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1.
J Affect Disord ; 313: 43-48, 2022 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-35753501

RESUMO

BACKGROUND: Improved treatments for bipolar disorder (BD) are needed. Drug repurposing aims to find novel targets for drugs that have been used for other indications. This study investigated the risk of psychiatric hospitalization associated with use of calcium-channel blockers (CCBs; dihydropyridines, diltiazem, verapamil) and adenosine modulators (allopurinol, dipyridamole) in BD in within-individual design. METHODS: Individuals diagnosed with BD (ICD-10: F30-F31) were identified from the inpatient, specialized outpatient, sickness absence, and disability pension registers during 1996-2018 in Finland (N = 60,045). The main outcome was hospitalization due to affective symptoms (ICD-10: F30-F39). Within-individual models in stratified Cox regression were used and adjusted hazard ratios (aHR) with 95 % confidence intervals (CIs) reported. RESULTS: Use of CCBs was associated with a decreased risk of hospitalization due to affective symptoms (aHR 0.83, 95 % CI 0.78-0.88) when all CCBs were analyzed together. Of specific CCBs, use of diltiazem (0.71, 0.55-0.91) and dihydropyridines (0.83, 0.78-0.89) were associated with a decreased risk but verapamil was not (0.93, 0.73-1.19). Use of adenosine modulators in general was associated with a decreased risk of hospitalizations due to affective symptoms (0.87, 0.79-0.96). Both allopurinol (0.85, 0.74-0.97) and dipyridamole (0.89, 0.78-1.00) were associated with a marginally decreased risk. Thiazide diuretic use as a negative control was not associated with the risk of hospitalization due to affective symptoms (0.97, 0.83-1.13). LIMITATIONS: Due to the observational nature of this study, causation cannot be confirmed. CONCLUSIONS: Dihydropyridines and diltiazem were associated with a decreased risk of psychiatric hospitalization in bipolar disorder. Results for allopurinol and dipyridamole were inconclusive.


Assuntos
Transtorno Bipolar , Di-Hidropiridinas , Adenosina/uso terapêutico , Alopurinol/efeitos adversos , Transtorno Bipolar/tratamento farmacológico , Bloqueadores dos Canais de Cálcio/efeitos adversos , Estudos de Coortes , Di-Hidropiridinas/uso terapêutico , Diltiazem/uso terapêutico , Dipiridamol/efeitos adversos , Humanos
2.
AAPS PharmSciTech ; 23(6): 173, 2022 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-35739362

RESUMO

Poor aqueous solubility is a common characteristic of new drug candidates, which leads to low or inconsistent oral bioavailability. This has sparked an interest in material efficient testing of solubility and dissolution rate. The aim was to develop a microgram scale video-microscopic method to screen the dissolution rates of poorly water-soluble drugs. This method was applied to six drugs (carvedilol, diazepam, dipyridamole, felodipine, fenofibrate, and indomethacin) in fasted state simulated intestinal fluid (FaSSIF), of indomethacin in buffer with varying pH, and of diazepam and dipyridamole in customized media. An additional aim was to track phase transformations for carbamazepine in FaSSIF. The dissolution rates and particle behavior of the drugs were investigated by tracking particle surface area over time using optical video-microscopy. Applying miniaturized UV spectroscopic dissolution resulted in a similar grouping of dissolution rates and pH effects, as for the video-microscopic setup. Using customized media showed that lysophospholipid enhanced the dissolution rate of diazepam and dipyridamole. The video-microscopic setup allowed for the nucleation of transparent particles on dissolving carbamazepine particles to be tracked over time. The developed setup offers a material efficient screening approach to group drugs according to dissolution rate, where the use of optical microscopy helps to achieve a high sample throughput.


Assuntos
Indometacina , Água , Carbamazepina , Diazepam , Dipiridamol , Solubilidade , Água/química
3.
Molecules ; 27(11)2022 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-35684390

RESUMO

Dipyridamole, apart from its well-known antiplatelet and phosphodiesterase inhibitory activities, is a promising old drug for the treatment of pulmonary fibrosis. However, dipyridamole shows poor pharmacokinetic properties with a half-life (T1/2) of 7 min in rat liver microsomes (RLM). To improve the metabolic stability of dipyridamole, a series of pyrimidopyrimidine derivatives have been designed with the assistance of molecular docking. Among all the twenty-four synthesized compounds, compound (S)-4h showed outstanding metabolic stability (T1/2 = 67 min) in RLM, with an IC50 of 332 nM against PDE5. Furthermore, some interesting structure-activity relationships (SAR) were explained with the assistance of molecular docking.


Assuntos
Dipiridamol , Fibrose Pulmonar Idiopática , Animais , Dipiridamol/farmacologia , Dipiridamol/uso terapêutico , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/metabolismo , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Ratos , Relação Estrutura-Atividade
4.
Int J Mol Sci ; 23(7)2022 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-35408815

RESUMO

Niemann Pick type C disease (NPC) is a rare disorder characterized by lysosomal lipid accumulation that damages peripheral organs and the central nervous system. Currently, only miglustat is authorized for NPC treatment in Europe, and thus the identification of new therapies is necessary. The hypothesis addressed in this study is that increasing adenosine levels may represent a new therapeutic approach for NPC. In fact, a reduced level of adenosine has been shown in the brain of animal models of NPC; moreover, the compound T1-11, which is able to weakly stimulate A2A receptor and to increase adenosine levels by blocking the equilibrative nucleoside transporter ENT1, significantly ameliorated the pathological phenotype and extended the survival in a mouse model of the disease. To test our hypothesis, fibroblasts from NPC1 patients were treated with dipyridamole, a clinically-approved drug with inhibitory activity towards ENT1. Dipyridamole significantly reduced cholesterol accumulation in fibroblasts and rescued mitochondrial deficits; the mechanism elicited by dipyridamole relies on activation of the adenosine A2AR subtype subsequent to the increased levels of extracellular adenosine due to the inhibition of ENT1. In conclusion, our results provide the proof of concept that targeting adenosine tone could be beneficial in NPC.


Assuntos
Doença de Niemann-Pick Tipo C , Adenosina/farmacologia , Animais , Dipiridamol/farmacologia , Dipiridamol/uso terapêutico , Reposicionamento de Medicamentos , Humanos , Camundongos , Doença de Niemann-Pick Tipo C/patologia , Estudo de Prova de Conceito
5.
Int J Mol Sci ; 23(2)2022 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-35054765

RESUMO

Elevation of intracellular cAMP levels has been implicated in glioma cell proliferation inhibition, differentiation, and apoptosis. Inhibition of phosphodiesterase is a way to elevate intracellular cAMP levels. The present study aimed to investigate the anti-glioma potential of dipyridamole, an inhibitor of phosphodiesterase. Upon treatment with dipyridamole, human U87 glioma cells decreased cell viability, clonogenic colonization, migration, and invasion, along with Noxa upregulation, Endoplasmic Reticulum (ER) stress, impaired autophagic flux, Yes-associated Protein 1 (YAP1) phosphorylation, and YAP1 reduction. Pharmacological and genetic studies revealed the ability of dipyridamole to initiate Noxa-guided apoptosis through ER stress. Additionally, the current study further identified the biochemical role of YAP1 in communicating with ER stress and autophagy under situations of dipyridamole treatment. YAP1 promoted autophagy and protected glioma cells from dipyridamole-induced apoptotic cell death. Dipyridamole impaired autophagic flux and rendered glioma cells more vulnerable to apoptotic cell death through ER stress-inhibitable YAP1/autophagy axis. The overall cellular changes caused by dipyridamole appeared to ensure a successful completion of apoptosis. Dipyridamole also duplicated the biochemical changes and apoptosis in glioma T98G cells. Since dipyridamole has additional biochemical and pharmacological properties, further research centered on the anti-glioma mechanisms of dipyridamole is still needed.


Assuntos
Apoptose , Autofagia , Dipiridamol/farmacologia , Estresse do Retículo Endoplasmático , Glioblastoma/tratamento farmacológico , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/fisiopatologia , Humanos , Inibidores de Fosfodiesterase/farmacologia , Fosforilação , Processamento de Proteína Pós-Traducional , Proteínas Proto-Oncogênicas c-bcl-2/genética , /metabolismo
6.
Cerebrovasc Dis ; 51(4): 493-498, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35034023

RESUMO

PURPOSE: The aim of this study is to investigate the effect of gradual dipyridamole titration and the incidence of dipyridamole-induced headache in patients with ischemic stroke or transient ischemic attack (TIA). METHODS: A randomized, double-blind, double-placebo, parallel group, phase 4 clinical trial (KCT0005457) was conducted between July 1, 2019, and February 25, 2020, at 15 medical centers in South Korea. The study included patients aged >19 years diagnosed with a noncardioembolic ischemic stroke or TIA within the previous 3 weeks. The participants were randomized 1:1:1 to receive Adinox® (aspirin 25 mg/dipyridamole 200 mg) and aspirin (100 mg) once daily for the first 2 weeks followed by Adinox® twice daily for 2 weeks (titration group), Adinox® twice daily for 4 weeks (standard group), and aspirin 100 mg once daily for 4 weeks (control group). The primary endpoint was incidence of headache over 4 weeks. The key secondary endpoint was mean cumulative headache. RESULTS: Ninety-six patients were randomized into the titration (n = 31), standard (n = 32), and control (n = 33) groups. The titration and standard groups (74.1% vs. 74.2%, respectively) showed no difference in the primary endpoint. However, the mean cumulated headache was significantly lower in the titration group than in the standard group (0.31 ± 0.46 vs. 0.58 ± 0.51, p = 0.023). Further, adverse drug reactions were more common in the standard group than in the titration group (28.1% vs. 9.7%, respectively, p = 0.054), although not significantly different. CONCLUSION: The titration strategy was effective in lowering the incidence of cumulative dipyridamole-induced headache.


Assuntos
Ataque Isquêmico Transitório , AVC Isquêmico , Acidente Vascular Cerebral , Aspirina/efeitos adversos , Dipiridamol/efeitos adversos , Método Duplo-Cego , Quimioterapia Combinada , Cefaleia/induzido quimicamente , Cefaleia/diagnóstico , Cefaleia/tratamento farmacológico , Humanos , Ataque Isquêmico Transitório/diagnóstico , Ataque Isquêmico Transitório/tratamento farmacológico , Inibidores da Agregação Plaquetária , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/tratamento farmacológico
7.
Br J Haematol ; 196(3): 690-699, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34553368

RESUMO

The anti-cancer potential of dipyridamole has been suggested from experiments, but evidence from population-based studies is still lacking. We aimed to explore if dipyridamole use was related to a lower risk of lymphoid neoplasms. We identified individuals with prescription of aspirin after diagnosis of ischaemic cerebrovascular disease since 2006 by linking several Swedish registers. In these aspirin users, those with dipyridamole prescription were further identified as the study group and patients without dipyridamole were randomly selected as reference group with 1:1 ratio using a propensity score-matching approach. After a median of 6·67 years of follow-up, a total of 46 patients with dipyridamole use developed lymphoid neoplasms with an incidence rate of 0·49 per 1 000 person-years, while the rate in the matched group was 0·74 per 1 000 person-years. As compared to non-users, dipyridamole users were associated with a significantly decreased risk of lymphoid neoplasms [hazard ratio (HR) = 0·65; 95% confidence interval (CI) = 0·43-0·98]. Specifically, the reduced risk was observed for non-Hodgkin lymphomas (HR = 0·64; 95% CI = 0·42-0·94), especially B-cell lymphomas (HR = 0·56; 95% CI = 0·35-0·88). Dipyridamole use was related to a lower risk of lymphoid neoplasms, indicating a clinical potential of dipyridamole to be an adjunct anti-tumour agent against lymphoid neoplasms.


Assuntos
Dipiridamol/efeitos adversos , Leucemia Linfoide/epidemiologia , Leucemia Linfoide/etiologia , Linfoma/epidemiologia , Linfoma/etiologia , Inibidores da Agregação Plaquetária/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Aspirina/efeitos adversos , Aspirina/uso terapêutico , Quimioprevenção , Comorbidade , Dipiridamol/uso terapêutico , Suscetibilidade a Doenças , Relação Dose-Resposta a Droga , Feminino , Humanos , Leucemia Linfoide/prevenção & controle , Linfoma/prevenção & controle , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/uso terapêutico , Vigilância da População , Pontuação de Propensão , Modelos de Riscos Proporcionais , Sistema de Registros , Medição de Risco , Fatores de Risco , Suécia/epidemiologia
8.
J Pharm Sci ; 111(1): 146-154, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34464648

RESUMO

In vitro precipitation assays are often applied to support drug and formulation development. Current methods applied to quantify the amount of dissolved drug, in particular (U)HPLC, require time-consuming sample preparation. Furthermore, small precipitates formed during the nucleation phase may not be removed quantitatively by filtration or centrifugation of the sample. Given the drawbacks of standard (U)HPLC analyses during the application in transfer experiments, it was the aim of this work to develop a robust and simple to implement in-line UV spectrophotometric method which accurately reflects the precipitation profile obtained from in vitro transfer assays. Based on the three model compounds cinnarizine, dipyridamole, and ketoconazole, the manuscript describes the development of a design of experiments (DoE) based approach to develop derivative UV spectrophotometric methods accounting for the change in media composition over time due to the dilution of simulated intestinal with simulated gastric fluid. An R script was developed which automatically identifies suitable wavelengths for in-line measurements. As an outcome of this study, a fast, robust, accurate, and specific derivative UV spectrophotometric methodology for measuring the concentration of dissolved drugs in in vitro transfer experiments was successfully developed. This method can flexibly be applied to multi-compartmental precipitation assays.


Assuntos
Produtos Biológicos , Cromatografia Líquida de Alta Pressão/métodos , Dipiridamol , Cetoconazol , Solubilidade
9.
Biomed Chromatogr ; 36(1): e5247, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34541698

RESUMO

In this study, we developed and validated a method to determine dipyridamole-related impurities in pharmaceutical dosage forms using the reversed-phase-HPLC technique. All impurities were separated on a YMC pack C8 (150 mm × 4.6 mm, 3.0 µm) analytical column using a suitable mobile phase. Mobile phase A was 10 mM concentration of phosphate buffer (pH adjusted to 4.7 by adding diluted orthophosphoric acid) and mobile phase B was buffer:acetonitrile:methanol (at the ratio of 30:40:30 v/v). The optimized chromatographic conditions used in the experiment were as follows: flow rate, 1.0 mL/min; injection volume, 10 µL and column temperature, 35°C. Chromatographic detection was performed at 295 nm. The stressed samples were analyzed for degradation under acidic, basic, peroxide, water hydrolysis, and physical degradation conditions. The proposed method was validated according to International Conference on Harmonization (ICH) guidelines, and found to be specific, linear, accurate and have a robust stability-indicating nature. The method showed excellent linearity from limit of quantification (LOQ) to 150% level of concentrations for all impurities. The correlation coefficient (r2 ) for all impurities was between 0.995 and 0.999. The recovery study was performed from LOQ to 150% level concentrations, with mean recovery values between 92.9% and 103.2%, respectively. The developed method can be used to determine dipyridamole and its relative impurities. The degradation and validated study results indicate its stability-indicating nature. Therefore, the method can be used in pharmaceutical research and development and quality control departments.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Cromatografia de Fase Reversa/métodos , Dipiridamol , Dipiridamol/análise , Dipiridamol/química , Dipiridamol/normas , Contaminação de Medicamentos , Estabilidade de Medicamentos , Limite de Detecção , Modelos Lineares , Preparações Farmacêuticas , Reprodutibilidade dos Testes
10.
J Nucl Cardiol ; 29(1): 113-122, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32651801

RESUMO

BACKGROUND: Regadenoson is a selective adenosine receptor agonist. It is currently unclear if the level of hyperemia differs between stress agents. We compared Myocardial Blood Flow (MBF) and Myocardial Flow Reserve (MFR) response on CZT-SPECT Myocardial Perfusion Imaging (MPI) to evaluate if dipyridamole and regadenoson could induce the same level of hyperemia. METHODS: 228 patients with dynamic CZT-SPECT MPI were retrospectively analyzed (66 patients stressed with regadenoson and 162 with dipyridamole) in terms of MBF and MFR. To rule out confounding factors, two groups of 41 patients were matched for clinical characteristics in a sub-analysis, excluding high cardiovascular risk patients. RESULTS: Overall stress MBF was higher in regadenoson patients (1.71 ± 0.73 vs. 1.44 ± 0.55 mL·min-1·g-1 for regadenoson and dipyridamole, respectively, p < .05). However, when confounding factors were ruled out, stress MBF (1.57 ± 0.56 vs. 1.61 ± 0.62 mL·min-1·g-1 for dipyridamole and regadenoson, respectively, p = .88) and MFR (2.62 ± 0.77 vs. 2.46 ± 0.76 for dipyridamole and regadenoson, respectively, p = .40) were not different between regadenoson and dipyridamole. CONCLUSIONS: Our results suggest that dipyridamole and regadenoson induce equivalent hyperemia in dynamic SPECT with similar stress MBF and MFR in comparable patients.


Assuntos
Hiperemia , Imagem de Perfusão do Miocárdio , Circulação Coronária , Dipiridamol/farmacologia , Humanos , Hiperemia/diagnóstico por imagem , Imagem de Perfusão do Miocárdio/métodos , Purinas , Pirazóis , Estudos Retrospectivos , Tomografia Computadorizada de Emissão de Fóton Único/métodos
11.
In. Soeiro, Alexandre de Matos; Leal, Tatiana de Carvalho Andreucci Torres; Accorsi, Tarso Augusto Duenhas; Gualandro, Danielle Menosi; Oliveira Junior, Múcio Tavares de; Caramelli, Bruno; Kalil Filho, Roberto. Manual da residência em cardiologia / Manual residence in cardiology. Santana de Parnaíba, Manole, 2 ed; 2022. p.921-927, ilus, tab.
Monografia em Português | LILACS | ID: biblio-1353766
12.
J Eukaryot Microbiol ; 69(2): e12881, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34918439

RESUMO

Naegleria fowleri is a pathogenic, free-living amoeba that causes primary amebic meningoencephalitis (PAM), a highly fatal disease of the central nervous system. N. fowleri demonstrates three forms: the trophozoite, flagellate, and cyst. Most studies have focused on the trophozoite limiting information on the cyst. The present study examined the ability of cysts to attach to, excyst into the trophozoite form, and destroy cell cultures. Additionally, the study assessed the ability of cysts to cause PAM in a murine model. The results demonstrated that exposure to cysts and transformation into trophozoites resulted in destruction of cell cultures. Specifically, the mixed glial cells exhibited an increase in lactate dehydrogenase (LDH) release compared with cells without cyst exposure. On day eight postexposure, there was a nearly fourfold increase in LDH. The cysts of N. fowleri were shown not to be infective in vivo in a murine model. The mediation of the encystment process by the intracellular concentration of cAMP was also investigated. Trophozoites were treated with dipyridamole, an inhibitor of cAMP-specific phosphodiesterases. Dipyridamole increased the rate of encystment by nearly twofold and increased the intracellular concentration of cAMP in cysts by nearly sixfold throughout this period suggesting that cAMP is a mediator of encystment for N. fowleri.


Assuntos
Amebíase , Infecções Protozoárias do Sistema Nervoso Central , Cistos , Naegleria fowleri , Animais , Dipiridamol , Modelos Animais de Doenças , Camundongos , Naegleria fowleri/fisiologia , Trofozoítos
13.
Int J Mol Sci ; 22(21)2021 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-34768920

RESUMO

Semaphorin 4D (Sema4D) is a neurotrophin that is secreted by osteoclasts and binds to its receptor PlexinB1 on osteoblasts to inhibit their differentiation and function. Adenosine A2A activation inhibits osteoclast Sema4D-mediated secretion, diminishes inflammatory osteolysis and prevents bone loss following tenofovir (one of the most used antivirals in HIV). Therefore, tenofovir might activate Sema4D signaling to alter bone turnover. Female C57Bl/6/A2AKO mice were ovariectomized and treated with saline (control), tenofovir 75 mg/Kg/day, dipyridamole 25 mg/Kg/day or a combination for 5 weeks and long bones were prepared for histology. Primary murine-induced osteoclast/osteoblast were challenged with tenofovir/dipyridamole 1 µM each, and the expression of Sema4D/PlexinB1, RhoA/ROCK/IGF1R was studied by RT-PCR, Western blot and immunostaining. In vivo tenofovir showed an increased expression of Sema4D when compared to control mice, and dipyridamole reverted the expression in an A2A-dependent manner. In vitro, tenofovir increases Sema4D expression and secretion in osteoclast precursors, and pre-treatment with dipyridamole reverted this effect. pRhoA and ROCK1 activation were increased and IRS1/IGF1R expression was diminished by tenofovir in the Vav3/ARHGAP18 mechanism in osteoblast precursors and reverted by dipyridamole in an A2A-dependent manner. This suggests that tenofovir increases bone loss by activation of Sema4D/PlexinB1 signaling, which inhibits osteoblast differentiation. Agents that increase local adenosine concentrations, such as dipyridamole, might prevent bone loss following the inhibition of this pathway.


Assuntos
Antígenos CD/metabolismo , Desenvolvimento Ósseo/efeitos dos fármacos , Reabsorção Óssea/induzido quimicamente , Dipiridamol/farmacologia , Receptor A2A de Adenosina/metabolismo , Semaforinas/metabolismo , Tenofovir/efeitos adversos , Animais , Osso e Ossos/metabolismo , Células Cultivadas , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Tenofovir/farmacologia , Quinases Associadas a rho/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo
14.
Stroke ; 52(10): 3258-3265, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34304604

RESUMO

Background and Purpose: Lifelong treatment with antiplatelet drugs is recommended following a transient ischemic attack or ischemic stroke. Bleeding complications may offset the benefit of antiplatelet drugs in patients at increased risk of bleeding and low risk of recurrent ischemic events. We aimed to investigate the net benefit of antiplatelet treatment according to an individuals' bleeding risk. Methods: We pooled individual patient data from 6 randomized clinical trials (CAPRIE [Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events], ESPS-2 [European Stroke Prevention Study-2], MATCH [Management of Atherothrombosis With Clopidogrel in High-Risk Patients], CHARISMA [Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance], ESPRIT [European/Australasian Stroke Prevention in Reversible Ischemia Trial], and PRoFESS [Prevention Regimen for Effectively Avoiding Second Strokes]) investigating antiplatelet therapy in the subacute or chronic phase after noncardioembolic transient ischemic attack or stroke. Patients were stratified into quintiles according to their predicted risk of major bleeding with the S2TOP-BLEED score. The annual risk of major bleeding and recurrent ischemic events was assessed per quintile for 4 scenarios: (1) aspirin monotherapy, (2) aspirin-clopidogrel versus aspirin or clopidogrel monotherapy, (3) aspirin-dipyridamole versus clopidogrel, and (4) aspirin versus clopidogrel. Net benefit was calculated for the second, third, and fourth scenario. Results: Thirty seven thousand eighty-seven patients were included in the analyses. Both risk of major bleeding and recurrent ischemic events increased over quintiles of predicted bleeding risk, but risk of ischemic events was consistently higher (eg, from 0.7%/y (bottom quintile) to 3.2%/y (top quintile) for major bleeding on aspirin and from 2.5%/y to 10.2%/y for risk of ischemic events on aspirin). Treatment with aspirin-clopidogrel led to more major bleedings (0.9%­1.7% per year), than reduction in ischemic events (ranging from 0.4% to 0.9/1.0% per year) across all quintiles. There was no clear preference for either aspirin-dipyridamole or clopidogrel according to baseline bleeding risk. Conclusions: Among patients with a transient ischemic attack or ischemic stroke included in clinical trials of antiplatelet therapy, the risk of recurrent ischemic events and of major bleeding increase in parallel. Antiplatelet treatment cannot be individualized solely based on bleeding risk assessment.


Assuntos
Ataque Isquêmico Transitório/prevenção & controle , Inibidores da Agregação Plaquetária/efeitos adversos , Inibidores da Agregação Plaquetária/uso terapêutico , Acidente Vascular Cerebral/prevenção & controle , Aspirina/uso terapêutico , Clopidogrel/uso terapêutico , Dipiridamol/uso terapêutico , Quimioterapia Combinada , Humanos , Hemorragias Intracranianas/epidemiologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Recidiva , Medição de Risco , Ticlopidina/uso terapêutico , Resultado do Tratamento
15.
Arch Cardiovasc Dis ; 114(6-7): 490-503, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34274252

RESUMO

BACKGROUND: Cardiovascular magnetic resonance imaging (CMR) is an accurate technique for assessing ventricular function, myocardial perfusion and viability; its development remains limited mainly because of logistical and time constraints. Data regarding optimization of a dedicated stress CMR workflow are needed. AIMS: This study aimed to describe the optimization of a dedicated workflow, and to assess the feasibility and safety of stress CMR in a large registry of>35,000 patients. METHODS: A large single-centre French registry of vasodilator stress CMR included consecutive patients referred between 2008 and 2019 for the detection of inducible ischaemia. Stress CMR was performed at 1.5 Tesla using dipyridamole. Clinical and demographic data, test quality, CMR findings, haemodynamic data and complications were recorded prospectively. A locally optimized workflow was described and evaluated. RESULTS: Among the 35,862 patients referred for vasodilator stress CMR (mean age 68.9±11.8 years; 64.1% male), the stress CMR protocol was completed in 35,013 (97.6%) patients; 144 (0.3%) patients with missing baseline data were excluded. The mean examination duration was 27±5min, with image quality optimal in 90.8%, suboptimal in 7.1% and poor in 0.5% of cases. Images were diagnostic in 97.9% of patients. No patients died during or immediately after CMR. Fifty-six (0.16%) patients had severe complications. The incidence of non-severe complications was low (1.5%), whereas minor symptoms occurred frequently (35.5%). The presence of ischaemia was associated with a higher incidence of severe complications, non-severe complications and minor symptoms (all P<0.001). CONCLUSIONS: This single-centre prospective registry of>35,000 referral patients with known or suspected CAD showed that stress CMR was feasible in clinical routine practice, with high diagnostic image quality and an excellent safety profile. Inducible ischaemia was associated with severe complications, non-severe complications and minor symptoms.


Assuntos
Dipiridamol/administração & dosagem , Cardiopatias/diagnóstico por imagem , Imageamento por Ressonância Magnética , Imagem de Perfusão do Miocárdio , Vasodilatadores/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Circulação Coronária , Estudos de Viabilidade , Feminino , França , Cardiopatias/fisiopatologia , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Sistema de Registros , Reprodutibilidade dos Testes , Função Ventricular , Fluxo de Trabalho
16.
Curr Opin Chem Biol ; 65: 74-84, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34274565

RESUMO

Drug repurposing aims to find new uses for already existing and approved drugs. We now provide a brief overview of recent developments in drug repurposing using machine learning alongside other computational approaches for comparison. We also highlight several applications for cancer using kinase inhibitors, Alzheimer's disease as well as COVID-19.


Assuntos
Doença de Alzheimer/tratamento farmacológico , COVID-19/tratamento farmacológico , Reposicionamento de Medicamentos/tendências , Aprendizado de Máquina , Neoplasias/tratamento farmacológico , Antineoplásicos/uso terapêutico , Antivirais/uso terapêutico , Clemastina/farmacologia , Biologia Computacional/métodos , Dipiridamol/farmacologia , Humanos , Hidroxicloroquina/farmacologia , Lenalidomida/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Piperazinas/farmacologia , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia
17.
Pak J Pharm Sci ; 34(1(Special)): 417-421, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34275788

RESUMO

In the detection of coronary heart diseases amongst the non-invasive techniques the role of myocardial perfusion imaging is indexed. The rationale of this study was to compare the different parameters and the association between the exercise MPI and vasodilator MPI in the detection of coronary artery disease (that is prolonged Qt interval with the size of perfusion defects). It was a cross-sectional prospective study with purposive non-probability sampling technique which was conducted in a tertiary care hospital from January 2020 to June 2020 for a period of 6 months. All patients regardless of gender were included in this study and age ranging from 30 to 80 years with comorbidities ranging from diabetes, hypertension and smokers were also included. A total of 100 patients were included in this study out of which 81% were male, 50% were diabetics, 69% were hypertensive, 39% had a history of coronary artery disease, 25% were smokers and 63% had hyperlipidemia. For statistical analysis SPSS 21 was applied and significant association was observed between DTS treadmill score and the perfusion defect in vasodilator MPI, corrected Qt interval and DTS tread mill score and between corrected Qt and size of the perfusion defect (P value < 0.001). It was thus seen that the different components of the noninvasive nuclear stress test tend to co-relate and thus aid in the detection of coronary artery disease increasing the accuracy of results.


Assuntos
Doença da Artéria Coronariana/fisiopatologia , Teste de Esforço/métodos , Síndrome do QT Longo/fisiopatologia , Imagem de Perfusão do Miocárdio/métodos , Vasodilatadores , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença da Artéria Coronariana/diagnóstico por imagem , Dipiridamol , Eletrocardiografia , Feminino , Humanos , Síndrome do QT Longo/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
18.
Am J Cardiol ; 154: 106-110, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34233833

RESUMO

Heart rate reserve (HRR) during physical or pharmacological stress is a sign of cardiac autonomic function and sympathetic reserve, but it can be reduced during exercise for confounders such as poor motivation, drugs or physical fitness. In this study we sought to assess the prognostic meaning of HRR during dipyridamole stress echocardiography (DSE) in patients with abnormal chronotropic response to exercise. From 2004 to 2019, we prospectively acquired and retrospectively analyzed 379 patients (age 62 ± 11 years; ejection fraction 60 ± 5%) with suspected (n = 243) or known (n = 136) chronic coronary syndromes, referred to DSE for chronotropic incompetence during upright bicycle exercise-electrocardiography test defined as HRR used [(peak HR - rest HR) / (220 - age) - rest HR] ≤80% in patients off and ≤62% in patients on beta-blockers. All patients were in sinus rhythm and underwent DSE (0.84 mg/kg) within 3 months of exercise testing. During DSE, age-independent HRR (peak/rest HR) ≤1.22 was considered abnormal. All patients were followed-up. All-cause death was the only outcome measure. HRR during DSE was normal in 275 (73%) and abnormal in 104 patients (27%). During a follow-up of 9.0 ± 4.2 years, 67 patients (18%) died. The 15-year mortality rate was 23% in patients with normal and 61% in patients with abnormal HRR (p < 0.0001). At multivariable analysis a blunted HRR during DSE was an independent predictor of outcome (hazard ratio 2.01, 95% confidence intervals 1.23-3.29; p = 0.005) with age and diabetes, while neither inducible ischemia nor ongoing beta-blocker therapy were significant predictors. In conclusion, a blunted HRR during DSE predicts a worse survival in patients with chronotropic incompetence during exercise test. HRR during DSE is an appealingly simple biomarker of cardiac autonomic dysfunction independent of imaging, exercise and beta-blocker therapy.


Assuntos
Sistema Nervoso Autônomo/fisiopatologia , Ecocardiografia sob Estresse , Tolerância ao Exercício/fisiologia , Frequência Cardíaca/fisiologia , Mortalidade , Idoso , Dipiridamol , Teste de Esforço , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Vasodilatadores
19.
Pol Arch Intern Med ; 131(9): 830-839, 2021 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-34142788

RESUMO

INTRODUCTION: Coronary Flow Velocity Reserve (CFVR) assessment may improve diagnostic and prognostic value of stress echocardiography (SE). OBJECTIVES: To compare the feasibility of CFVR assessment in the left anterior descending (LAD) artery in four types of SE: dobutamine (DOB), dipyridamole (DIP), rapid pacing (PAC) and bicycle exercise (EXE). PATIENTS AND METHODS: We subjected 369 patients, mean (SD) age: 67 (11) to SE with DOB (n = 230), DIP (n = 73), PAC (n = 22) or EXE (n = 44). CFVR was measured as the ratio of peak diastolic coronary flow velocity (CFV) during exercise, pharmacological stress or pacing and peak diastolic CFV at rest in distal or mid LAD. RESULTS: The feasibility was excellent during PAC (100%), DOB (95%) and DIP (95%) and lower during EXE (73%, P < 0.01 vs other groups). In multivariable analysis the EXE protocol was a predictor of LAD flow loss during SE, with OR = 7.89 (95% CI 2.17 - 31.33), P = 0.002. CFVR was lower with PAC 1.7 (1.4 - 2.0) as compared to DOB 2.1 (1.7 - 2.5), DIP 2.1 (1.8 - 2.5) and EXE 2.0 (1.7 - 2.3), P < 0.05 for all. CONCLUSIONS: CFVR in LAD can be obtained during all forms of SE, but the feasibility is significantly higher with PAC and pharmacological tests as compared to EXE, which was identified in our study as the independent predictor of the loss of LAD flow recording at the peak of stress test.


Assuntos
Dobutamina , Ecocardiografia sob Estresse , Idoso , Velocidade do Fluxo Sanguíneo , Circulação Coronária , Dipiridamol , Estudos de Viabilidade , Humanos
20.
Mov Disord ; 36(10): 2387-2392, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34137476

RESUMO

BACKGROUND: New pharmacological targets are needed for restless legs syndrome. Preclinical data suggest that a hypoadenosinergic state plays an important pathogenetic role. OBJECTIVE: The objective of this study was to determine whether inhibitors of equilibrative nucleoside transporters, for example, dipyridamole, could provide effective symptomatic treatment. METHODS: A 2-week double-blind, placebo-controlled crossover study assessed the efficacy of dipyridamole (possible up-titration to 300 mg) in untreated patients with idiopathic restless legs syndrome. Multiple suggested immobilization tests and polysomnography were performed after each treatment phase. Severity was assessed weekly using the International Restless Legs Rating Scale, Clinical Global Impression, and the Medical Outcomes Study Sleep scale. The primary end point was therapeutic response. RESULTS: Twenty-eight of 29 patients recruited were included. International Restless Legs Rating Scale scores improved from a mean ± standard deviation of 24.1 ± 3.1 at baseline to 11.1 ± 2.3 at the end of week 2, versus 23.7 ± 3.4 to 18.7 ± 3.2 under placebo (P < 0.001). Clinical Global Impression, Medical Outcomes Study Sleep, and Multiple Suggested Immobilization Test scores all improved (P < 0.001). The mean effective dose of dipyridamole was 217.8 ± 33.1 mg/d. Sleep variables improved. The mean periodic leg movement index at the end of treatment with dipyridamole was 8.2 ± 3.5 versus. 28.1 ± 6.7 under placebo. Side effects (dipyridamole vs placebo) included abdominal distension (18% vs. 7%), dizziness (10.7% vs 7.1%), diarrhea, and asthenia (each 7.1% vs 3.6%). CONCLUSIONS: Dipyridamole has significant therapeutic effects on both sensory and motor symptoms of restless legs syndrome and on sleep. Our findings confirm the efficacy of dipyridamole in restless legs syndrome predicted from preclinical studies and support a key role of adenosine in restless legs syndrome. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Assuntos
Síndrome das Pernas Inquietas , Estudos Cross-Over , Dipiridamol/uso terapêutico , Agonistas de Dopamina , Método Duplo-Cego , Humanos , Polissonografia , Síndrome das Pernas Inquietas/tratamento farmacológico , Resultado do Tratamento
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