Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 7.878
Filtrar
1.
Expert Opin Drug Saf ; 23(4): 487-495, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38497691

RESUMO

BACKGROUND: Hemorrhage represents the most common and serious side effect of antithrombotic agents. Many studies have compared the risk of bleeding between different antithrombotic agents, but analysis of time-to-onset for hemorrhage induced by these drugs is yet sparse. METHODS: We conducted a retrospective study based on the adverse drug reaction reports on antithrombotic agents collected by the Henan Adverse Drug Reaction Monitoring Center. We assessed the reporting odds ratio to determine the disproportionate reporting signals for bleeding and the Weibull shape parameter was used to evaluate the time-to-onset data. RESULTS: In the signal detection, crude low molecular weight heparin-hemorrhage was found as a positive signal. The hemorrhage for most antithrombotic agents was random failure profiles. In particular, the hazard of hemorrhage decreased over time for warfarin and clopidogrel and increased for alteplase, nadroparin, and dipyridamole. CONCLUSION: We found that the risk of bleeding in patients taking Crude low molecular weight heparins was significantly higher compared to other antithrombotic agents, but with a small magnificence, which may be attributed to the severely irrational use of this medication under improper management. Statistics in days, results showed that the risk of bleeding decreased over time for warfarin and clopidogrel and increased for alteplase, nadroparin, and dipyridamole.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Fibrinolíticos , Humanos , Fibrinolíticos/efeitos adversos , Varfarina/efeitos adversos , Nadroparina/efeitos adversos , Clopidogrel/efeitos adversos , Ativador de Plasminogênio Tecidual/efeitos adversos , Estudos Retrospectivos , Farmacovigilância , Hemorragia/induzido quimicamente , Hemorragia/epidemiologia , Anticoagulantes/efeitos adversos , Dipiridamol/efeitos adversos , Inibidores da Agregação Plaquetária/efeitos adversos
2.
J Am Heart Assoc ; 13(4): e031270, 2024 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-38362899

RESUMO

BACKGROUND: Resting coronary flow velocity (CFV) in the mid-distal left anterior descending coronary artery can be easily assessed with transthoracic echocardiography. In this observational study, the authors sought to assess the relationship between resting CFV, CFV reserve (CFVR), and outcome in patients with chronic coronary syndromes. METHODS AND RESULTS: In a prospective multicenter study design, the authors retrospectively analyzed 7576 patients (age, 66±11 years; 4312 men) with chronic coronary syndromes and left ventricular ejection fraction ≥50% referred for dipyridamole stress echocardiography. Recruitment (years 2003-2021) involved 7 accredited laboratories, with interobserver variability <10% for CFV measurement at study entry. Baseline peak diastolic CFV was obtained by pulsed-wave Doppler in the mid-distal left anterior descending coronary artery. CFVR (abnormal value ≤2.0) was assessed with dipyridamole. All-cause death was the only end point. The mean CFV of the left anterior descending coronary artery was 31±12 cm/s. The mean CFVR was 2.32±0.60. During a median follow-up of 5.9±4.3 years, 1121 (15%) patients died. At multivariable analysis, resting CFV ≥32 cm/s was identified by a receiver operating curve as the best cutoff and was independently associated with mortality (hazard ratio [HR], 1.24 [95% CI, 1.10-1.40]; P<0.0001) together with CFVR ≤2.0 (HR, 1.78 [95% CI, 1.57-2.02]; P<0.0001), age, diabetes, history of coronary surgery, and left ventricular ejection fraction. When both CFV and CFVR were considered, the mortality rate was highest in patients with resting CFV ≥32 cm/s and CFVR ≤2.0 and lowest in patients with resting CFV <32 cm/s and CFVR >2.0. CONCLUSIONS: High resting CFV is associated with worse survival in patients with chronic coronary syndromes and left ventricular ejection fraction ≥50%. The value is independent and additive to CFVR. The combination of high resting CFV and low CFVR is associated with the worst survival.


Assuntos
Vasos Coronários , Função Ventricular Esquerda , Masculino , Humanos , Pessoa de Meia-Idade , Idoso , Estudos Prospectivos , Estudos Retrospectivos , Volume Sistólico , Vasos Coronários/diagnóstico por imagem , Dipiridamol , Circulação Coronária , Ecocardiografia sob Estresse/métodos , Velocidade do Fluxo Sanguíneo
3.
Biol Pharm Bull ; 47(1): 14-22, 2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-37880111

RESUMO

Though the physiological effects of adenosine and adenine nucleotides on purinergic receptors in cancer cells have been well studied, the influence of extracellular guanosine and guanine nucleotides on breast cancer cells remains unclear. Here, we show that extracellular guanosine and guanine nucleotides decrease the viability and proliferation of human breast cancer SKBR-3 cells. Treatment with guanosine or guanine nucleotides increased mitochondrial production of reactive oxygen species (ROS), and modified the cell cycle. Guanosine-induced cell death was suppressed by treatment with adenosine or the equilibrium nucleoside transporter (ENT) 1/2 inhibitor dipyridamole, but was not affected by adenosine receptor agonists or antagonists. These results suggest that guanosine inhibits adenosine uptake through ENT1/2, but does not antagonize adenosine receptors. In contrast, guanosine triphosphate (GTP)-induced cell death was suppressed not only by adenosine and dipyridamole, but also by the A1 receptor agonist 2-chloro-N6-cyclopentyladenosine (CCPA), suggesting that GTP-induced cell death is mediated in part by an antagonistic effect on adenosine A1 receptor. Thus, both guanosine and GTP induce apoptosis of breast cancer cells, but via at least partially different mechanisms.


Assuntos
Neoplasias da Mama , Nucleotídeos de Guanina , Humanos , Feminino , Nucleotídeos de Guanina/metabolismo , Nucleotídeos de Guanina/farmacologia , Guanosina/farmacologia , Neoplasias da Mama/tratamento farmacológico , Guanosina Trifosfato/farmacologia , Adenosina/farmacologia , Adenosina/metabolismo , Dipiridamol
4.
ACS Appl Mater Interfaces ; 16(1): 166-177, 2024 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-38143309

RESUMO

Tumor-associated platelets can bind to tumor cells and protect circulating tumor cells from NK-mediated immune surveillance. Tumor-associated platelets secrete cytokines to induce the epithelial-mesenchymal transition (EMT) in tumor cells, which promotes tumor metastasis. Combining chemotherapeutic agents with antiplatelet drugs can reduce the occurrence of metastasis, but the systemic application of chemotherapeutic agents and antiplatelet drugs is prone to causing serious side effects. Therefore, delivering drugs to the tumor microthrombus site for long-lasting inhibition is a problem that needs to be addressed. Here, we show that small molecule peptide nanoparticles containing the Cys-Arg-Glu-Lys-Ala (CREKA) peptide can deliver the platelet inhibitor dipyridamole (DIP) and the chemotherapeutic drug paclitaxel (PTX) to tumor tissues, thereby inhibiting tumor-associated platelet function while killing tumor cells. The drug-loaded nanoparticles PD/Pep1 inhibited platelet-tumor cell interactions, were effectively taken up by tumor cells, and underwent morphological transformation induced by alkaline phosphatase (ALP) to prolong the retention time of the drugs. After intravenous injection, PD/Pep1 can target tumors and inhibit tumor metastasis. Thus, this small molecule peptide nanoformulation provides a simple strategy for efficient drug delivery and shows promise as a novel cancer therapy platform.


Assuntos
Nanopartículas , Células Neoplásicas Circulantes , Humanos , Paclitaxel , Inibidores da Agregação Plaquetária/farmacologia , Dipiridamol/farmacologia , Peptídeos/farmacologia , Peptídeos/química , Nanopartículas/química , Linhagem Celular Tumoral
5.
Neurochem Res ; 49(3): 744-757, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38102341

RESUMO

White matter lesions (WMLs) resulting from chronic cerebral hypoperfusion (CCH) are the leading cause of vascular dementia (VaD). This study aimed to investigate whether dipyridamole could alleviate WMLs by regulating the phenotype of disease-associated microglia (DAM) through equilibrative nucleoside transporter 2 (ENT2) and adenosine A2A receptor (Adora2a) and to clarify the underlying molecular mechanisms. CCH rat models were constructed to mimic VaD. Morris water maze and Luxol Fast Blue staining were employed to assess cognitive function and quantify the severity of WMLs, respectively. Immunofluorescent staining was performed to analyze the activation of glial cells and the phenotypic transformation of DAM. Additionally, levels of ENT2, proteins in the NF-κB and ERK1/2 pathways and inflammatory cytokines were detected. The results indicated that dipyridamole diminished the activation and proliferation of microglia and astrocytes, increased the expression of myelin basic protein and ameliorated WMLs and cognitive decline in CCH rats. Further study revealed that dipyridamole decreased the expression of ENT2 and inhibited the activation of ERK1/2 and NF-κB signaling pathways, which ultimately converted DAM to anti-inflammatory phenotype and suppressed the levels of TNF-α, IL-1ß, IL-6 in WMLs. However, Adora2a inhibitor (SCH58261) attenuated above effects. Our study demonstrates that dipyridamole facilitates the conversion of DAM to the anti-inflammatory phenotype through ENT2/Adora2a pathway and inhibits the activation of ERK1/2 and NF-κB signaling pathways, thereby alleviating neuroinflammation in WMLs. The current findings establish the basis for using dipyridamole to treat VaD.


Assuntos
Isquemia Encefálica , Doenças do Sistema Nervoso , Substância Branca , Ratos , Animais , Microglia/metabolismo , NF-kappa B/metabolismo , Substância Branca/metabolismo , Dipiridamol/farmacologia , Dipiridamol/uso terapêutico , Dipiridamol/metabolismo , Isquemia Encefálica/metabolismo , Doenças do Sistema Nervoso/metabolismo , Anti-Inflamatórios/farmacologia , Modelos Animais de Doenças
6.
Colloids Surf B Biointerfaces ; 234: 113725, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38157764

RESUMO

The recent "cell-based theory" of coagulation suggests that platelets serve as the site of coagulation factor reactions, making platelets an effective target for inhibiting membrane thrombosis. Unfortunately, there is limited research on how blood purification membranes affect platelet intracellular signaling. In this study, we modified polyethersulfone (PES) membranes with the platelet phosphodiesterase (PDE) inhibitor dipyridamole (DIP) and investigated the effects of the DIP/PES (DP) membranes on platelet adhesion, activation, aggregation, and secretion, as well as the role of the PDE-cyclic adenosine monophosphate (cAMP) intracellular signaling pathway. Additionally, we evaluated the hemocompatibility and preliminary in vivo safety of DP membranes. Our results demonstrate that the modified DP membranes effectively inhibited platelet adhesion, membrane CD62P expression, and plasma soluble P-selectin activation levels. Furthermore, we confirmed that DP membranes achieved platelet aggregation inhibition and reduced platelet factor 4 and ß-thromoglobulin secretion levels by inhibiting platelet intracellular PDE-cAMP signaling. Moreover, the modified DP membranes exhibited good anticoagulant and red blood cell membrane stability and complement resistance and demonstrated preliminary biocompatibility in mouse experiments. Collectively, these findings highlight the potential application of DP dialysis membranes in blood purification for critically ill patients.


Assuntos
Inibidores de Fosfodiesterase , Diálise Renal , Humanos , Camundongos , Animais , Inibidores de Fosfodiesterase/farmacologia , Inibidores de Fosfodiesterase/metabolismo , Inibidores da Agregação Plaquetária/farmacologia , Dipiridamol/metabolismo , Dipiridamol/farmacologia , Plaquetas , Agregação Plaquetária
7.
Pol J Vet Sci ; 26(4): 549-557, 2023 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-38088299

RESUMO

Cyclosporine is an immunosuppressive drug that is used to prevent tissue rejection in organ transplants and to treat autoimmune diseases such as psoriasis and rheumatoid arthritis. It has important toxic effects in many organs such as the liver and kidney. The aim of this study was to determine and compare the effectiveness of the single and combined treatment of dipyridamole, which is a vasodilator and has an antioxidant effect, ketotifen which is toll-like receptor-4 inhibitory and has an antioxidant effect, quercetin which is an antioxidant and has an anti-inflammatory effect in cyclosporine-induced hepatorenal toxicity. Forty-eight Wistar Albino rats were divided into 7 groups. The research period was 21 days. The cyclosporine increased serum ALT and AST levels, in contrast to their increased levels prevented by all the treatments. The serum creatinine level decreased significantly with ketotifen and combined treatment, while cyclosporine partially increased serum creatinine and urea levels. The urine microalbumin and protein levels were increased significantly by cyclosporine, whereas they decreased with dipyridamole treatment. The protein levels decreased by quercetin and combined treatments. The kidney injury molecule- 1 and retinol-binding protein levels were increased by the cyclosporine, while ketotifen treatment partially decreased them. In conclusion, ketotifen and dipyridamole can prevent cyclosporine- induced hepatorenal toxicity and quercetin can increase the effectiveness of this treatment.


Assuntos
Antioxidantes , Quercetina , Ratos , Animais , Quercetina/farmacologia , Quercetina/uso terapêutico , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Ciclosporina/toxicidade , Cetotifeno/farmacologia , Cetotifeno/uso terapêutico , Dipiridamol/farmacologia , Dipiridamol/uso terapêutico , Creatinina , Rim , Ratos Wistar , Fígado , Estresse Oxidativo
8.
J Nanobiotechnology ; 21(1): 260, 2023 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-37553670

RESUMO

Thrombotic vascular disorders, specifically thromboembolisms, have a significant detrimental effect on public health. Despite the numerous thrombolytic and antithrombotic drugs available, their efficacy in penetrating thrombus formations is limited, and they carry a high risk of promoting bleeding. Consequently, the current medication dosage protocols are inadequate for preventing thrombus formation, and higher doses are necessary to achieve sufficient prevention. By integrating phototherapy with antithrombotic therapy, this study addresses difficulties related to thrombus-targeted drug delivery. We developed self-assembling nanoparticles (NPs) through the optimization of a co-assembly engineering process. These NPs, called DIP-FU-PPy NPs, consist of polypyrrole (PPy), dipyridamole (DIP), and P-selectin-targeted fucoidan (FU) and are designed to be delivered directly to thrombi. DIP-FU-PPy NPs are proposed to offer various potentials, encompassing drug-loading capability, targeted accumulation in thrombus sites, near-infrared (NIR) photothermal-enhanced thrombus management with therapeutic efficacy, and prevention of rethrombosis. As predicted, DIP-FU-PPy NPs prevented thrombus recurrence and emitted visible fluorescence signals during thrombus clot penetration with no adverse effects. Our co-delivery nano-platform is a simple and versatile solution for NIR-phototherapeutic multimodal thrombus control.


Assuntos
Nanopartículas , Trombose , Dipiridamol/farmacologia , Nanopartículas/uso terapêutico , Selectina-P , Fototerapia/métodos , Polímeros , Pirróis , Trombose/tratamento farmacológico , Animais
9.
Sci Rep ; 13(1): 11717, 2023 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-37474599

RESUMO

Intensive antiplatelet therapy did not reduce recurrent stroke/transient ischaemic attack (TIA) events as compared with guideline treatment in the Triple Antiplatelets for Reducing Dependency after Ischaemic Stroke (TARDIS) trial, but did increase the frequency and severity of bleeding. In this pre-specified analysis, we investigated predictors of bleeding and the association of bleeding with outcome. TARDIS was an international prospective randomised open-label blinded-endpoint trial in participants with ischaemic stroke or TIA within 48 h of onset. Participants were randomised to 30 days of intensive antiplatelet therapy (aspirin, clopidogrel, dipyridamole) or guideline-based therapy (either clopidogrel alone or combined aspirin and dipyridamole). Bleeding was defined using the International Society on Thrombosis and Haemostasis five-level ordered categorical scale: fatal, major, moderate, minor, none. Of 3,096 participants, bleeding severity was: fatal 0.4%, major 1.5%, moderate 1.2%, minor 11.4%, none 85.5%. Major/fatal bleeding was increased with intensive as compared with guideline therapy: 39 vs. 17 participants, adjusted hazard ratio 2.21, 95% CI 1.24-3.93, p = 0.007. Bleeding events diverged between treatment groups in the 8-35 day period but not in the 0-7 or 36-90 day epochs. In multivariate analysis more, and more severe, bleeding events were seen with increasing age, female sex, pre-morbid dependency, increased time to randomisation, prior major bleed, prior antiplatelet therapy and in those randomised to triple vs guideline antiplatelet therapy. More severe bleeding was associated with worse clinical outcomes across multiple physical, emotional and quality of life domains.Trial registration ISRCTN47823388 .


Assuntos
Isquemia Encefálica , Ataque Isquêmico Transitório , AVC Isquêmico , Acidente Vascular Cerebral , Feminino , Humanos , Inibidores da Agregação Plaquetária/efeitos adversos , Isquemia Encefálica/tratamento farmacológico , Ataque Isquêmico Transitório/tratamento farmacológico , Clopidogrel/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Estudos Prospectivos , Qualidade de Vida , Aspirina/efeitos adversos , Hemorragia/tratamento farmacológico , Dipiridamol/uso terapêutico , Quimioterapia Combinada , AVC Isquêmico/tratamento farmacológico , Doença Aguda
10.
Eur J Pharm Biopharm ; 189: 48-55, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37301301

RESUMO

The prediction of oral absorption from a supersaturating drug delivery system (SDDS) remains a significant challenge. Here we evaluated the effects of the degree and duration of supersaturation on in vivoabsorption for dipyridamole and ketoconazole. Various dose concentrations of supersaturated suspensions were prepared by a pH shift method, and in vitro dissolution and in vivo absorption profiles were determined. For dipyridamole, the duration of supersaturation decreased with the increase of the dose concentration owing to rapid precipitation. For ketoconazole, the initially constant dissolved concentrations due probably to the liquid-liquid phase separation (LLPS) as a reservoir were observed at high dose concentrations. However, the LLPS did not delay the peak plasma concentration of ketoconazole in rats, indicating that drug molecules were immediately released from the oil phase to the bulk aqueous phase. For both model drugs, the degree of supersaturation, but not the duration of supersaturation, correlated with systemic exposure, indicating quick drug absorption before precipitation. Therefore, the degree of supersaturation is an important parameter compared with the duration of supersaturation for enhancing the in vivo absorption of highly permeable drugs. These findings would help develop a promising SDDS.


Assuntos
Dipiridamol , Cetoconazol , Ratos , Animais , Cetoconazol/química , Preparações Farmacêuticas , Solubilidade
11.
Int J Cardiol ; 387: 131107, 2023 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-37271285

RESUMO

The three major techniques for clinically diagnosing coronary heart disease, including angina associated with myocardial ischemia, are coronary angiography, myocardial perfusion imaging, and drug stress echocardiography. Compared to the first two methods, which are invasive or involve the use of radionuclides, drug stress echocardiography is increasingly used in clinical practice due to its non-invasive, low-risk, and controllable nature, and wide applicability. We developed a novel methodology to demonstrate knowledge graph-based efficacy analysis of drug stress echocardiography as a complement to traditional meta-analysis. By measuring coronary flow reserve (CFR), we discovered that regional ventricular wall abnormalities (RVWA) and drug-loaded cardiac ultrasound can be used to detect coronary artery disease. Additionally, drug-loaded cardiac ultrasound can be used to identify areas of cardiac ischemia, stratify risks, and determine prognosis. Furthermore, adenosine stress echocardiography(ASE) can determine atypical symptoms of coronary heart disease with associated cardiac events through CFR and related quantitative indices for risk stratification. Using a knowledge graph-based approach, we investigated the positive and negative effects of three drugs - Dipyridamole, Dobutamine, and Adenosine - for coronary artery disease analysis. Our findings show that Adenosine has the highest positive effect and the lowest negative effect among the three drugs. Due to its minimal and controlled side effects, and high sensitivity for diagnosing coronary microcirculation disorders and multiple lesions, adenosine is frequently used in clinical practice.


Assuntos
Doença da Artéria Coronariana , Isquemia Miocárdica , Humanos , Doença da Artéria Coronariana/diagnóstico por imagem , Ecocardiografia sob Estresse/métodos , Prognóstico , Reconhecimento Automatizado de Padrão , Isquemia Miocárdica/diagnóstico por imagem , Adenosina , Dipiridamol , Dobutamina , Medição de Risco
12.
Biomolecules ; 13(5)2023 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-37238718

RESUMO

Stress-induced myocardial perfusion defects found in dipyridamole-thallium-201 single-photon emission computed tomography imaging may indicate vascular perfusion abnormalities and risk of obstructive or nonobstructive coronary heart disease. Besides nuclear imaging and subsequent coronary angiography (CAG), no blood test can indicate whether dysregulated homeostasis is associated with stress-induced myocardial perfusion defects. This study investigated the expression signature of long noncoding RNAs (lncRNAs) and genes involved in vascular inflammation and stress response in the blood of patients with stress-induced myocardial perfusion abnormalities (n = 27). The results revealed an expression signature consisting of the upregulation of RMRP (p < 0.01) and downregulations of THRIL (p < 0.01) and HIF1A (p < 0.01) among patients with a positive thallium stress test and no significant coronary artery stenosis within 6 months after baseline treatment. We developed a scoring system based on the expression signatures of RMRP, MIAT, NTT, MALAT1, HSPA1A, and NLRP3 to predict the need for further CAG among patients with moderate-to-significant stress-induced myocardial perfusion defects (area under the receiver operating characteristic curve = 0.963). Therefore, we identified a dysregulated expression profile of lncRNA-based genes in the blood that could be valuable for the early detection of vascular homeostasis imbalance and personalized therapy.


Assuntos
Doença das Coronárias , RNA Longo não Codificante , Humanos , RNA Longo não Codificante/genética , Dipiridamol , Angiografia Coronária , Tomografia Computadorizada de Emissão de Fóton Único/métodos
13.
J Nucl Cardiol ; 30(6): 2477-2489, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37258955

RESUMO

BACKGROUND: 82Rb PET is commonly performed using the same injected activity in all patients, resulting in lower image quality in larger patients. This study compared 82Rb dosing with exponential vs proportional functions of body weight on the standardization of myocardial perfusion image (MPI) quality. METHODS: Two sequential cohorts of N = 60 patients were matched by patient weight. Rest and dipyridamole stress 82Rb PET was performed using 0.1 MBq·kg-2 exponential and 9 MBq·kg-1 proportional dosing. MPI scans were compared qualitatively with visual image quality scoring (IQS) and quantitatively using the myocardium-to-blood contrast-to-noise ratio (CNR) and blood background signal-to-noise ratio (SNR) as a function of body weight. RESULTS: Average (min-max) patient body weight was 81 ± 18 kg (46-137 kg). Proportional dosing resulted in decreasing CNR, SNR, and visual IQS with increasing body weight (P < 0.05). Exponential dosing eliminated the weight-dependent decreases in these image quality metrics that were observed in the proportional dosing group. CONCLUSION: 82Rb PET dosing as an exponential (squared) function of body weight produced consistent stress perfusion image quality over a wide range of patient weights. Dramatically lower doses can be used in lighter patients, with the equivalent population dose shifted toward the heavier patients to standardize diagnostic image quality.


Assuntos
Doença da Artéria Coronariana , Imagem de Perfusão do Miocárdio , Humanos , Tomografia por Emissão de Pósitrons/métodos , Tomografia Computadorizada por Raios X , Dipiridamol , Radioisótopos de Rubídio , Peso Corporal , Imagem de Perfusão do Miocárdio/métodos , Doença da Artéria Coronariana/diagnóstico por imagem
14.
AAPS J ; 25(3): 45, 2023 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-37085637

RESUMO

Assessing in vivo performance to inform formulation selection and development decisions is an important aspect of drug development. Biopredictive dissolution methodologies for oral dosage forms have been developed to understand in vivo performance, assist in formulation development/optimization, and forecast the outcome of bioequivalence studies by combining them with simulation tools to predict plasma profiles in humans. However, unlike compendial dissolution methodologies, the various biopredictive methodologies have not yet been harmonized or standardized. This manuscript presents the initial phases of an effort to develop best practices and move toward standardization of the biopredictive methodologies through the Product Quality Research Institute (PQRI, https://pqri.org ) entitled "The standardization of in vitro predictive dissolution methodologies and in silico bioequivalence study Working Group." This Working Group (WG) is comprised of participants from 10 pharmaceutical companies and academic institutes. The project will be accomplished in a total of five phases including assessing the performance of dissolution protocols designed by the individual WG members, and then building "best practice" protocols based on the initial dissolution profiles. After refining the "best practice" protocols to produce equivalent dissolution profiles, those will be combined with physiologically based biopharmaceutics models (PBBM) to predict plasma profiles. In this manuscript, the first two of the five phases are reported, namely generating biopredictive dissolution profiles for ibuprofen and dipyridamole and using those dissolution profiles with PBBM to match the clinical plasma profiles. Key experimental parameters are identified, and this knowledge will be applied to build the "best practice" protocol in the next phase.


Assuntos
Dipiridamol , Ibuprofeno , Humanos , Solubilidade , Comprimidos , Academias e Institutos , Modelos Biológicos , Administração Oral
15.
Cell Oncol (Dordr) ; 46(4): 953-967, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36939950

RESUMO

PURPOSE: Available evidence indicates that dipyridamole enhances the anti-thrombotic effects of aspirin for the prevention of secondary strokes. Aspirin is a well-known non-steroid anti-inflammatory drug. This anti-inflammatory property has turned aspirin into a potential drug for inflammation-related cancers such as colorectal cancer (CRC). Here, we aimed to explore whether the anti-cancer effect of aspirin against CRC could be improved by combined administration with dipyridamole. METHODS: Population-based clinical data analysis was conducted to assess a possible therapeutic effect of combined dipyridamole and aspirin treatment in inhibiting CRC compared with either monotherapy. This therapeutic effect was further verified in different CRC mouse models, i.e. an orthotopic xenograft mouse model, an AOM/DSS mouse model, an Apcmin/+ mouse model and a patient derived xenograft (PDX) mouse model. The in vitro effects of the drugs on CRC cells were tested using CCK8 and flow cytometry assays. RNA-Seq, Western blotting, qRT-PCR and flow cytometry were used to identify the underlying molecular mechanisms. RESULTS: We found that dipyridamole combined with aspirin had a better inhibitory effect on CRC than either monotherapy alone. The enhanced anti-cancer effect of the combined use of dipyridamole with aspirin was found to rely on the induction of an overwhelmed endoplasmic reticulum (ER) stress and subsequent pro-apoptotic unfolded protein response (UPR), which was different from the anti-platelet effect. CONCLUSIONS: Our data indicate that the anti-cancer effect of aspirin against CRC may be enhanced by combined administration with dipyridamole. In case further clinical studies confirm our findings, these may be repurposed as adjuvant agents.


Assuntos
Aspirina , Neoplasias Colorretais , Humanos , Animais , Camundongos , Aspirina/farmacologia , Aspirina/uso terapêutico , Dipiridamol/farmacologia , Dipiridamol/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Anti-Inflamatórios/uso terapêutico , Resposta a Proteínas não Dobradas , Apoptose
16.
Neurochem Res ; 48(6): 1889-1899, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36729312

RESUMO

Epilepsy is characterized by the manifestation of spontaneous and recurrent seizures. The high prevalence of comorbidities associated with epilepsy, such as cognitive dysfunction, affects the patients quality of life. Adenosine signaling modulation might be an effective alternative to control seizures and epilepsy-associated comorbidities. This study aimed to verify the role of adenosine modulation on the seizure development and cognitive impairment induced by pentylenetetrazole (PTZ) in zebrafish. At first, animals were submitted to a training session in the inhibitory avoidance test and, after 10 min, they received an intraperitoneal injection of valproate, adenosine A1 receptor agonist cyclopentyladenosine (CPA), adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), adenosine A2A receptor antagonist ZM 241385, adenosine deaminase inhibitor erythro-9-(2-hydroxy-3-nony1)-adenine hydrochloride (EHNA) or the nucleoside transporter inhibitor dipyridamole. Thirty min after the intraperitoneal injection, the animals were exposed to 7.5 mM PTZ for 10 min, where they were evaluated for latency to reach the seizure stages (I, II, and III). Finally, 24 h after the training session, the animals were submitted to the inhibitory avoidance test to verify their cognitive performance during the test session. Valproate, CPA, and EHNA showed antiseizure effects and prevented the memory impairment induced by PTZ exposure. DPCPX, ZM 241385, and dipyridamole pretreatments caused no changes in seizure development; however, these drugs prevented memory impairment without altering locomotion. Our results reinforce the antiseizure effects of adenosine signaling and support the idea that the involvement of adenosine in memory processes may be a target for preventive strategies against cognitive impairment associated with epilepsy.


Assuntos
Epilepsia , Pentilenotetrazol , Animais , Pentilenotetrazol/toxicidade , Adenosina/farmacologia , Peixe-Zebra , Ácido Valproico/efeitos adversos , Qualidade de Vida , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Convulsões/prevenção & controle , Dipiridamol/efeitos adversos
17.
Plast Reconstr Surg ; 152(2): 270e-280e, 2023 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-36723712

RESUMO

BACKGROUND: Three-dimensional printed bioceramic scaffolds composed of 100% ß-tricalcium phosphate augmented with dipyridamole (3DPBC-DIPY) can regenerate bone across critically sized defects in skeletally mature and immature animal models. Before human application, safe and effective bone formation should be demonstrated in a large translational animal model. This study evaluated the ability of 3DPBC-DIPY scaffolds to restore critically sized calvarial defects in a skeletally immature, growing minipig. METHODS: Unilateral calvarial defects (~1.4 cm) were created in 6-week-old Göttingen minipigs ( n = 12). Four defects were filled with a 1000 µm 3DPBC-DIPY scaffold with a cap (a solid barrier on the ectocortical side of the scaffold to prevent soft-tissue infiltration), four defects were filled with a 1000 µm 3DPBC-DIPY scaffold without a cap, and four defects served as negative controls (no scaffold). Animals were euthanized 12 weeks postoperatively. Calvariae were subjected to micro-computed tomography, 3D reconstruction with volumetric analysis, qualitative histologic analysis, and nanoindentation. RESULTS: Scaffold-induced bone growth was statistically greater than in negative controls ( P ≤ 0.001), and the scaffolds with caps produced significantly more bone generation compared with the scaffolds without caps ( P ≤ 0.001). Histologic analysis revealed woven and lamellar bone with haversian canals throughout the regenerated bone. Cranial sutures were observed to be patent, and there was no evidence of ectopic bone formation or excess inflammatory response. Reduced elastic modulus and hardness of scaffold-regenerated bone were found to be statistically equivalent to native bone ( P = 0.148 for reduced elastic modulus of scaffolds with and without caps and P = 0.228 and P = 0.902 for hardness of scaffolds with and without caps, respectively). CONCLUSION: 3DPBC-DIPY scaffolds have the capacity to regenerate bone across critically sized calvarial defects in a skeletally immature translational pig model. CLINICAL RELEVANCE STATEMENT: This study assessed the bone generative capacity of 3D-printed bioceramic scaffolds composed of 100% ß-tricalcium phosphate and augmented with dipyridamole placed within critical-sized calvarial defects in a growing porcine model.


Assuntos
Regeneração Óssea , Tecidos Suporte , Animais , Suínos , Humanos , Microtomografia por Raio-X , Porco Miniatura , Crânio/cirurgia , Dipiridamol/farmacologia , Impressão Tridimensional , Osteogênese
18.
Purinergic Signal ; 19(3): 551-564, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-36781825

RESUMO

Some non-adenosinergic drugs are reported to also act through adenosine receptors (ARs). We used mouse hypothermia, which can be induced by agonism at any of the four ARs, as an in vivo screen for adenosinergic effects. An AR contribution was identified when a drug caused hypothermia in wild type mice that was diminished in mice lacking all four ARs (quadruple knockout, QKO). Alternatively, an adenosinergic effect was identified if a drug potentiated adenosine-induced hypothermia. Four drugs (dipyridamole, nimodipine, cilostazol, cyclosporin A) increased the hypothermia caused by adenosine. Dipyridamole and nimodipine probably achieved this by inhibition of adenosine clearance via ENT1. Two drugs (cannabidiol, canrenoate) did not cause hypothermia in wild type mice. Four other drugs (nifedipine, ranolazine, ketamine, ethanol) caused hypothermia, but the hypothermia was unchanged in QKO mice indicating non-adenosinergic mechanisms. Zinc chloride caused hypothermia and hypoactivity; the hypoactivity was blunted in the QKO mice. Interestingly, the antidepressant amitriptyline caused hypothermia in wild type mice that was amplified in the QKO mice. Thus, we have identified adenosine-related effects for some drugs, while other candidates do not affect adenosine signaling by this in vivo assay. The adenosine-modulating drugs could be considered for repurposing based on predicted effects on AR activation.


Assuntos
Adenosina , Hipotermia , Camundongos , Animais , Adenosina/farmacologia , Hipotermia/induzido quimicamente , Nimodipina/efeitos adversos , Receptores Purinérgicos P1 , Dipiridamol/efeitos adversos
19.
JACC Cardiovasc Imaging ; 16(1): 78-94, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36599572

RESUMO

BACKGROUND: Subendocardial ischemia is commonly diagnosed but not quantified by imaging. OBJECTIVES: This study sought to define size and severity of subendocardial and transmural stress perfusion deficits, clinical associations, and outcomes. METHODS: Regional rest-stress perfusion in mL/min/g, coronary flow reserve, coronary flow capacity (CFC), relative stress flow, subendocardial stress-to-rest ratio and stress subendocardial-to-subepicardial ratio as percentage of left ventricle were measured by positron emission tomography (PET) with rubidium Rb 82 and dipyridamole stress in serial 6,331 diagnostic PETs with prospective 10-year follow-up for major adverse cardiac events with and without revascularization. RESULTS: Of 6,331 diagnostic PETs, 1,316 (20.7%) had severely reduced CFC with 41.4% having angina or ST-segment depression (STΔ) >1 mm during hyperemic stress, increasing with size. For 5,015 PETs with no severe CFC abnormality, 402 (8%) had angina or STΔ during stress, and 82% had abnormal subendocardial perfusion with 8.7% having angina or STΔ >1 mm during dipyridamole stress. Of 947 cases with stress-induced angina or STΔ >1 mm, 945 (99.8%) had reduced transmural or subendocardial perfusion reflecting sufficient microvascular function to increase coronary blood flow and reduce intracoronary pressure, causing reduced subendocardial perfusion; only 2 (0.2%) had normal subendocardial perfusion, suggesting microvascular disease as the cause of the angina. Over 10-year follow-up (mean 5 years), severely reduced CFC associated with major adverse cardiac events of 44.4% compared to 8.8% for no severe CFC (unadjusted P < 0.00001) and mortality of 15.2% without and 6.9% with revascularization (P < 0.00002) confirmed by multivariable Cox regression modeling. For no severe CFC, mortality was 3% with and without revascularization (P = 0.90). CONCLUSIONS: Reduced subendocardial perfusion on dipyridamole PET without regional stress perfusion defects is common without angina, has low risk of major adverse cardiac events, reflecting asymptomatic nonobstructive diffuse coronary artery disease, or angina without stenosis. Severely reduced CFC causes angina in fewer than one-half of cases but incurs high mortality risk that is significantly reduced after revascularization.


Assuntos
Doença da Artéria Coronariana , Isquemia Miocárdica , Imagem de Perfusão do Miocárdio , Humanos , Prevalência , Estudos Prospectivos , Circulação Coronária , Tomografia Computadorizada por Raios X , Valor Preditivo dos Testes , Isquemia Miocárdica/diagnóstico por imagem , Isquemia Miocárdica/epidemiologia , Isquemia Miocárdica/complicações , Angina Pectoris , Dipiridamol , Imagem de Perfusão do Miocárdio/métodos
20.
Eur J Pharm Biopharm ; 184: 139-149, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36709922

RESUMO

Coamorphization has been proven to be an effective approach to improve bioavailability of poorly soluble active pharmaceutical ingredients (APIs) by virtue of solubilization, and also contributes to overcome limitation of physical stability associated with amorphous drug alone. In current work, a co-amorphous formulation of dipyridamole (DPM), a poor solubility drug, with p-hydroxybenzoic acid (HBA) was prepared and investigated. At a molar ratio of 1:2, DPM and HBA were melted result in the formation of a binary co-amorphous system. The DPM-HBA co-amorphous was structurally characterized by powder X-ray diffraction (PXRD), temperature modulated differential scanning calorimetry (mDSC), high performance liquid chromatography (HPLC) and solution state 1H nuclear magnetic resonance (1H NMR). The molecular mechanisms in the co-amorphous were further analysed via Fourier-transform infrared (FTIR) and Raman spectroscopies, as well as density functional theory (DFT) calculation. All the results consistently revealed the presence of hydrogen bonding interactions between -OH of DPM and -COOH on HBA. Accelerated test and glass transition kinetics showed excellent physical stability of DPM-HBA co-amorphous compared with amorphous DPM along with glass transition temperatures (Tg). The phase-solubility study indicated that complexation occurred between DPM and HBA in solution, which contributed to the solubility and dissolution enhancement of DPM in co-amorphous system. Pharmacokinetic study of co-amorphous DPM-HBA in mouse plasma revealed that the DPM exhibited 1.78-fold and 2.64-fold improvement in AUC0­∞ value compared with crystalline and amorphous DPM, respectively. This current study revealed coamorphization is an effective approach for DPM to improve the solubility and biopharmaceutical performance.


Assuntos
Dipiridamol , Camundongos , Animais , Solubilidade , Temperatura de Transição , Difração de Raios X , Varredura Diferencial de Calorimetria , Estabilidade de Medicamentos , Espectroscopia de Infravermelho com Transformada de Fourier
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...