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OBJECTIVE: To investigate changes in the chemical composition of malts under different germination cycles and prepared with different processing methods, thus providing a reference for the clinical application of malt in disease treatment. METHODS: Nine malt samples were analyzed by ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS/MS), and the MS fragmentation pathway of 4 compounds (including hordenine, gramine, N-methyltyramine and catechin) were also analyzed. RESULTS: By database comparison and literature search, we detected 31 compounds in raw barley and 33 compounds in both raw malt and roasted malt. Nonetheless, the most of these 33 compounds were detected higher contents in raw malt than in roasted malt. Besides, we detected 15 compounds in brown malt. At Day1 of germination, 31 compounds were detected in malt, without two alkaloids (representative: hordenine). At Day2-5, 33 compounds were detected, with different contents as shown by the peak area comparison; hordenine had a gradually increasing abundance; and nearly one third of the chemical components in barley increased gradually, one third decreased gradually, and one third tended to be stable. CONCLUSION: Malts under different germination cycles and prepared with different processing methods have varying active ingredients, and especially brown malt exhibits a serious loss of compounds. The tight association between the chemical composition and clinical application of malt offers a basis to the clinically scientific and reasonable selection of Chinese medicinal materials for treatment purposes.
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Medicamentos de Ervas Chinesas , Hordeum , Espectrometria de Massas em Tandem , Cromatografia Líquida de Alta Pressão , Medicamentos de Ervas Chinesas/química , Estrutura MolecularRESUMO
Background: The dopamine D2 receptor (DRD2) plays an important role in the increased prolactin (PRL) levels associated with the pathogenesis of antipsychotic drugs (ADs). Elevated prolactin levels can affect people's quality of life. Maiya alkaloids has been used to treat diseases associated with high PRL levels. Maiya, is a processed product of the mature fruits of Hordeum vulgare L. (a gramineous plant) after sprouting and drying and also a common Chinese herbal drug used in the clinic, is traditionally used to treat abnormal lactation, and is currently used clinically for the treatment of abnormal PRL levels. Aims: Epigenetic mechanisms can be related to DRD2 expression. We investigated the role of DRD2 methylation in the induction of PRL expression by ADs and the mechanism underlying the effects of total barley maiya alkaloids (TBMA) on this induction. Methods: The methylation rate of DRD2 in 46 people with schizophrenia who took risperidone was detected by MassARRAY sequencing. Humans were long term users of Ris. Seventy Sprague Dawley female rats were divided into seven groups. A rat model of risperidone-induced PRL was established, and the potential protective effects of TBMA and its components [e.g., hordenine (Hor)] on these increased PRL levels were investigated. The PRL concentration was detected by Enzyme-linked immunosorbent assay. PRL, DRD2, and DNA methyltransferase (DNMT1, DNMT3α, and DNMT3ß) protein and mRNA expression were detected by western blotting and real-time polymerase chain reaction (RT-PCR), respectively. The positive rate of methylation in the DRD2 promoter region of rats was detected by MassARRAY sequencing. Results: Clinical studies showed that the positive rate of DRD2 methylation associated with increased PRL levels induced by ADs was significantly higher than in the normal prolactinemia (NPRL) group. In vivo and vitro, TBMA and Hor inhibited this induction of PRL expression and increased DRD2 expression by inhibiting the expression of the DNMTs. Conclusions: TBMA and hordenine increased DRD2 expression by inhibiting DNMT-dependent DRD2 methylation.
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Skin computed tomography (CT) image based on improved marching cubes (MC) algorithm was explored to evaluate the therapeutic effect of internal administration of Liangxue Xiaoyin decoction combined with medicated bath in the treatment of psoriasis vulgaris. 712 patients with psoriasis vulgaris blood heat syndrome in hospital were recruited as the research object, which were randomly divided into observation group (TCM oral therapy combined with medicinal bath) and control group (TCM oral therapy), each with 356 cases. Psoriasis area and severity index (PASI), pruritus degree, and clinical treatment effect were compared. The results showed that the reconstruction time of median method was greatly shorter, and the algorithm efficiency was improved by 40.6290%. After treatment, the psoriasis area and severity index (PASI) score of the observation group was 5.61 ± 1.15, ΔPASI = (22.64 ± 2.15). ΔPASI% = 80.14%, which were greatly higher than the control group ((9.41 + 1.56) points, ΔPASI = (18.84 + 1.65) points, ΔPASI% = 66.69%) (P < 0.05). After treatment, the itching degree of the observation group was 3.03 ± 1.01 points, which was lower than that of the control group ((3.71 ± 1.06) points), and the itching degree of the observation group was greater than that of the control group, with substantial difference (P < 0.05). The total effective rate of observation group (88.76%) was higher than that of control group (71.07%) (P < 0.05). Therefore, skin CT image based on the improved MC algorithm can evaluate the therapeutic effect of internal administration of Liangxue Xiaoyin decoction combined with medicated bath in the treatment of psoriasis vulgaris. The internal administration of Liangxue Xiaoyin decoction combined with medicated bath had a good effect on the treatment of psoriasis vulgaris and was of certain clinical application value.
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Medicamentos de Ervas Chinesas/uso terapêutico , Fitoterapia , Psoríase/diagnóstico por imagem , Psoríase/tratamento farmacológico , Adolescente , Adulto , Idoso , Algoritmos , Banhos , Biologia Computacional , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Interpretação de Imagem Radiográfica Assistida por Computador/estatística & dados numéricos , Índice de Gravidade de Doença , Usos Terapêuticos , Tomografia Computadorizada por Raios X/estatística & dados numéricos , Adulto JovemRESUMO
Abstract This study aimed to establish and compare models of mammary gland hyperplasia (MGH) with hyperprolactinemia (HPRL) using two different methods. The models provide information on the relationship between mammary gland hyperplasia and associated hormones. Model A was constructed using intramuscular injections of estradiol benzoate injection (EBI), followed by progesterone (P), and then metoclopramide dihydrochloride (MDI). Model B was designed by administering MDI, follow by EBI, and then P intramuscularly. Model B showed higher MGH progression compared with model A. Notably, increase in estradiol (E2) was negatively correlated with prolactin (PRL) secretion. However, PRL levels in model B were significantly higher compared with the levels in model A. Estrogen (ER), prolactin receptor (PRLR), and progesterone receptor (PR) mRNA and protein expression levels in model B rats were positively correlated with changes in the corresponding hormone levels. However, E2, P, and PRL levels in model A showed no direct relationship with levels of the mRNAs of related hormones and protein expression levels. Our results suggest that model B is an appropriate model of MGH with HPRL that can be used to perform further studies about the interactions of the E2, P, and PRL hormones in this disorder.
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Animais , Feminino , Ratos , Hiperprolactinemia , Hiperplasia/patologia , Progesterona , Prolactina , Receptores da Prolactina , Receptores de Progesterona , Western Blotting/métodos , Secreções Corporais , Glândulas Mamárias Humanas/anatomia & histologia , Injeções Intramusculares/efeitos adversos , Injeções Intramusculares/instrumentação , MétodosRESUMO
This study aimed to employ a population pharmacokinetic (PK) model to optimize the dosing regimen of voriconazole (VRC) in children with a critical illness. A total of 99 children aged from 0.44 to 13.58 years were included in this study. The stability and predictive performance of the final model were evaluated by statistical and graphical methods. The optimal dosing regimen was proposed for children with different body weights, CYP2C19 phenotypes, and coadministrations with omeprazole. The PK of VRC was described by a two-compartment model with nonlinear Michaelis-Menten elimination. Body weight, CYP2C19 phenotype, and omeprazole were significant covariates on the maximum velocity of elimination (Vmax), which had an estimated typical value of 18.13 mg · h-1. Bayesian estimation suggested that the dose-normalized concentration and total exposure (peak concentration [Cmax]/D, trough concentration [Cmin]/D, and area under the concentration-time curve over 24 h [AUC24]/D) were significantly different between extensive metabolizer (EM) patients and poor metabolizer (PM) patients. To achieve the target concentration early, two loading doses of 9 mg · kg-1 of body weight every 12 h (q12h) were reliable for most children, whereas three loading doses of 6 to 7.5 mg · kg-1 q8h were warranted for young children weighing ≤18 kg (except for PM patients). The maintenance doses decreased about 30 to 40% in PM patients compared to that in EM patients. For children aged <2 years, in EM patients, the maintenance dose could be as high as 9 mg · kg-1. The maintenance dose of VRC was supposed to decrease slightly when coadministered with omeprazole. A population PK model of intravenous VRC for critically ill children has been successfully developed. It is necessary to adjust dosing regimens according to the CYP2C19 genotype. Optimal dosing regimens have been recommended based on the final model.
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Antifúngicos , Estado Terminal , Antifúngicos/uso terapêutico , Teorema de Bayes , Criança , Pré-Escolar , Humanos , Fenótipo , VoriconazolRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Barley maiya from gramineous plants (Hordeum vulgare L.) is obtained from ripe fruits through germination and drying. It is often used to treat diseases associated with high prolactin levels. OBJECTIVE: To investigate the anti-hyperprolactinemia (anti-HPRL) mechanisms of total barley maiya alkaloids (TBMA) and hordenine. METHODS: This experiment included 9 groups: Normal group, TBMA group, hordenine group, TBMA + haloperidol group, TBMA + forskolin group, TBMA + 8-bromo-cAMP group, hordenine + haloperidol group, hordenine + forskolin group, and hordenine + 8-bromo-cAMP group. The prolactin (PRL) concentration in the supernatant and the total cAMP concentration in the cells were detected by ELISA. The expression levels of PRL, dopamine D2 receptor (DRD2) and cAMP/PKA/CREB protein were measured by Western Blot. RESULTS: In the TBMA group and the hordenine group, the PRL level in MMQ cells was significantly decreased, but in GH3 cells there was no change. DRD2 expression level was markedly increased, cAMP concentration was decreased, and the activity of PKA and CREB declined in MMQ cells. Compared with the TBMA group, there was a significant decrease of DRD2 expression level, a remarkable increase of PRL secretion and an increase of cAMP/PKA/CREB expression in MMQ cells within the TBMA + haloperidol group. Compared with the forskolin group, there was no significant change in PRL secretion and cAMP/PKA/CREB expression level in MMQ cells within the TBMA + forskolin group. There was a decrease in PRL secretion and cAMP/PKA/CREB expression level in MMQ cells within the TBMA + 8-bromo-cAMP group compared with the 8-bromo-cAMP group. Compared with the hordenine group, DRD2 expression level was significantly decreased, PRL secretion was markedly increased, and cAMP/PKA/CREB expression level was increased in MMQ cells within the hordenine + haloperidol group. There was no significant change in PRL secretion and cAMP/PKA/CREB expression level in MMQ cells within the hordenine + forskolin group compared with the forskolin group and within the hordenine + 8-bromo-cAMP group compared with the 8-bromo-cAMP group. CONCLUSION: TBMA and hordenine can both play an anti-HPRL role via DRD2, and TBMA can also act on PKA targets to exert its anti-HPRL effect. TBMA and hordenine may be potential treatment strategies for HPRL.
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Alcaloides/farmacologia , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Hordeum/química , Prolactina/antagonistas & inibidores , Tiramina/análogos & derivados , Alcaloides/química , Animais , Antieméticos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Colforsina/química , Colforsina/farmacologia , Proteínas Quinases Dependentes de AMP Cíclico/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Haloperidol/farmacologia , Ratos , Receptores de Dopamina D2 , Transdução de Sinais , Tiramina/química , Tiramina/farmacologiaRESUMO
Malt is the mature fruit of Hordeum vulgare L. after germination and drying and has been applied for treatment female abnormal galactorrhea. Previous studies have showed total alkaloids in malt have anti-HPRL effect. However, total alkaloids of malt change with the growth cycle, and the specified levels of total alkaloids in different bud length of malt have not been decided. To determine the definitive level of total alkaloids in different buds of malt and the most suitable bud length for clinical application by comparing effects on hyperprolactinemia rat. During the budding of malt, the content of total alkaloids first increased and then decreased, and it peaked at a bud length of 0.75 cm. Treated the HPRL model rats with different buds of malt, the PRL level was decreased, the number of PRLpositive cells and the mRNA expression level in the pituitary were significantly declined, and the number of dopamine D1 and D2 receptors in the hypothalamus was increased. The above changes were most significant in 0.75 cm bud. These results suggest that in terms of the content of effective substance and the effects on HPRL model rats, a malt bud length of 0.75 cm is optimal for clinical application.
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Animais , Feminino , Ratos , Hordeum/classificação , Benchmarking/métodos , Plântula/efeitos adversos , Hiperprolactinemia/classificação , Dopamina , Germinação , Alcaloides/efeitos adversos , Sistema Endócrino/anormalidades , FrutasRESUMO
WHAT IS KNOWN AND OBJECTIVE: Since the December 2019 discovery of several cases of coronavirus disease 2019 (COVID-19) in Wuhan, China, the infection has spread worldwide. Our aim is to report on the clinical characteristics, treatments and prognoses of COVID-19. METHODS: This was a retrospective, single-centre, case series of 136 patients who were diagnosed with COVID-19 at Wuhan Third Hospital in Wuhan, China, between 28 January 2020 and 12 February 2020. The clinical characteristics, laboratory tests, treatment features and prognoses were summarized. RESULTS AND DISCUSSION: The 136 patients were divided into a moderate (M) group (n = 103, 75.7%) and a severe and critical (SC) group (n = 33, 24.3%). There were significant differences in the incidences of concomitant chronic medical illnesses (eg, hypertension, diabetes and cardiovascular disease), fever, dry cough and dyspnoea among the two groups (P < .05). Compared with those in the M group, lymphocyte count (LYM) decreased significantly in the SC group, while the serum levels of C-reactive protein (CRP), procalcitonin (PCT), creatinine (Cre), D-dimer, lactic dehydrogenase (LDH), myoglobin (MB) and troponin I (cTnl) increased significantly in the SC group (P < .05). The main therapeutic drugs were antivirals, antibiotics, glucocorticoids, immunomodulators, traditional Chinese medicine preparations and symptomatic support drugs. There were significant differences in the incidences of shock, myocardial injury, acute respiratory distress syndrome (ARDS) and renal injury among the two groups (P < .05). Among the 136 patients, 99 (72.7%) were cured, 14 (10.3%) were transferred to other hospital and 23 (16.9%) died. WHAT IS NEW AND CONCLUSION: Elderly patients with chronic diseases are more likely to develop severe or critical COVID-19 with multiple organ damage or systemic injuries. The improvement of LYM and CRP may be associated with the prognoses of COVID-19. The combined use of three or more antiviral drugs is to be avoided. The combination of broad-spectrum antibacterial drugs is not recommended and the risk of drug-induced liver injury should be monitored. Throughout a patient's hospitalization, their treatment plan should be evaluated and adjusted according to their vital signs, clinical symptoms, laboratory tests and imaging changes. Patients should receive effective psychological counselling.
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Infecções por Coronavirus/terapia , Pneumonia Viral/terapia , Adulto , Fatores Etários , Idoso , Antivirais/uso terapêutico , Biomarcadores/sangue , COVID-19 , China/epidemiologia , Comorbidade , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/mortalidade , Feminino , Glucocorticoides/uso terapêutico , Humanos , Fatores Imunológicos/uso terapêutico , Contagem de Linfócitos , Masculino , Medicina Tradicional Chinesa , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/mortalidade , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Resultado do TratamentoRESUMO
Hordenine is an active compound found in several foods, herbs and beer. In this work, a novel sorbent was fabricated for selective solid-phase extraction (SPE) of hordenine in biological samples. The organic polymer sorbent was synthesized in one step in the plastic barrel of a syringe by a pre-polymerization solution consisting of methacrylic acid (MAA), 4-vinylphenylboronic acid (VB) and ethylene glycol dimethacrylate (EGDMA). The conditions for preparation were optimized to generate a poly(MAA-VB-EGMDA) monolith with good permeability. The monolith exhibited good enrichment efficiency towards hordenine. By using tyramine as the internal standard, a poly(MAA-VB-EGMDA)-based SPE-HPLC method was established for analysis of hordenine. Conditions for SPE, including volume of eluting solvent, pH of sample solution, sampling rate and sample volume, were optimized. The proposed SPE-HPLC method presented good linearity (R(2) = 0.9992) within 10-2000 ng/mL and the detection limits was 3 ng/mL, which is significantly more sensitive than reported methods. The method was also applied in plasma and urine samples; good capability of removing matrices was observed, while hordenine in low content was well extracted and enriched. The recoveries were from 90.6 to 94.7% and from 89.3 to 91.5% for the spiked plasma and urine samples, respectively, with the relative standard deviations <4.7%.
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Ácidos Borônicos/química , Cromatografia Líquida de Alta Pressão/métodos , Etilenoglicóis/química , Metacrilatos/química , Extração em Fase Sólida/métodos , Tiramina/análogos & derivados , Compostos de Vinila/química , Humanos , Modelos Lineares , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Extração em Fase Sólida/instrumentação , Tiramina/sangue , Tiramina/química , Tiramina/urinaRESUMO
Objective. Fructus Hordei Germinatus is widely used in treating hyperprolactinemia (hyperPRL) as a kind of Chinese traditional herb in China. In this study, we investigated the anti-hyperPRL activity of water extract of Fructus Hordei Germinatus (WEFHG) and mechanism of action. Methods. Effect of WEFHG on serum prolactin (PRL), estradiol (E2), progesterone (P), follicle-stimulating hormone (FSH), luteinizing hormone (LH), and hypothalamus protein kinase A (PKA) and cyclic adenosine monophosphate (cAMP) levels of hyperPRL rats were investigated. And effect of WEFHG on PRL secretion, D2 receptors, and dopamine transporters (DAT) was studied in MMQ, GH3, and PC12 cells, respectively. Results. WEFHG reduced the secretion of PRL in hyperPRL rats effectively. In MMQ cell, treatment with WEFHG at 1-5 mg/mL significantly suppressed PRL secretion and synthesis. Consistent with a D2-action, WEFHG did not affect PRL in rat pituitary lactotropic tumor-derived GH3 cells that lack the D2 receptor expression but significantly increased the expression of D2 receptors and DAT in PC12 cells. In addition, WEFHG reduced the cAMP and PKA levels of hypothalamus in hyperPRL rats significantly. Conclusions. WEFHG showed anti-hyperPRL activity via dopamine D2 receptor, which was related to the second messenger cAMP and PKA.
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PURPOSE: To investigate the distribution of statin therapy correlated gene polymorphism allele CYP2D6*10 (C188T) in Ningxia Hui nationality and to discuss the relationship between the gene polymorphism allele CYP2D6*10 (C188T) and the lipid-lowering efficacy of simvastatin and hyperlipidemia. MATERIALS AND METHODS: One hundred and fifty healthy people (80 males and 70 females) and 200 hyperlipidemia patients (105 males and 95 females) were recruited at Ningxia People's Hospital. Genotypes were determined by using allele-specific amplification (ASA-PCR) in 150 healthy controls and 200 patients with hyperlipidemia. Relationships between genotypes and lipid levels and the lipid-lowering efficacy of simvastatin were analyzed. RESULTS: The distribution frequency of the CYP2D6*10 allele was 47.6% in the Ningxia Hui nationality. There was no significant correlation between the CYP2D6*10 allele and hyperlipidemia. At 8 weeks after treatment with simvastatin, total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels were more obviously decreased with the CC genotype than the CT and TT genotypes, with significant differences. CONCLUSION: Distribution of the gene polymorphism of CYP2D6*10 is ethnically and geographical different. The allele T of CYP2D6*10 is not related to hyperlipidemia. CC expression seemed to increase the lipid-lowering effects of simvastatin. The hyperlipidemia patients with CC genotype should take lower doses of simvastatin than those with CT/TT genotype in the Ningxia Hui population.
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LDL-Colesterol/sangue , Citocromo P-450 CYP2D6/genética , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipidemias/tratamento farmacológico , Sinvastatina/uso terapêutico , Adulto , Idoso , Glicemia/análise , HDL-Colesterol/sangue , Feminino , Genótipo , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Hiperlipidemias/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Sinvastatina/administração & dosagemRESUMO
The study investigated the pharmacodynamism and mechanism of Chinese medicinal formula-Huiru Yizeng Yihao (NO.1 HRYZ) on the model rats of hyperpro-lactinemia and the model rats of hyperplasia of mammary gland (HMG), and studied the internal connection between hyperprolactinemia and HMG.. The hyperprolactinemia rat models were established by injecting metoclopramide dihydrochloride in the back of rats. The model rat of HMG was prepared by injecting estradiol in the thigh muscle of the rats and progesterone consecutively, while the tails of rats were clipped with tongs. Rats were treated with either NO.1 HRYZ or positive control drugs for four weeks. The concentrations of sex hormone in rat serum were examined using ELISA kits, and the morphology of mammary gland tissue in all group rats was observed with microscope. NO.1 HRYZ significantly decreased prolactin (PRL) and increased estradiol (E2), progesterone (P), follicle stimulating hormone (FSH), luteinizing hormone (LH) concentrations of hyperprolactinemia rats. It decreased E2, PRL, FSH, gonadotropin-releasing hormone (GnRH), 5-hydroxytryptamine (5-HT) and increased P concentrations of HMG rat. It also eliminated hyperplasia of lobules and gland alveolus compared with the model group. Treatment with NO.1 HRYZ could significantly regulate the sex hormone disorder of hyperprolactinemia and HMG rat models, and could eliminate the formation of HMG. Hyperprolactinemia was closely correlated with HMG, and hyperprolactinemia promoted the formation of HMG.
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Medicamentos de Ervas Chinesas/uso terapêutico , Hormônios Esteroides Gonadais/sangue , Hormônio Liberador de Gonadotropina/sangue , Hiperprolactinemia/tratamento farmacológico , Glândulas Mamárias Humanas/efeitos dos fármacos , Fitoterapia , Prolactina/sangue , Animais , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/farmacologia , Estradiol/sangue , Feminino , Gonadotropinas Hipofisárias/sangue , Humanos , Hiperplasia , Hiperprolactinemia/sangue , Hiperprolactinemia/induzido quimicamente , Hiperprolactinemia/complicações , Magnoliopsida , Glândulas Mamárias Humanas/patologia , Metoclopramida , Progesterona/sangue , Ratos , Ratos Wistar , Serotonina/sangueRESUMO
The overactivation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) is considered a final common effector in ischemia/reperfusion (I/R) injury. The aim of the current study was to examine the precise time course of the activation of PARP in peripheral leukocytes and the reperfused myocardium tissue on myocardial I/R injury from the same rat and to identify the relationship between myocardial infarct size and the degree of PARP activation in circulating leukocytes. Another aim of the study was to test the effect of 3-aminobenzamide (a well-known and widely used PARP inhibitor) on the activation of PARP in the reperfused myocardium and peripheral leukocytes. Poly(ADP-ribose) polymerase activation was measured by Western blotting for its product, poly(ADP-ribose) (PAR). The localization of PARP activation was determined by PAR immunohistochemistry. The results showed that poly(ADP-ribosyl)ation was detected 15 min, peaked 2 to 6 h, and remained markedly detectable 24 h in the reperfused heart after I/R model. Similarly, PAR content of the leukocytes increased in cells isolated just after reperfusion from the same rat. Immunohistochemical studies localized the staining of PAR primarily to the cardiac myocytes and vascular endothelial cells. At 6 h, there was a significant linear correlation between infarct size and PARP activity, whereas at 2 and 24 h, no relationship was found. The PARP inhibitor 3-aminobenzamide (3-AB, 20 mg kg⻹ i.v. injection 15 min before reperfusion, and every 2 h thereafter for 6 h) markedly reduced infarct size through depressing the activation of the enzyme in myocytes and peripheral leukocytes even when the treatment is initiated at 2 h after reperfusion.