggregation were evaluated for anticoagulation and antiplatelet aggregation activity. In this study, we found that CDDP had no significant effect on the metabolism of CLP in rats. In pharmacodynamic studies, the combination group showed significant synergistic antiplatelet activity compared with the CLP or CDDP groups alone. Based on pharmacokinetic and pharmacodynamic results, CDDP and CLP have synergistic effects on antiplatelet aggregation and anticoagulation.

Mechanochemical Oxidative Degradation of Thienopyridine Containing Drugs: Toward a Simple Tool for the Prediction of Drug Stability.

The long-term stability of an active-pharmaceutical ingredient and its drug products plays an important role in the licensing process of new pharmaceuticals and for the application of the drug at the patient. It is, however, difficult to predict degradation profiles at early stages of the development of new drugs, making the entire process very time-consuming and costly. Forced mechanochemical degradation under controlled conditions can be used to realistically model long-term degradation processes naturally occurring in drug products, avoiding the use of solvents, thus excluding irrelevant solution-based degradation pathways. We present the forced mechanochemical oxidative degradation of three platelet inhibitor drug products, where the drug products contain thienopyridine. Model studies using clopidogrel hydrogen sulfate (CLP) and its drug formulation Plavix show that the controlled addition of excipients does not affect the nature of the main degradants. Experiments using drug products Ticlopidin-neuraxpharm and Efient show that significant degradation occurs after short reaction times of only 15 min. These results highlight the potential of mechanochemistry for the study of degradation processes of small molecules relevant to the prediction of degradation profiles during the development of new drugs. Furthermore, these data provide exciting insights into the role of mechanochemistry for chemical synthesis in general.