RESUMO
BACKGROUND: Dinutuximab ß can be used to treat children with high-risk neuroblastoma (NB). Due to its high price, whether dinutuximab ß is cost-effective for the treatment of high-risk NB remains uncertain. Therefore, assessing the cost-effectiveness of dinutuximab ß in children with high-risk NB is of high importance. METHODS: The health utilities and economic outcomes in children with high-risk NB were projected using a partitioned survival model. The individual patient data (IPD) of add-on treatment with dinutuximab ß (GD2 group) were derived from the literature, while the IPD of traditional therapy (TT group) were obtained from retrospective data of Shanghai Children's Medical Center. Treatment costs included drugs, adverse event-related expenses, and medical resource use. Utility values were obtained from the literature. Costs and quality-adjusted life-years (QALYs) were measured over a 10-year time horizon. Deterministic sensitivity analyses (DSA) and probabilistic sensitivity analyses (PSA) were also conducted. RESULTS: Compared with the TT group, QALY increased in the GD2 group by 0.72 with an increased cost of $171,269.70, leading to an incremental cost-effectiveness ratio of 236,462.75$/QALY. DSA showed that the price of dinutuximab ß was the main factor on the results than other parameters. Compared with the TT group, the GD2 group could not be cost-effective in the PSA at the $37,920/QALY threshold. CONCLUSION: Results found that dinutuximab ß is not a cost-effective treatment option for children with high-risk NB unless its price is significantly reduced.
RESUMO
Novel furoxan/coumarin hybrids were synthesized, and pharmacologic studies showed that the compounds displayed potent antiproliferation activities via downregulating both the phosphatidylinositide 3-kinase (PI3K) pathway and the mitogen-activated protein kinase (MAPK) pathway. To investigate the preclinical pharmacokinetic (PK) properties of three candidate compounds (CY-14S-4A83, CY-16S-4A43, and CY-16S-4A93), liquid chromatography, in tandem with the mass spectrometry LC-MS/MS method, was developed and validated for the simultaneous determination of these compounds. The absorption, distribution, metabolism, and excretion (ADME) properties were investigated in in vitro studies and in rats. Meanwhile, physiologically based pharmacokinetic (PBPK) models were constructed using only in vitro data to obtain detailed PK information. Good linearity was observed over the concentration range of 0.01−1.0 µg/mL. The free drug fraction (fu) values of the compounds were less than 3%, and the clearance (CL) values were 414.5 ± 145.7 mL/h/kg, 2624.6 ± 648.4 mL/h/kg, and 500.6 ± 195.2 mL/h/kg, respectively. The predicted peak plasma concentration (Cmax) and the area under the concentration-time curve (AUC) were overestimated for the CY-16S-4A43 PBPK model compared with the experimental ones (fold error > 2), suggesting that tissue accumulation and additional elimination pathways may exist. In conclusion, the LC-MS/MS method was successively applied in the preclinical PK studies, and the detailed information from PBPK modeling may improve decision-making in subsequent new drug development.
Assuntos
Oxidiazóis , Espectrometria de Massas em Tandem , Ratos , Animais , Cromatografia Líquida/métodos , Espectrometria de Massas em Tandem/métodos , Cumarínicos , Modelos Biológicos , FarmacocinéticaRESUMO
OBJECTIVE: To investigate the effect of G protein-coupled receptor 17 (GPR17) on hypoxia injury in retinal ganglion cells in vitro. METHODS: CoCl2 (400 µmol/L) was used to induce hypoxic injury in RGC-5 cells. The expression of GPR17 and the effect of GPR17 ligands were investigated, and the role of GPR17 in hypoxia injury was further studied by transfection of RGC-5 cells with GPR17 small interfering RNA (siRNA). The cell viability was determined by MTT and the cell apoptosis rate was detected by flow cytometry analysis. The expression of GPR17 mRNA was determined with RT-PCR. RESULTS: mRNA expressions of GPR17 in RGC-5 cells with and without CoCl2 treatment were 0.36±0.05 and 0.26±0.08(P<0.01). Compared with hypoxia without any treatment, pretreatment with GPR17 agonists (LTD4, UDP, UDP-G) significantly reduced cell viability (the survival rates of cells decreased by 29.6%, 31.8% and 33.9%, all P<0.01), while the effect of GPR17 antagonist (cangrelor) was the opposite (the survival rates of cells increased by 33.2%, P<0.01). Transfection with GPR17 SiRNA inhibited hypoxia-induced up-expression of GPR17 mRNA (P<0.01)and reduced cell apoptosis[rates of cell apoptosis were(39.73±2.06)%,(42.50±3.64)% and (24.98±2.16)% for blank control, NC siRNA and GPR17 siRNA groups, P<0.01]. CONCLUSIONS: GPR17 may mediate hypoxia injury in RGC-5 cells, while the knockdown of GPR17 can reduce the hypoxia injury.
Assuntos
Sobrevivência Celular , Hipóxia , Receptores Acoplados a Proteínas G , Células Ganglionares da Retina , Apoptose , Hipóxia Celular/genética , Linhagem Celular , Cobalto , Regulação da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Hipóxia/induzido quimicamente , Hipóxia/genética , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Células Ganglionares da Retina/efeitos dos fármacosRESUMO
Background: Neurokinin-1 receptor antagonists have improved the management of chemotherapy-induced nausea and vomiting (CINV), but to date there has been no prospective comparison between oral aprepitant and intravenous fosaprepitant in pediatric oncology patients. Methods: Our study was a double-parallel study, and the distribution ratio was 1:1. Children aged 2-12 years who were undergoing moderate or highly emetogenic chemotherapy (MEC or HEC) were randomly assigned to receive ondansetron and dexamethasone combined with either a single dose of intravenous fosaprepitant (arm A), or 3 days of oral aprepitant (arm B). The primary outcome measure was the rate of complete response (CR) of CINV within the acute phase, defined as from the start through 24 hours after the last chemotherapy dose. Response during the delayed phase, overall response, and use of rescue antiemetics were also assessed. Results: We prospectively evaluated 108 eligible patients, including 55 receiving fosaprepitant. Study observations were made during a single cycle for each patient. The occurrence of CR in the acute phase was statistically higher for patients receiving fosaprepitant (95% vs. 79%, P=0.018<0.05). Modest differences were seen in CR rates during the delayed phase (71% vs. 66%, P=0.586), and overall response rate (69% vs. 57%, P=0.179). The use of antiemetic rescue medicines was similar between arms A (11%) and B (7%). Conclusions: Fosaprepitant produced more CRs of CINV in the acute phase than did aprepitant, although there were no statistical differences in delayed phase response, overall response, or use of rescue antiemetics. This study confirms the safety, efficacy, and potential advantages of fosaprepitant in reducing CINV in pediatric oncology patients. Trial Registration: ClinicalTrials.gov identifier: NCT04873284.
RESUMO
Vincristine (VCR) is a vital component in numerous treatment regimens for pediatric blood cancer. VCR-induced peripheral neuropathy (VIPN) represents a type of VCR toxicity influenced by multiple factors, including age, race, genetic traits, dosage, interactions, and administration regimen. However, the dose-response relationship of VIPN remains elusive. VCR is primarily metabolized by cytochrome P450 (CYP) 3 A to generate the major metabolite M1. To date, there is a lack of literature documenting the pharmacokinetics (PK) characteristics of VCR and M1 in Chinese children within a 96 h timeframe. To address the gap, a developed LC-MS/MS method was successfully employed in the PK study of VCR and M1 in Chinese pediatric acute lymphoblastic leukemia (ALL) patients. M1 was obtained through in vitro metabolism experiments, and mixed plasma samples of M1 and VCR were prepared. Plasma samples were pre-processed using the solid-phase extraction (SPE) technique. Samples were loaded into ProElut C18 Cartridges, washed with 5% methanol aqueous solution, and eluted with methanol. The eluent was concentrated and reconstituted for liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. The standard calibration curves for VCR and M1 were 0.1-50 ng/mL and 0.05-5 ng/mL, respectively, with linear coefficients exceeding 0.99. Accuracy and precision of quality control (QC) samples fell within 115%. The analytical approach satisfied the quantitative demands for VCR and M1 in plasma samples within 96 h. VCR was metabolized to M1 at a relatively constant proportion (5.37%-18.06%) of VCR in vivo. No significant differences were observed in PK parameters of VCR in Chinese children compared to other countries and races. Further investigation is required to identify the key factors influencing VIPN in Chinese children.
Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Espectrometria de Massas em Tandem , Vincristina , Criança , Humanos , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida , População do Leste Asiático , Metanol , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Espectrometria de Massas em Tandem/métodos , Vincristina/metabolismo , Vincristina/farmacocinética , Vincristina/uso terapêutico , ChinaRESUMO
Pharmacokinetic characterization plays a vital role in drug discovery and development. Although involving numerous laboratory animals with error-prone, labor-intensive, and time-consuming procedures, pharmacokinetic profiling is still irreplaceable in preclinical studies. With physiologically based pharmacokinetic (PBPK) modeling, the in vivo profiles of drug absorption, distribution, metabolism, and excretion can be predicted. To evaluate the application of such an approach in preclinical investigations, the plasma pharmacokinetic profiles of seven commonly used probe substrates of microsomal enzymes, including phenacetin, tolbutamide, omeprazole, metoprolol, chlorzoxazone, nifedipine, and baicalein, were predicted in rats using bottom-up PBPK models built with in vitro data alone. The prediction's reliability was assessed by comparison with in vivo pharmacokinetic data reported in the literature. The overall predicted accuracy of PBPK models was good with most fold errors within 2, and the coefficient of determination (R2) between the predicted concentration data and the observed ones was more than 0.8. Moreover, most of the observation dots were within the prediction span of the sensitivity analysis. We conclude that PBPK modeling with acceptable accuracy may be incorporated into preclinical studies to refine in vivo investigations, and PBPK modeling is a feasible strategy to practice the principles of 3Rs.
RESUMO
In order to improve the benefit-risk ratio of pharmacokinetic (PK) research in the early development of new drugs, in silico and in vitro methods were constructed and improved. Models of intrinsic clearance rate (CLint) were constructed based on the quantitative structure-activity relationship (QSAR) of 7882 collected compounds. Moreover, a novel in vitro metabolic method, the Bio-PK dynamic metabolic system, was constructed and combined with a physiology-based pharmacokinetic model (PBPK) model to predict the metabolism and the drug-drug interaction (DDI) of azidothymidine (AZT) and fluconazole (FCZ) mediated by the phase II metabolic enzyme UDP-glycosyltransferase (UGT) in humans. Compared with the QSAR models reported previously, the goodness of fit of our CLint model was slightly improved (determination coefficient (R2) = 0.58 vs. 0.25-0.45). Meanwhile, compared with the predicted clearance of 61.96 L/h (fold error: 2.95-3.13) using CLint (8 µL/min/mg) from traditional microsomal experiment, the predicted clearance using CLint (25 µL/min/mg) from Bio-PK system was increased to 143.26 L/h (fold error: 1.27-1.36). The predicted Cmax and AUC (the area under the concentration-time curve) ratio were 1.32 and 1.84 (fold error: 1.36 and 1.05) in a DDI study with an inhibition coefficient (Ki) of 13.97 µM from the Bio-PK system. The results indicate that the Bio-PK system more truly reflects the dynamic metabolism and DDI of AZT and FCZ in the body. In summary, the novel in silico and in vitro method may provide new ideas for the optimization of drug metabolism and DDI research methods in early drug development.
RESUMO
OBJECTIVE: This study aimed to investigate the correlation of L-asparaginase (L-asp) activity, anti-L-asp antibody, asparagine and glutamine levels with the risks of adverse events (AEs), especially anaphylaxis, in pediatric acute lymphoblastic leukemia (ALL) patients who underwent polyethylene glycol-conjugated L-asp (PEG-asp)-contained treatment. METHODS: Plasma samples were collected from 91 pediatric ALL patients who underwent PEG-asp-contained treatment on the 7th day after drug administration. Plasma L-asp activity, anti-L-asp antibody level, asparagine level and glutamine level were detected. Meanwhile, AEs related to PEG-asp administration were recorded. RESULTS: AEs occurred in 13 (14.3%) patients, among which 7 (7.7%) patients had anaphylaxis, while another 6 patients had non-anaphylaxis AEs (including 4 (4.4%) patients who had acute pancreatitis, 1 (1.1%) patient who had abdominal pain and diarrhea, as well as 1 (1.1%) patient who had nausea and vomiting). L-asp activity was decreased, while asparagine and glutamine levels were increased in patients with AEs compared to patients without AEs, and ROC curves showed that they were correlated with higher AEs risk. Notably, further analyses revealed that L-asp activity, anti-L-asp antibody, asparagine and glutamine levels were highly correlated with anaphylaxis risk, but they were not associated with the risk of non-anaphylactic AEs. CONCLUSION: The measurement of L-asp activity, anti-L-asp antibody level, asparagine level and glutamine level might assist the prevention of anaphylaxis-related AEs in pediatric ALL patients who underwent PEG-asp-contained treatment.
Assuntos
Anafilaxia/sangue , Anafilaxia/etiologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Asparaginase/sangue , Hipersensibilidade a Drogas/sangue , Hipersensibilidade a Drogas/etiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Adolescente , Fatores Etários , Anafilaxia/diagnóstico , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Asparaginase/antagonistas & inibidores , Asparagina/sangue , Biomarcadores/sangue , Criança , Pré-Escolar , Hipersensibilidade a Drogas/diagnóstico , Feminino , Glutamina/sangue , Humanos , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Prognóstico , Curva ROCRESUMO
BACKGROUND AND PURPOSE: Multidrug resistance (MDR) is a great challenge and obstacle in cancer treatment. It is a common problem in the treatment of acute myeloid leukemia (AML). Whether grape seed proanthocyanidin extract (GSPE) could reverse MDR in patients with AML is still unknown. The aim of this study was to investigate the MDR reverse ability of GSPE and its possible mechanism in vitro. MATERIALS AND METHODS: Human leukemia cell line HL-60 cells and HL-ADR cells were used. MTT assay were employed to identify the cytotoxic effects of different chemotherapeutic drugs and reverse ability of GSPE. Flow cytometry assays were used to verify the cell apoptosis induced by GSPE. MDR-related genes expression was tested by real-time polymerase chain reaction (Q-PCR). MDR-related protein expression was assessed by Western blotting assays. The genes and their related protein expression of multidrug resistance-associated protein 1 (MRP1), multidrug resistance protein 1 (MDR1) and lung resistance-related protein (LRP) were tested in this study. KEY RESULTS: We found that HL-60/ADR cells were resistant to a variety of chemotherapeutic drugs, including cytarabine (Ara-C), adriamycin (ADR), vincristine (VCR), daunorubicin (DNR), mitoxantrone (MTZ), pirarubicin (THP), homoharringtonine (HHT) and etoposide (VP16). Co-treatment with GSPE could significant lower the IC50 of Ara-C and ADR in HL-60/ADR cells (P < 0.01). MDR related mRNA and their protein expression of MRP1 and MDR1 were significant highly expressed in HL-60/ADR cells than HL-60 cells (P < 0.01). But only protein expression of LRP was higher in HL-60/ADR cells than HL-60 cells (P < 0.05). GSPE could induce a higher intracellular level of ADR in HL-60/ADR cells. It could also inhibit Akt phosphorylation resulted in the down regulation of MRP1, MDR1 and LRP and induce cell apoptosis. 25.0 µg/mL GSPE significant inhibited the Akt phosphorylation (P < 0.05). CONCLUSION AND IMPLICATIONS: GSPE-reversed MDR of HL-60/ADR cells might be associated with the inhibition of the PI3K/Akt signaling pathway, which resulted in the down-regulation the expression of MRP1, MDR1 and LRP. These results provide that GSPE may serve as a combination therapy in AML chemotherapy for future study.
Assuntos
Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Extrato de Sementes de Uva/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proantocianidinas/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Apoptose , Linhagem Celular Tumoral , Resistência a Múltiplos Medicamentos/genética , Resistencia a Medicamentos Antineoplásicos/genética , Expressão Gênica , Células HL-60 , Humanos , FosforilaçãoRESUMO
Epileptic spasms are a catastrophic form of epilepsy. When epileptic spasms occur under 2-year-old, they may be also called "infantile spasms". Adrenocorticotropic hormone (ACTH) is recommended as first line intervention for the treatment of epileptic spasms without tuberous sclerosis complex. The chief risks of ACTH therapy are immunosuppression and hypertension. We reported rare cases of abnormal high blood pressure in two male epileptic spasms patients during ACTH therapy. Both patients' blood pressure reached a high blood pressure stage 2 on the 9th day and 10th day of ACTH treatment, respectively. The blood pressure returned to normal range after the drug dosage was reduced or stopped. The lower level of neutrophil%, neutrophil count, and a higher level of lymphocyte%, lymphocyte count and prealbumin than normal range were observed in both patients before ACTH therapy. The neutrophil to lymphocyte rate might be a predictor for high blood pressure among patients treated with ACTH. The rates of both patients were under 0.50 (0.42 for Case 1 and 0.17 for Case 2). We reported the documented cases in two Chinese pediatric patients who suffered from epileptic spasms treated with ACTH resulted in abnormal high blood pressure, which could be predicted by using neutrophil to lymphocyte rate. We also mentioned serum prealbumin might be another predictor. More clinical data is required to elucidate the relationship between serum prealbumin level and blood pressure.
RESUMO
BACKGROUND: Accumulating evidence has suggested the polymorphisms of methylenetetrahydrofolate reductase (MTHFR) were associated with susceptibility to childhood acute lymphoblastic leukemia (ALL). However, the known conclusions of currently known polymorphic loci (677 C > T and 1298 A > C) remain controversial. This study was to investigate new genetic biomarkers for ALL by analyzing the MTHFR polymorphisms at the 3'-untranslated region, which is a location bound by miRNAs. METHODS: Polymorphisms of rs4846049 (miR-555 binding) were assessed by PCR amplification and direct sequencing in 110 ALL patients and 105 healthy controls. The relative expression of MTHFR was detected by qRT-PCR. RESULTS: Overall, genotype distribution or allele carrier frequencies were not significantly different between patients with ALL and healthy controls (P > 0.05). Subgroup analysis results showed that T allele (OR = 0.134, 95% CI = 0.028-0.639; P=0.005) or genotypes with T allele (TT + GT) (OR = 0.133, 95% CI: 0.024-0.727; P=0.017) may be a protective factor for ALL susceptibility in patients with age >8 years. This conclusion was also true for the group only focusing on the precursor B-cell ALL patients. Furthermore, karyotype abnormality was more commonly observed in patients with the GG genotype (56.0%) compared to carriers of TT (0%) or GT (40.6%) genotypes, while c-myc break frequency was significantly higher in TT carriers (33%) than that of patients with GT (3.1%) or GG (0%) genotypes. PCR analysis showed patients carrying the GG genotype of rs4846049 exhibited the reduced mRNA expression of MTHFR. CONCLUSION: MTHFR rs4846049 polymorphism may be associated with increased risk of childhood with ALL and MTHFR mRNA expression.
Assuntos
Regiões 3' não Traduzidas/genética , Predisposição Genética para Doença/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo de Nucleotídeo Único/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Alelos , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Frequência do Gene/genética , Genótipo , Humanos , Lactente , MasculinoRESUMO
BACKGROUND: Probiotic supplementation in early life may be effective in preventing atopic dermatitis (AD); however, results regarding efficacy have been controversial. OBJECTIVE: The aim of our study was to investigate the effect of probiotic supplementation on the risk of AD. METHODS: We systematically searched PubMed, EBSCO, Embase and Web of Science databases up to 8 March 2018 for potentially relevant studies regarding probiotic supplementation and AD. Included infants and children were those with probiotic exposure in utero and/or after birth who were not previously diagnosed with AD. We calculated the odds ratios (ORs) and 95% confidence intervals (CIs) and used the Jadad and Newcastle-Ottawa scales to assess methodologic quality. RESULTS: A total of 28 studies met the inclusion criteria. Compared with controls, probiotic treatment was associated with a reduced risk of AD (OR 0.69; 95% CI 0.58-0.82, P < 0.0001). The use of probiotics during both the prenatal and the postnatal period significantly reduced the incidence of AD (OR 0.67; 95% CI 0.54-0.82); however, analysis of studies of probiotics given prenatally only or postnatally only did not reach statistical significance. CONCLUSIONS: Our meta-analysis showed that probiotic supplementation during both the prenatal and the postnatal period reduced the incidence of AD in infants and children. Our findings suggest that starting probiotic treatment during gestation and continuing through the first 6 months of the infant's life may be of benefit in the prevention of AD.
Assuntos
Dermatite Atópica/prevenção & controle , Suplementos Nutricionais , Exposição Materna , Probióticos/administração & dosagem , Ensaios Clínicos como Assunto , Dermatite Atópica/epidemiologia , Feminino , Humanos , Incidência , Lactente , Saúde do Lactente/estatística & dados numéricos , Recém-Nascido , Cuidado Pós-Natal/métodos , Gravidez , Cuidado Pré-Natal/métodos , Resultado do TratamentoRESUMO
CONCLUSION: Both methylprednisolone (MTH) and dexamethasone (DEX) could successfully and effectively penetrate the round window membrane (RWM) into perilymph. RWM topical application and otocyst infusion with MTH and DEX result in high perilymph drug concentrations and low plasma levels. An intratympanic administration schedule for DEX or MTH could be carried out twice daily. OBJECTIVE: To explore the pharmacokinetics of DEX and MTH in the inner ear fluids and plasma following systemic and local administration. MATERIALS AND METHODS: Three routes of administration of steroids were used in guinea pigs: intracardial injection, otocyst infusion and RWM topical application by granule gelfoam soaked with steroids. Samples of blood or perilymph of the scala tympani were collected at 1-6 h after administration. High-performance liquid chromatography was used to assay concentrations of steroids. RESULTS: Both the topical application and infusion administration resulted in a significantly higher concentration of steroids in perilymph than intracardial injection. The level of steroids in the perilymph reached a peak at 1-2 h after dosing, and this was maintained at a relatively high level for several hours. The intracardial injection with steroids yielded very low perilymph levels at all sampling times after administration.
Assuntos
Dexametasona/farmacocinética , Metilprednisolona/farmacocinética , Perilinfa/metabolismo , Administração Tópica , Animais , Permeabilidade Capilar/fisiologia , Dexametasona/administração & dosagem , Cobaias , Coração , Injeções , Taxa de Depuração Metabólica/fisiologia , Metilprednisolona/administração & dosagem , Membrana dos Otólitos/metabolismo , Janela da Cóclea/metabolismoRESUMO
Background: Up to date, the efficacy and safety of warfarin treatment in atrial fibrillation patients receiving hemodialysis remain controversial. So we performed this meta-analysis to try to offer recommendations regarding warfarin management in this population. Methods: We searched Pubmed, Embase, and Cochrane library and reviewed relevant reference lists from 1980 to March 2018. Studies were included if they described the risks of mortality, stroke, and bleeding events with or without warfarin in atrial fibrillation patients receiving hemodialysis. Results: Overall, the use of warfarin was not associated with mortality (OR = 0.95, 95%CI = 0.89-1.02), stroke (OR = 1.06, 95% CI = 0.87-1.30) and ischemic stroke (OR = 0.85, 95% CI = 0.68-1.05), but its use could increase the risks of hemorrhagic stroke (OR = 1.34, 95% CI = 1.13-1.59) and major bleeding (OR = 1.24, 95% CI = 1.14, 1.35). In subgroup analyses, when analyses were mainly restricted to atrial fibrillation patients who were undergoing hemodialysis and taking other anticoagulation agents, warfarin therapy didn't reduce the risks for mortality (OR = 0.98, 95% CI = 0.68-1.42) and ischemic stroke (OR = 1.03, 95% CI = 0.89-1.19), but significantly increased the risks of stroke (OR:1.14, 95% CI = 1.01-1.29) and bleeding events such as hemorrhagic stroke (OR = 1.42, 95% CI = 1.14-1.77) and major bleeding (OR = 1.24, 95% CI = 1.14-1.35). While in patients who didn't take other anticoagulation agents or aspirin, warfarin use was not associated with all-cause mortality (OR = 0.90, 95% CI = 0.78-1.04), or any stroke (OR = 1.00, 95% CI = 0.71-1.40). Its use was associated with significantly decreased risk of ischemic stroke (OR = 0.71, 95% CI = 0.60-0.85), but not associated with hemorrhagic stroke (OR = 1.45, 95% CI = 0.83-2.55). Besides, another subgroup analysis showed that warfarin therapy didn't exert a protective role in patients with normal serum lipid levels (OR = 1.04, 95% CI = 0.85-1.26), but seemed to decrease the risk of ischemic stroke in patients with hyperlipidemia (OR = 0.38, 95% CI = 0.11-1.29). Conclusion: Our results suggested that it was necessary to prescribe warfarin for the prevention of ischemic events in hemodialysis patients with atrial fibrillation, but if these patients were already prescribed with other anticoagulants for the treatment of other co-existing diseases, then warfarin was not recommended.
RESUMO
BACKGROUND: Natalizumab (NAT), a humanized monoclonal antibody, which binds in both α4ß1 integrins and α4ß7 integrins, is approved for the treatment of multiple sclerosis (MS) and Crohn's disease (CD). An uncommon but serious adverse event from NAT treatment is known as progressive multifocal leukoencephalopathy (PML). However, clinical comprehensive safety evidence of NAT is limited. METHODS: We will search Medline, Embase, Cochrane library, and ClinicalTrials.gov website from inception to May 9, 2018. Double-blind, randomized placebo-controlled trials reporting safety data of NAT will be eligible for inclusion. Outcome variables will include adverse events (AEs) varying degrees and AEs occurring in ≥ 5% patients with NAT or placebo. STATA software (version 12, Statacorp, College Station, TX) will be utilized to assess risk of bias and synthesize data. Outcomes will be reported by weight mean difference (WMD), risk ratios (RRs), and their 95% confidence intervals (95% CIs). I statistic will be used to evaluate heterogeneity among studies. RESULTS: This systemic review and meta-analysis will evaluate serious AEs and AEs of NAT as compared to placebo. CONCLUSION: Our study will provide a comprehensive picture of AEs of NAT.
Assuntos
Doença de Crohn/tratamento farmacológico , Fatores Imunológicos/efeitos adversos , Esclerose Múltipla/tratamento farmacológico , Natalizumab/efeitos adversos , Método Duplo-Cego , Humanos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
INTRODUCTION: The α4ß7 integrin is heterodimeric cell surface receptors expressed on most leukocytes. Mucosal addressing cell adhesion molecule 1(MAdCAM-1) is an exclusive ligand for α4ß7 integrin. Areas covered: This article will highlight the progress that has been made in the discovery and development of α4ß7 integrin inhibitors, and their use in the treatment of inflammatory bowel diseases, multiple sclerosis, asthma, hepatic disorders, human immunodeficiency virus, allergic conjunctivitis and type 1 diabetes. Expert opinion: α4ß7 integrin inhibitors have attracted much interest for their clinical implication. Natalizumab and Vedolizumab are monoclonal antibodies (mAbs) successfully utilized clinically. Natalizumab is a mAbs of α4-subunit blocking both α4ß1 and α4ß7 integrin. Vedolizumab selectively targets the α4ß7 integrin. Several mAbs are still in the process of research and development. Among these mAbs, etrolizumab selectively against the ß7-subunit and AMG-181 specifically against the α4ß7 integrin are the most promising anti-α4ß7 integrin antibodies. Despite the unclear development stage of TR-14035 and R411, several low molecular compounds show bright future of further development, such as AJM300 and CDP323. In addition, results from laboratory data show that peptide inhibitors, such as peptide X, are effective α4ß7 integrin inhibitors.
Assuntos
Desenho de Fármacos , Integrinas/antagonistas & inibidores , Animais , Moléculas de Adesão Celular , Humanos , Imunoglobulinas/metabolismo , Integrinas/metabolismo , Ligantes , Mucoproteínas/metabolismo , Patentes como AssuntoRESUMO
BACKGROUND: Natalizumab (NAT), a humanized monoclonal antibody, binding in both α4ß1 and α4ß7 integrins, is approved for the treatment of Multiple Sclerosis (MS) and Crohn's Disease (CD). This review highlights the detailed Pharmacokinetics (PK) and Pharmacodynamics (PD) information of NAT, with the Pharmacogenomics (PG) properties of NAT. METHODS: We undertake a systemic English-language search of Medline, EMBASE, Cochrane Library electronic databases to identify all potential studies with PK, PD or PG properties of NAT (up to October 2017). RESULTS: Five papers contain detailed pharmacokinetic parameters are included in this review. Body weight is the most important factor associated with NAT concentration. Greater PK similarity and PD comparability is observed following Subcutaneous (SC) administration than Intramuscular (IM) administration. Initial difference in PK measures was observed between SC and Intravenous (IV) administration. However, trough NAT serum concentrations are similar between SC and IV administration after repeated dosing. Antibodies against NAT result in a low serum NAT concentration and cause a loss of efficacy of NAT. Gln-152, Lys-201, and Lys-256 are the three important point mutation on the α4 residues that NAT binds to. Syndecan-1 gene is a potential candidate gene for personalized approach for NAT use in MS. CONCLUSION: As MS is a disease that affects young women most and NAT can pass placental barrier before delivery and into breast milk, a proper risk-benefit analysis of NAT therapy in lactating women are still needed. The relationship between Single Nucleotide Polymorphisms (SNPs) and NAT treatment are still not clear.
Assuntos
Fatores Imunológicos , Integrina alfa4/antagonistas & inibidores , Natalizumab , Variantes Farmacogenômicos , Animais , Humanos , Fatores Imunológicos/farmacologia , Fatores Imunológicos/uso terapêutico , Integrina alfa4/imunologia , Natalizumab/farmacologia , Natalizumab/uso terapêuticoRESUMO
BACKGROUND: The pediatric pharmacy research status of children's hospitals in China is still unknown. Our previous findings suggest the regional differences in academic level in tertiary (grade III level A) children's hospitals in China. METHODS: This systemic evaluation described in this protocol will be conducted to follow the Cochrane Handbook. We will perform a systemic literature search of relevant databases including Chinese databases (CNKI, Wanfang Data, VIP Paper Check System) and English databases (Medline, EMbase, Cochrane Library) from inception to December 31, 2018. The search strategy will be enacted according to the guidance offered from the Cochrane Handbook. Two rounds of searches will be conducted to prevent the omission of relevant literature. A pre-set grading standard will be used to give calculation weight (W) to evaluate the quality of each article. Data synthesis will be performed using STATA software (version 13.1, Statacorp, College Station, Texas). Pediatric pharmacy development index (PPDI) of each hospital will be used to evaluate the pediatric pharmacy development in each tertiary children's hospitals. The cumulative calculation weight (∑W) and annual calculation weight (∑yearW) will be used to evaluate the academic level of pharmaceutical departments in different tertiary children's hospitals. Subgroup analysis will be performed to compare the number of different types of articles published between different hospitals base on different research areas such as policy research, basic research, and clinical research. RESULTS: In this article, we will evaluate pediatric pharmacy development and the research area of pediatric pharmacy experts in China. Based on the results from this research, we will analyze the professional backgrounds of pediatric pharmacy experts from 23 tertiary children's hospitals in China. According to the contents and research directions of literature published by the pediatric pharmacy experts in these 23 hospitals, we will determine the professional field of pediatric pharmacy experts and establish an expert database. In the process of formulating the related national or local policies in the future, the expert database will be selected accurately to reach the expert consensus. CONCLUSION: Our study will provide a comprehensive picture of pediatric pharmacy development in China. The pediatrics pharmacy expert's database constructed by this study will be used to build consensus on pediatric pharmacology in the future.
Assuntos
Pediatria/normas , Serviço de Farmácia Hospitalar/normas , Desenvolvimento de Programas/normas , China , Protocolos Clínicos , Atenção à Saúde/métodos , Humanos , Pediatria/métodos , Serviço de Farmácia Hospitalar/métodos , Desenvolvimento de Programas/métodosRESUMO
BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a novel class of oral antidiabetic drugs, which mainly increase urinary glucose excretion through reducing renal glucose reabsorption. There is still a concern about the overall safety profile of SGLT2 inhibitors. In this systematic review and meta-analysis, we will assess the clinical adverse effects of SGLT2 inhibitors in type 2 diabetes mellitus. METHODS: This systemic review and meta-analysis described in this protocol will be conducted to follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline. We will search Medline, EMbase, the Cochrane library and the ClinicalTrials.gov Website from 1946 to June 2018. Studies will be screened by title, abstract, and full text independently in duplicate. Double-blinded, placebo-controlled, and randomized controlled trials reporting safety data of SGLT2 inhibitors will be eligible for inclusion. Outcomes will include adverse events (AEs) varying degrees and AEs occurring in ≥3% patients or AEs aroused concerns by the Food and Drug Administration (FDA). The assessment of risk bias and data synthesis will be performed using STATA software (version12, Statacorp, College Station, TX). Outcomes will be reported by risk ratios for dichotomous outcomes and weighted mean difference (WMD) for continuous outcomes and their 95% confidence intervals. Subgroup, sensitivity, regression analyses will be performed to evaluate intertrial heterogeneity and bias of the results. I statistic will be used to evaluate heterogeneity among studies. RESULTS: This systemic review and meta-analysis will evaluate AEs occurring in ≥3% patients or AEs aroused concerns by the FDA of SGLT2i as compared to placebo. CONCLUSION: Our study will provide a comprehensive picture of AEs of SGLT2 inhibitors.