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1.
Anticancer Drugs ; 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34459455

RESUMO

BACKGROUND: Colorectal cancer (CRC) is a prevalent malignant tumor with a poor prognosis. Circular RNA (circRNA) circ_0007334 is related to cell proliferation in CRC. This study is designed to explore the role and mechanism of circ_0007334 in CRC progression. METHODS: Circ_0007334, microRNA-577 (miR-577) and kruppel-like factor 12 (KLF12) levels were measured by real-time quantitative PCR (RT-qPCR). Exosomes were detected by a transmission electron microscope and nanoparticle tracking analysis (NTA). CD63, TSG101, matrix metallopeptidase-2 (MMP-2), MMP-9, VEGFA and KLF12 protein levels were examined by western blot assay. The binding relationship between miR-577 and circ_0007334 or KLF12 was predicted by circRNA interactome or Starbase and verified by a dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. Cell viability, colony number, migration, invasion and angiogenesis were detected by cell counting kit-8 (CCK-8), colony formation, wound healing, transwell and tube formation assays. The biological role of circ_0007334 was examined by the xenograft tumor model in vivo. RESULTS: Circ_0007334 and KLF12 were increased, and miR-577 was decreased in CRC tissues and cells. Also, circ_0007334 expression was upregulated in CRC cell-derived exosomes. Circ_0007334 deficiency repressed cell viability, colony formation, migration, invasion, and angiogenesis in CRC cells. Mechanically, circ_0007334 could regulate KLF12 expression by sponging miR-577. Circ_0007334 downregulation or exosomal circ_0007334 silencing blocked CRC tumor growth in vivo. CONCLUSION: These results presented that circ_0007334 deficiency exerts a tumor-suppressor by the miR-577/KLF12 axis in CRC, and indicated that exosomal circ_0007334 could hinder CRC tumor growth and angiogenesis in vivo. Our findings provided a novel therapeutic strategy for CRC.

2.
Br J Clin Pharmacol ; 2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34322894

RESUMO

AIMS: We investigated savolitinib pharmacokinetics (PK) when administered alone or in combination with rifampicin, itraconazole or famotidine, and investigated midazolam PK when administered with or without savolitinib in healthy males. METHODS: Savolitinib PK was evaluated before/after: rifampicin (600 mg once daily [QD] for 5 days); itraconazole (200 mg QD for 5 days); a single dose of famotidine (40 mg QD) 2 hours before savolitinib. Midazolam PK was evaluated before/after midazolam (1 mg QD) with or without savolitinib (600 mg QD). Each study enrolled 20, 16, 16 and 14 volunteers, respectively. Plasma samples were collected to determine the effect on PK. RESULTS: The geometric mean ratios (GMR, %) (90% confidence intervals [CIs]) for savolitinib alone and in combination for Cmax , AUC respectively, were 45.4 (41.4-49.9), 38.5 (34.2-43.3) in the rifampicin study (n = 18); 105.2 (87.7-126.3), 108.4 (96.3-122.1) in the itraconazole study (n = 16); and 78.8 (67.7-91.7), 87.4 (81.2-94.2) in the famotidine study (n = 16). The GMRs (90% CIs) for midazolam alone and in combination with savolitinib for Cmax , AUC respectively, were 84.1 (70.0-101.0), 96.7 (92.4-101.1) (n = 14). Savolitinib alone or in combination was well tolerated. CONCLUSIONS: Co-dosing of rifampicin significantly reduced exposure to savolitinib vs savolitinib alone; co-dosing of itraconazole or midazolam with savolitinib had no clinically significant effect on savolitinib or midazolam PK, respectively. Co-dosing of famotidine with savolitinib reduced exposure to savolitinib, although this was not considered clinically meaningful. No new savolitinib-related safety findings were observed.

3.
J Pharmacol Sci ; 147(1): 104-113, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34294360

RESUMO

Circular RNAs (circRNAs) have been shown to be involved in the progression of many diseases, including cancer. However, the role of circ_0101802 in the proliferation, migration and invasion of colorectal cancer (CRC) has not been studied. Our results showed that circ_0101802 was highly expressed in CRC tumor tissues and cells. Functional experiments suggested that circ_0101802 knockdown could inhibit the proliferation, migration and invasion of CRC cells in vitro and CRC tumorigenesis in vivo. In the terms of mechanism, we discovered that circ_0101802 could act as a sponge of miR-1236-3p, and miR-1236-3p could target MACC1. The rescue experiments revealed that miR-1236-3p inhibitor could reverse the inhibition effect of circ_0101802 silencing on CRC proliferation, migration and invasion, and MACC1 overexpression also could abolish the negative regulation of miR-1236-3p on CRC proliferation, migration and invasion. More important, our data confirmed that circ_0101802 sponged miR-1236-3p to positively regulate MACC1. In summary, our results revealed that circ_0101802 functioned as a tumor promoter in CRC, which could facilitate CRC proliferation, migration and invasion via regulating the miR-1236-3p/MACC1 axis.

4.
Ann Palliat Med ; 10(6): 6518-6534, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34154362

RESUMO

BACKGROUND: Isoniazid (INH), rifampicin (RMP), pyrazinamide (PZA), and ethambutol (EMB) are the four most common drugs for the first-line treatment of tuberculosis (TB). Although chemotherapy drugs are widely used in the treatment of TB, and achieved good results, but the side effects, especially anti-tuberculosis drug-induced liver injury (ATDILI), cannot be overlooked. Many researchers have made efforts to uncover the association of cytochrome P450 (CYP) enzyme genetic polymorphisms with ATDILI. In this study, we systematically reviewed and meta-analyzed the relationship between CYP polymorphism and susceptibility to ATDILI. METHODS: We carried out literature searches of PubMed, Ovid, the Cochrane Library, Web of Science and Chinese National Knowledge Infrastructure (CNKI). Medical Subject Headings (MeSH) terms including "cytochrome P450 enzyme", "drug-induced liver injury", "polymorphism", "tuberculosis", and "hepatotoxicity" were used as keywords for our searches. RESULTS: The pooled odds ratio (OR) of all studies for CYP2E1 to the risk of ATDILI was 1.18 [95% confidence interval (CI): 0.82-1.71]. The articles in this meta-analysis were observed to be mildly heterogeneous. Further subgroup analysis revealed that the patients who receiving a four-drug protocol (INH + RIF + PZA + EMB) or three-drug protocol (INH + RIF + PZA) regimens showed a higher risk of ATDILI than those who receiving INH alone. However, subgroup analyses according to participants' ethnic origin, study type, and the definition of ATDILI produced no statistically significant results. Associations between other genes in the CYP family and ATDILI were indistinct and equivocal. DISCUSSION: Our meta-analysis has uncovered an association between CYP2E1 RsaI/PstI polymorphisms and ATDILI, especially among patients who receive a four-drug (INH + RIF + PZA + EMB) or three-drug (INH + RIF + PZA) anti-TB treatment regimen.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Tuberculose , Antituberculosos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/genética , Sistema Enzimático do Citocromo P-450/genética , Humanos , Polimorfismo Genético/genética , Tuberculose/tratamento farmacológico
5.
J Gastrointest Surg ; 2021 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-33904057

RESUMO

PURPOSE: The purpose of this study was to determine the risk factors for the development of a permanent stoma in laparoscopic intersphincteric resection (LS-ISR) for ultralow rectal adenocarcinoma and to develop and validate a prediction model to predict the probability of permanent stoma after surgery. METHODS: A primary cohort consisting of 301 consecutive patients who underwent LS-ISR was enrolled in this study. Multivariable logistic regression analysis was used to identify risk factors and develop the nomogram. The performance of the nomogram was assessed with respect to its calibration, discrimination, and clinical usefulness. An independent validation cohort contained 91 consecutive patients from January 2012 to January 2019. RESULTS: The permanent stoma rate was 11.3% (34/301) in the primary cohort and 18.7% (17/91) in the validation cohort. Multivariable analysis revealed that nCRT (OR, 3.195; 95% CI, 1.169-8.733; P=0.024), ASA score of 3 (OR, 5.062; 95% CI, 1.877-13.646; P=0.001), distant metastasis (OR, 14.645; 95% CI, 3.186-67.315; P=0.001), and anastomotic leakage (OR, 11.308; 95% CI, 3.650-35.035; P<0.001) were independent risk factors for permanent stoma, and a nomogram was established. The AUCs of the nomogram were 0.842 and 0.858 in the primary and validation cohorts, respectively. The calibration curves showed good calibration in both cohorts. Decision curve analysis demonstrated that the nomogram was clinically useful. CONCLUSION: We developed and validated a nomogram for ultralow rectal adenocarcinoma patients who underwent LS-ISR, and the nomogram could help surgeons identify which patients are at a higher risk of a permanent stoma after surgery.

6.
Life Sci ; 272: 119189, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33571516

RESUMO

AIMS: Acute pancreatitis (AP) is an inflammatory disease of the pancreas that may affect local tissues or remote organ systems, while severe acute pancreatitis (SAP) is a life-threatening disorder associated with multiple organ failure. In this investigation, we set about to determine whether microRNA-29a-3p (miR-29a-3p) carried by mesenchymal stem cell (MSCs)-derived extracellular vesicles (EVs) affects the myocardial injury during SAP. MAIN METHODS: EVs were isolated from MSCs of rat bone marrow by differential centrifugation. An SAP rat model was developed and treated with MSCs-EVs and/or alteration of miR-29a-3p and HMGB1 expression, followed by assessment of the rats' cardiac function and inflammation. Next, cardiomyocytes H9C2 were co-cultured with MSC-EVs and internalization of EVs was evaluated, followed by evaluation of whether EVs could transmit miR-29a-3p cargos into H9C2 cells and affect their biological functions. KEY FINDINGS: EVs derived from MSCs were observed to protect against SAP-induced myocardial injury. In SAP-induced rats, miR-29a-3p was under-expressed in myocardial tissues. In addition, we also confirmed that miR-29a-3p could be transferred into the H9C2 cardiomyocytes by MSC-derived EVs, which downregulated the expression of inflammatory markers and improve cardiac function to attenuate myocardial injury. Furthermore, miR-29a-3p inhibited the expression of HMGB1 to downregulate TLR4 expression and further inactivate the Akt signaling pathway. SIGNIFICANCE: These findings support the cardioprotective action of miR-29a-3p transmitted by MSCs-derived EVs in SAP-induced myocardial injury via downregulation of the HMGB1/TLR4/Akt axis, highlighting a promising target for the EV-based therapy for SAP.


Assuntos
MicroRNAs/genética , Isquemia Miocárdica/genética , Isquemia Miocárdica/prevenção & controle , Animais , Apoptose/genética , China , Vesículas Extracelulares/genética , Vesículas Extracelulares/metabolismo , Coração/fisiologia , Inflamação/metabolismo , Masculino , Células-Tronco Mesenquimais/metabolismo , MicroRNAs/metabolismo , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Pancreatite/complicações , Pancreatite/genética , Pancreatite/metabolismo , Substâncias Protetoras/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/genética
7.
BMC Nephrol ; 22(1): 28, 2021 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-33441103

RESUMO

BACKGROUND: Roxadustat has been shown effective in treating patients with anemia due to chronic kidney disease. However, its long-term effect on clinical outcomes and socioeconomic burden and safety remains unclear. METHODS/DESIGN: This is a multicenter, prospective, longitudinal observational cohort study assessing if Roxadustat improves prognosis in dialysis patients. Primary outcomes will be major adverse cardiovascular events (MACE), defined as composites of cardiovascular death, myocardial infarction, cerebral infarction, hospitalization because of heart failure; all-cause mortality, and annual economic costs in two years. The data will be collected via Research electronic data capture (REDCap) based database as well as software-based dialysis registry of Sichuan province. The primary outcomes for the ROAD study participants will be compared with those in the dialysis registry cohort. Data at baseline and study follow up will also be compared to assess the association between Roxadustat and long-term clinical outcomes. DISCUSSION: The main objective of this study is to the assess long-term association of Roxadustat on MACE, all-cause mortality, socio-economic burden, safety in dialysis patients, which will provide guidance for designing further large randomized controlled trials to investigate this clinic question. STUDY REGISTRATION: The study has been registered in Chinese Clinical Trials Registry (ROAD, ROxadustat in treating Anemia in Dialysis patients, registration number ChiCTR1900025765) and provincial observational cohort database (Renal disEAse observational CoHort database, REACH, ChiCTR1900024926), registered 07 September 2019, http://www.chictr.org.cn .

8.
Clin Transl Sci ; 14(4): 1222-1230, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33503308

RESUMO

In order to encourage innovative medicine to address Chinese unmet medical needs, China has changed its drug regulatory landscape to speed up access to new medicines. In order to understand the fast-changing landscape and to enable planning of more global drug development programs and study designs in China, we reviewed 15 published clinical pharmacology-related guidances by the National Medical Products Administration (NMPA), and compared them with reference guidances from the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), or the International Conference on Harmonization (ICH), to understand the similarities and differences, especially any China-specific requirements, such as ethnic sensitivity analysis. Overall, by reviewing these clinical pharmacology-related NMPA guidances, it is clear that NMPA guidances are very similar to FDA, EMA, and ICH guidances. There are no relevant differences in the major principles, but some differences in structure, contents, and focus were noted. The NMPA is adapting flexibility statements into newly published guidances. Ethnic sensitivity analysis needs to be implemented early in drug development plans. The NMPA encourages sponsors to conduct early clinical trials in China or include China early in multiregional clinical trials, and to obtain safety, efficacy, and pharmacokinetic data for ethnic sensitivity analysis. Depending on the stage of development, ethnic sensitivity analysis can be conducted using in vitro or literature data, other Asian clinical data, or Chinese clinical data.

9.
Front Pharmacol ; 11: 585487, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33381036

RESUMO

Type 2 diabetes mellitus (T2DM) is a chronic disease that has become a global public health problem. Studies on T2DM prevention and treatment mostly focus on discovering therapeutic drugs. Artemisinin and its derivatives were originally used as antimalarial treatments. In recent years, the roles of artemisinins in T2DM have attracted much attention. Artemisinin treatments not only attenuate insulin resistance and restore islet ß-cell function in T2DM but also have potential therapeutic effects on diabetic complications, including diabetic kidney disease, cognitive impairment, diabetic retinopathy, and diabetic cardiovascular disease. Many in vitro and in vivo experiments have confirmed the therapeutic utility of artemisinin and its derivatives on T2DM, but no article has systematically demonstrated the specific role artemisinin plays in the treatment of T2DM. This review summarizes the potential therapeutic effects and mechanism of artemisinin and its derivatives in T2DM and associated complications, providing a reference for subsequent related research.

10.
Nephrology (Carlton) ; 25(11): 829-838, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32108975

RESUMO

OBJECTIVE: To further determine the efficacy and safety of direct-acting antiviral (DAA)-based treatments in hepatitis C virus (HCV) infected patients with renal function impairment. METHODS: MEDLINE, EMBASE and the Cochrane Library were searched for relevant studies. All studies assessing the efficacy and safety of DAA-based treatments against HCV infection in patients with renal impairment and HCV infection were eligible for inclusion. Outcomes assessed included efficacy outcomes and safety outcomes. Summary estimates were obtained using an inverse-variance weighted random effect model and Freeman-Tukey double arcsine transformation. RESULTS: Twenty-seven studies (n = 1048 participants) were included. The majority of included studies were of fair quality with Newcastle-Ottawa scale scores between 4 and 6. The pooled virologic response rates at the end of treatment or 4, 12, 24 weeks after treatment (ie, EOTR, SVR4, SVR12 and SVR24 rates) were 97.0% (95% confidence interval [CI], 94.0%-99.0%), 80.9% (95% CI, 49.3%-98.7%), 94.1% (95% CI, 91.6%-96.3%) and 89.6% (95% CI, 75.5%-98.1%), respectively. The pooled relapse rate was 6.4% (95% CI, 3.4%-10.4%). The pooled incidence of adverse events and severe adverse events leading to discontinuation were 47.6% (95% CI, 35.0%-60.4%) and 2.9% (95% CI, 1.4%-5.0%), respectively. High heterogeneity among studies exists for SVR4 and SVR24 rates. Formal statistical testing did not identify the presence of publication bias for all measured outcomes except the relapse rate. CONCLUSION: The results support the efficacy and safety of DAA-based treatments in this population. Future studies with better design, larger sample size and longer follow up will be the next step. SUMMARY AT A GLANCE This systematic review evaluated the efficacy and safety of direct-acting antiviral based therapies in hepatitis C infection in patients with renal impairment. The majority of studies were of fair quality only. These therapies were found to be highly efficacious although there were high rates of adverse events.

11.
Trials ; 21(1): 219, 2020 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-32093742

RESUMO

BACKGROUND: Idiopathic membranous nephropathy (IMN) remains the leading cause of adult nephrotic syndrome. Immunosuppressive therapy with cyclophosphamide (CTX) is often successful in reducing proteinuria, but its use is associated with severe side effects. Tacrolimus (TAC) is effective in achieving complete remission (CR) in patients with IMN. However, whether it is as effective as CTX in inducing and maintaining complete or partial remission in these patients is unknown. This trial aims to test TAC monotherapy for its non-inferiority to CTX in inducing long-term remission of proteinuria. METHODS: Patients with biopsy-proven IMN with nephrotic syndrome will be randomized into a 12-month treatment period with oral TAC of 0.05-0.1 mg/kg/day for 6 months or with CTX + glucocorticoid. The efficacy of the treatment will be assessed by the remission status (based on changes in proteinuria) and relapse rate. DISCUSSION: This study will test whether treatment with TAC monotherapy is superior to CTX with glucocorticoid in inducing long-term remission of proteinuria in patients with adult IMN. The role of serum anti-PLA2R antibodies in the early assessment of the response to therapy using different therapeutic regimens will also be clarified. TRIAL REGISTRATION: ClinicalTrials.gov ChiCTR1800016140. Registered 12 June 2017. http://www.chictr.org.cn.


Assuntos
Ciclofosfamida/administração & dosagem , Glomerulonefrite Membranosa/tratamento farmacológico , Glucocorticoides/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Tacrolimo/uso terapêutico , Adolescente , Adulto , Idoso , Autoanticorpos/sangue , Ciclofosfamida/efeitos adversos , Quimioterapia Combinada , Glucocorticoides/efeitos adversos , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Receptores da Fosfolipase A2/imunologia , Tacrolimo/efeitos adversos , Adulto Jovem
12.
Clin Pharmacol Drug Dev ; 9(7): 833-840, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-31960624

RESUMO

Tezepelumab, a human immunoglobulin G2 monoclonal antibody against thymic stromal lymphopoietin, is currently under clinical development for the treatment of severe, uncontrolled asthma. This phase 1, randomized, placebo-controlled, single-ascending-dose study assessed the safety, tolerability, pharmacokinetics, and immunogenicity of subcutaneous tezepelumab in healthy Japanese men. Participants were assigned to 1 of 3 tezepelumab dose cohorts (35, 105, or 280 mg; n = 8 per cohort) and randomized (6:2) to receive a single subcutaneous dose of tezepelumab or placebo, with a follow-up period of 84 to 112 days. The overall incidences and severities of treatment-emergent adverse events were similar across tezepelumab doses and between the tezepelumab and placebo groups. Tezepelumab was absorbed slowly, reaching a maximum serum concentration (mean, 5.2-39.7 µg/mL) after 7 to 10 days. Area under the concentration-time curve (mean, 207.2-1612.0 µg · day /mL) increased in an approximate dose-proportional manner. Tezepelumab had a long terminal serum half-life (mean, 23.9-26.3 days) and a small apparent distribution volume, suggesting limited distribution into peripheral tissues. No participants developed anti-tezepelumab antibodies. Single-dose, subcutaneous administration of tezepelumab 35 to 280 mg resulted in an acceptable safety profile with linear pharmacokinetics in healthy Japanese men. No clear differences in tezepelumab safety and pharmacokinetics between Japanese and non-Japanese populations were identified.


Assuntos
Anticorpos Monoclonais Humanizados/farmacocinética , Asma/tratamento farmacológico , Citocinas/antagonistas & inibidores , Fenômenos do Sistema Imunológico/efeitos dos fármacos , Imunoglobulina G/farmacologia , Adulto , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/imunologia , Grupo com Ancestrais do Continente Asiático/etnologia , Asma/sangue , Asma/imunologia , Índice de Massa Corporal , Estudos de Casos e Controles , Relação Dose-Resposta a Droga , Esquema de Medicação , Voluntários Saudáveis/estatística & dados numéricos , Humanos , Imunoglobulina G/imunologia , Injeções Subcutâneas , Masculino , Efeito Placebo , Segurança , Índice de Gravidade de Doença
13.
Platelets ; 31(8): 1019-1027, 2020 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-31851564

RESUMO

Thrombocytopenia is a common hematological abnormality in patients with cirrhotic hypersplenism. Splenectomy with paraesophagogastric devascularization (SPD) is a conventional surgical therapy which can reverse pancytopenia in these patients. Platelets are traditionally recognized for their central role in hemostasis. However, the status of platelet aggregation in chronic hepatitis B patients with cirrhotic hypersplenism before and after SPD has not been reported yet. A total of 41 cirrhotic patients and 31 healthy controls were included in this study. Platelet aggregation was detected by AggRAM® Advanced Modular System (Helena Laboratories, USA). ELISA was used to detect the cytokines closely related to platelet aggregation. Expressions of platelet membrane glycoproteins (GPs) were evaluated by flow cytometric analysis. Platelet aggregation was found to be decreased distinctly in the cirrhotic patients, and to be restored to normal level after SPD. The cirrhotic patients showed higher plasma levels of the cytokines HMGB1, PEDF, vWF, cAMP and cGMP, which also improved partially after SPD. Moreover, the cirrhotic patients had much lower expression of GPIIb/IIIa, GPIbα and P-selectin than either the healthy controls or SPD patients at basal or activated level. Generally, SPD benefits cirrhotic patients with bleeding tendencies by improving platelet counts and aggregation. GPIIb/IIIa may be the key membrane protein responsible for the change in platelet aggregation before and after SPD.


Assuntos
Fibrose/etiologia , Hepatite B Crônica/complicações , Hepatite B Crônica/cirurgia , Hiperesplenismo/etiologia , Agregação Plaquetária/fisiologia , Esplenectomia/métodos , Adulto , Estudos de Casos e Controles , Feminino , Fibrose/patologia , Hepatite B Crônica/sangue , Humanos , Hiperesplenismo/patologia , Masculino , Pessoa de Meia-Idade
14.
Clin Pharmacokinet ; 59(4): 447-462, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31788764

RESUMO

BACKGROUND AND OBJECTIVE: Several review articles have been published discussing gastric acid-related drug-drug interactions (DDIs) mediated by coadministration of antacids, histamine H2 receptor antagonists, or proton pump inhibitors, but are not sufficiently comprehensive in capturing all documented DDIs with acid-reducing agents (ARAs) and tend to focus on gastric pH-dependent DDIs and/or basic drugs. Subsequently, several new drugs have been approved, and new information is available in the literature. The objective of this systematic review is to comprehensively identify oral medications that have clinically meaningful DDIs, including loss of efficacy or adverse effects, with gastric ARAs, and categorize these medications according to mechanism of interaction. METHODS: An indepth search of clinical data in the PDR3D: Reed Tech Navigator™ for Drug Labels, University of Washington Drug-Drug Interaction Database, DailyMed, Drugs@FDA.gov, and UpToDate®/Lexicomp® Drug and Drug Interaction screening tool was conducted from 1 June to 1 August 2018. The PDR3D, University of Washington Drug-Drug Interaction Database, and DailyMed were searched with terms associated with gastric acid and ARAs. Conflicting findings were further investigated using the UpToDate®/Lexicomp® screening tool. Clinical relevance was assessed on whether an intervention was needed, and prescribing information and/or literature supporting the DDI. RESULTS: Through the search strategy, 121 medications were found to clinically meaningfully interact with ARAs. For 38 medications the mechanism of interaction with ARAs was identified as gastric pH dependent, and for 83 medications the interaction was found to be not gastric pH mediated, with mechanisms involving metabolic enzymes, transporters, chelation, and urine alkalization. Additionally, 109 medications were studied and did not have a clinically meaningful interaction with ARAs. CONCLUSION: This review may provide a resource to healthcare professionals in aiding the care of patients by increasing awareness of interactions with ARAs and may also identify and potentially aid in avoiding clinically relevant DDIs and preventing risk of treatment failure and/or adverse effects. Advances in non-clinical predictions of gastric pH-mediated DDIs may guide the need for a future clinical evaluation.


Assuntos
Ácido Gástrico/química , Antagonistas dos Receptores H2 da Histamina/farmacocinética , Inibidores da Bomba de Prótons/farmacocinética , Substâncias Redutoras/farmacocinética , Administração Oral , Pessoal Técnico de Saúde/educação , Conscientização , Bases de Dados Factuais , Interações Medicamentosas , Antagonistas dos Receptores H2 da Histamina/administração & dosagem , Antagonistas dos Receptores H2 da Histamina/farmacologia , Humanos , Concentração de Íons de Hidrogênio/efeitos dos fármacos , Preparações Farmacêuticas , Inibidores da Bomba de Prótons/administração & dosagem , Inibidores da Bomba de Prótons/farmacologia , Substâncias Redutoras/administração & dosagem , Substâncias Redutoras/efeitos adversos , Substâncias Redutoras/farmacologia , Segurança , Resultado do Tratamento
15.
Int Urol Nephrol ; 51(4): 677-690, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30830657

RESUMO

BACKGROUND: Hepatitis B virus (HBV) infection is a public health challenge, especially in China. In clinical practice, HBV infection is associated with nephropathy. Impaired renal function is frequently observed in compensated Chronic Hepatitis B (CHB) and cirrhosis (LC). Thus, renal function must be monitored to avoid nephrotoxic effects before and during nucleoside analog treatment. Investigating the predictive markers of early renal dysfunction is essential. New GFR-predicting equations, based on Pcr and/or CystC, have been recently recommended in the general population, but their performance in liver disease patients has been rarely studied. In this study, we will discuss how to detect renal dysfunction in patients with HBV infection. METHODS: A total of 16 LC patients and 23 CHB patients were enrolled in this study, and we collected and compared the clinical data of the two groups. The estimated glomerular filtration rates (eGFRs) were also calculated by several equations. All patients received 99mTc-DTPA dynamic radionuclide imaging examinations to obtain mGFRs as the reference standard. To evaluate the performance of any equation in the CHB and LC groups, paired t test, Pearson's correlation, Kappa analysis and Bland-Altman plots were utilized. Moreover, all 39 subjects were divided into two groups (according to GFR > 90 mL/min/1.73 m2). We compared the serum and urinary markers of kidney injury between the two groups and selected the indicators of renal injury by univariate analysis. RESULTS: The mGFR was 72.26 ± 20.69 mL/min/1.73 m2 in the LC group, and 87.49 ± 25.91 mL/min/1.73 m2 in the CHB group. The paired t test results of eGFR and mGFR showed no difference between eGFR (estimated by the CHINAcr-cys equation) and mGFR (p > 0.05) in the compensated LC and CHB groups. The difference between mGFR and eGFR estimated by other methods was obvious (p < 0.05). Comparing the eGFRs (estimated by 5 different equations) with mGFR in the compensated LC and CHB groups, Pearson's correlation showed that only eGFR (estimated by the CHINAcr-cys equation) had a significant correlation coefficient in CHB (r = 0.678, p = 0.000) and had the highest R2 (R2 = 0.459) among all other measures. The kappa consistency test showed that eGFR from CHINAscr-cys had poor consistency with mGFR in the compensated LC group but moderate consistency in the CHB group. Bland-Altman consistency analysis showed that in the CHB group, the CHINAcr-cys and CKD-EPIcr equations presented narrower acceptable limits than did the aMDRD, c-aMDRD, and CKD-EPIcr-cys equations (62.8, 56.1 vs .85.7, 102.9, 93.6 mL/min per 1.73 m2). In the compensated LC group, the CHINAcr-cys and CKD-EPIcr equations presented narrower acceptable limits than did the aMDRD, c-aMDRD, and CKD-EPIcr-cys equations (83.6, 81.3 vs. 98, 113.5, 106.3 mL/min per 1.73 m2). Serum or urinary markers were compared with renal function (GFR > 90 mL/min/1.73 m2) and showed International normalized ratio (INR) (p = 0.009), creatinine (p = 0.006), urine N-acetyl-ß-glucosaminidase (NAG) (p = 0.001) and serum cystatin C (CysC) (p = 0.044). CONCLUSION: The CHINAcr-cys equation may be more suitable for the estimation of GFR in Chinese patients with CHB or compensated cirrhosis. INR, creatinine, NAG, and CysC are proper biomarkers for screening renal dysfunction in Chinese patients with CHB or compensated LC.


Assuntos
Taxa de Filtração Glomerular , Hepatite B Crônica/fisiopatologia , Rim/fisiopatologia , Cirrose Hepática/fisiopatologia , Conceitos Matemáticos , Acetilglucosaminidase/urina , Adulto , Creatinina/sangue , Creatinina/urina , Cistatina C/sangue , Feminino , Humanos , Coeficiente Internacional Normatizado , Rim/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único , Pentetato de Tecnécio Tc 99m
16.
Clin Pharmacol Drug Dev ; 8(4): 549-558, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30500110

RESUMO

Saxagliptin is an orally administered, highly potent, and selective dipeptidyl peptidase-4 inhibitor for the management of type 2 diabetes mellitus. This study was conducted to determine the effect of magnesium and aluminum hydroxides plus simethicone, famotidine, and omeprazole on the pharmacokinetics of saxagliptin and its active metabolite, 5-hydroxy saxagliptin. This was an open-label, randomized, 5-treatment, 5-period, 3-way crossover study in 15 healthy subjects. Mean Cmax of saxagliptin was 26% lower, but AUC was almost unchanged when saxagliptin was coadministered with Maalox Max. Mean Cmax was 14% higher, but AUC was almost unchanged when saxagliptin was coadministered with famotidine. Changes in pharmacokinetics of 5-hydroxy saxagliptin generally paralleled the changes in saxagliptin. These pharmacokinetic changes were unlikely to be clinically meaningful. Coadministration of omeprazole did not affect saxagliptin Cmax or AUC. Saxagliptin in combination with these medicines resulted in no unexpected safety or tolerability findings in these healthy subjects. No dose adjustment of saxagliptin or separation in the time of saxagliptin dosing is necessary with medicines that raise gastric pH when coadministered with saxagliptin.


Assuntos
Adamantano/análogos & derivados , Hidróxido de Alumínio/administração & dosagem , Dipeptídeos/farmacocinética , Famotidina/administração & dosagem , Hidróxido de Magnésio/administração & dosagem , Omeprazol/administração & dosagem , Simeticone/administração & dosagem , Adamantano/administração & dosagem , Adamantano/sangue , Adamantano/farmacocinética , Adulto , Área Sob a Curva , Estudos Cross-Over , Dipeptídeos/administração & dosagem , Dipeptídeos/sangue , Combinação de Medicamentos , Interações Medicamentosas , Feminino , Voluntários Saudáveis , Humanos , Masculino , Taxa de Depuração Metabólica , Adulto Jovem
17.
BMC Nephrol ; 19(1): 316, 2018 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-30409112

RESUMO

BACKGROUND: Kimura's disease (KD) is a rare chronic inflammatory disorder with a high incidence of renal involvement. In this report, we present a case study of KD-associated nephrotic syndrome combined with minimal change disease (MCD) and acute renal tubular injury. Meanwhile, the clinical and histopathological characteristics of 26 patients with KD presenting with renal involvement were retrospectively evaluated. CASE PRESENTATION: Here, we report a case study of a 59-year-old male patient with KD confirmed by a lymph node biopsy. He developed widespread edema and decreased urine output. A palpable swollen mobile and non-tender lymph node behind the left ear was observed upon admission. A renal biopsy revealed minimal-change lesions and acute renal tubular injury. The patient received hemodialysis because of the oliguria and renal insufficiency, and an initial dose of 40 mg/d methylprednisolone and then continued treatment with 40 mg/d prednisolone. He exhibited a good clinical response to the steroid after 6 weeks of treatment. Of the other 26 patients included in the review, 13 patients presented with mesangial proliferative glomerulonephritis, 4 with membranous nephropathy, 3 with MCD, 3 with focal segmental glomerulosclerosis, 2 with IgA nephropathy and 1 with acute tubular injury. With the exception of 2 patients who progressed to end-stage renal disease and received hemodialysis, the majority of patients responded well to treatment with corticosteroids alone. CONCLUSIONS: MCD combined with acute renal tubular injury is rare in patients with KD presenting with renal involvement. Corticosteroids may be a beneficial treatment for renal injury in patients with KD.


Assuntos
Hiperplasia Angiolinfoide com Eosinofilia/complicações , Hiperplasia Angiolinfoide com Eosinofilia/diagnóstico , Nefrose Lipoide/complicações , Nefrose Lipoide/diagnóstico , Síndrome Nefrótica/complicações , Síndrome Nefrótica/diagnóstico , Hiperplasia Angiolinfoide com Eosinofilia/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Nefrose Lipoide/sangue , Síndrome Nefrótica/sangue
18.
Sci Rep ; 8(1): 13662, 2018 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-30209279

RESUMO

To compare the long-term efficacy of corticosteroids (P) alone or in combination with cyclophosphamide (CTX), leflunomide (LEF), or Angiotensin-convertase inhibitors or angiotensin II receptor blockers (ACEI/ARB) in treatment for IgA nephropathy (IgAN), 311 patients with IgAN were identified. Therapeutic effectiveness (including progression, partial remission, complete remission) and combined renal endpoint (defined as 30% reduction in eGFR or ESRD) were compared based on different therapies. After immunosuppressive and ACEI/ARB treatment, the levels of eGFR, proteinuria and albumin were significantly improved at the last follow-up, the extent of improvement of eGFR, proteinuria, and albumin was more notable in P + CTX group and P + LEF group. 41%, 52.2%, 55.3% and 55.2% in P + CTX, P + LEF, P and ACEI/ARB group achieved complete remission, respectively. Multivariate regression analysis indicated that only proteinuria (Relative risk (RR) 0.82(0.72-0.94), P = 0.004) and tubular atrophy/interstitial fibrosis (RR 0.26(0.13-0.57), P = 0.001) were predictors for complete remission. The optimal cutoffs of eGFR was 47.085 ml/min/1.73 m2 predicting renal function recovery in P + CTX therapy. In conclusion, tubular atrophy/interstitial fibrosis and massive proteinuria were poor predictors for complete remission in IgAN, it appears as though patients may have benefited from immunosuppressive treatment but that comparison to a well-matched contemporary control group or, ideally, a randomized controlled clinical trial, would be required to show this.


Assuntos
Corticosteroides/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Tratamento Conservador/métodos , Ciclofosfamida/uso terapêutico , Glomerulonefrite por IGA/tratamento farmacológico , Imunossupressores/uso terapêutico , Leflunomida/uso terapêutico , Adulto , Albuminúria/urina , Feminino , Taxa de Filtração Glomerular/fisiologia , Humanos , Imunossupressão/métodos , Túbulos Renais/patologia , Masculino , Nefrite Intersticial/patologia , Proteinúria/urina , Estudos Retrospectivos , Resultado do Tratamento
19.
Magn Reson Imaging ; 52: 46-52, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29852212

RESUMO

PURPOSE: To investigate the diagnostic value of intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) for discriminating axillary metastatic from non-metastatic lymph nodes (LNs) in rabbit models. MATERIALS AND METHODS: The institutional animal care and use committee approved this study. Forty New Zealand white rabbits were randomly divided into two groups. The axillary LN models were created by inoculating VX2 cell suspension and complete Freund's adjuvant in the mammary glands of 20 female rabbits of each group, respectively. Conventional MRI and IVIM DWI were performed after animal models successfully established. Images of axillary LNs were analyzed with regard to long-axis diameter (L), short-axis diameter (S), apparent diffusion coefficient (ADC) and IVIM parameters (D, D*, f). Receiver operating characteristic analyses were conducted to determine the diagnostic performance of aforementioned criteria. RESULTS: A total of 42 metastatic and 30 non-metastatic LNs were successfully isolated. ADC and D of metastatic LNs were significantly lower than those of non-metastatic ones (all P < 0.001), whereas D* was statistically higher (P = 0.033). L, S, and f showed no significant difference between the two groups (P = 0.089, 0.058, 0.054, respectively). Optimal cutoff values, area under the curve, sensitivity, and specificity for differentiation were as follows: ADC = 1.101 × 10-3 mm2/s, 0.886, 78.6%, 90.0%; D = 0.938 × 10-3 mm2/s, 0.927, 83.3%, 93.3%; and D* = 12.635 × 10-3 mm2/s, 0.657, 52.4%, 80.0%. CONCLUSION: IVIM DWI is useful to distinguish metastatic from non-metastatic LNs in axilla. D was the most discriminative variable for predicting metastatic LNs.


Assuntos
Imagem de Difusão por Ressonância Magnética/métodos , Linfonodos/diagnóstico por imagem , Linfonodos/patologia , Neoplasias Mamárias Experimentais/patologia , Animais , Axila , Modelos Animais de Doenças , Feminino , Humanos , Metástase Linfática/patologia , Movimento (Física) , Curva ROC , Coelhos , Sensibilidade e Especificidade
20.
Dig Dis Sci ; 63(7): 1860-1867, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29721775

RESUMO

BACKGROUND: Hematopoietic abnormality is a common cause of cirrhotic hypersplenism (CH) complications and death; it causes serious adverse effects and is associated with bleeding, anemia, infection in CH patients. However, the underlying mechanism is unclear. AIMS: We aimed to investigate the effects of the spleen on hematopoiesis and hematopoietic stem/progenitor cells (HSPCs) in CH patients. METHODS: Eleven CH patients were enrolled to assess the effects of the spleen on HSPC functions. Hematopoietic changes were examined by flow cytometry analysis. HSPC functions were detected with colony-forming assays and in vitro cell cultures. Enzyme-linked immunosorbent assay (ELISA) was used to test the concentration of epithelial growth factor (EGF). RESULTS: The number of HSPCs was decreased in CH patients and was rescued after splenectomy. Serum from CH patients dysregulated HSPCs function, and serum from splenectomy patients restored the dysregulated HSPC function in vitro. The concentration of EGF was decreased in CH patients and was restored to normal level after splenectomy. EGF rescued the dysregulated HSPCs function in vitro. CONCLUSIONS: The spleen can regulate the functions of HSPCs in CH patients by regulating EGF signaling. EGF may be a therapeutic target for CH treatment.


Assuntos
Fator de Crescimento Epidérmico/metabolismo , Hematopoese Extramedular , Células-Tronco Hematopoéticas/metabolismo , Hiperesplenismo/etiologia , Cirrose Hepática/complicações , Baço/metabolismo , Proliferação de Células , Células Cultivadas , Fator de Crescimento Epidérmico/sangue , Feminino , Células-Tronco Hematopoéticas/patologia , Humanos , Hiperesplenismo/metabolismo , Hiperesplenismo/patologia , Hiperesplenismo/cirurgia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Transdução de Sinais , Baço/patologia , Baço/cirurgia , Esplenectomia , Fatores de Tempo , Resultado do Tratamento
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