RESUMO
PURPOSE: Network analysis was conducted to systematically analyze the relationship between causative drugs and types of drug-related problems (DRPs) in hospitalized patients with hematologic malignancies. METHODS: A total of 1187 DRPs identified in hematology wards between 2013 and 2015 were analyzed. DRPs were classified into 11 sub-domains for problems and 35 sub-domains for causes according to Pharmaceutical Care Network Europe classification. Causative drugs were classified by Anatomical Therapeutic Chemical code. Network analytic tool was used to represent the relationship between drugs, causes, and problems. In-degree centrality (CD-in) was calculated to identify major causes of DRPs. RESULTS: The following drugs accounted for more than 5% of DRP, including antibacterials (J01, 26.5%), drugs for acid-related disorders (A02, 11.5%), antiemetics (A04, 9.7%), antifungals (J02, 8.8%), and antineoplastic agents (L01, 7.0%). Inappropriate combinations (C1.3, CD-in of 161) of drugs for acid-related disorders, antifungals, and antineoplastic agents were major causes of DRPs and induced non-optimal effects of drug treatment (P1.2). Inappropriate dose adjustments (C3.6, CD-in of 151) of antibacterials lowered effects (P1.2) and increased side effects (P2.1). Missing necessary synergistic or preventive drugs, especially antiemetics, (C1.8, CD-in of 54) resulted in untreated indication (P1.4). CONCLUSIONS: DRPs were mainly related to medications for supportive care. More attention should be paid to interactions of drugs used for acid-related disorders, dose adjustment of antibacterials, and omission of antiemetics in hospitalized patients with hematologic malignancy.
Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Neoplasias Hematológicas/complicações , Hospitalização/tendências , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Neoplasias Hematológicas/patologia , Humanos , Pacientes Internados , Masculino , Pessoa de Meia-Idade , Metanálise em Rede , Estudos RetrospectivosRESUMO
BACKGROUND: Exploratory preclinical, as well as clinical trials, may involve a small number of patients, making it difficult to calculate and analyze the pharmacokinetic (PK) parameters, especially if the PK parameters show very high inter-individual variability (IIV). In this study, the performance of a classical first-order conditional estimation with interaction (FOCE-I) and expectation maximization (EM)-based Markov chain Monte Carlo Bayesian (BAYES) estimation methods were compared for estimating the population parameters and its distribution from data sets having a low number of subjects. METHODS: In this study, 100 data sets were simulated with eight sampling points for each subject and with six different levels of IIV (5%, 10%, 20%, 30%, 50%, and 80%) in their PK parameter distribution. A stochastic simulation and estimation (SSE) study was performed to simultaneously simulate data sets and estimate the parameters using four different methods: FOCE-I only, BAYES(C) (FOCE-I and BAYES composite method), BAYES(F) (BAYES with all true initial parameters and fixed ω 2 ), and BAYES only. Relative root mean squared error (rRMSE) and relative estimation error (REE) were used to analyze the differences between true and estimated values. A case study was performed with a clinical data of theophylline available in NONMEM distribution media. NONMEM software assisted by Pirana, PsN, and Xpose was used to estimate population PK parameters, and R program was used to analyze and plot the results. RESULTS: The rRMSE and REE values of all parameter (fixed effect and random effect) estimates showed that all four methods performed equally at the lower IIV levels, while the FOCE-I method performed better than other EM-based methods at higher IIV levels (greater than 30%). In general, estimates of random-effect parameters showed significant bias and imprecision, irrespective of the estimation method used and the level of IIV. Similar performance of the estimation methods was observed with theophylline dataset. CONCLUSIONS: The classical FOCE-I method appeared to estimate the PK parameters more reliably than the BAYES method when using a simple model and data containing only a few subjects. EM-based estimation methods can be considered for adapting to the specific needs of a modeling project at later steps of modeling.
Assuntos
Demografia/métodos , Algoritmos , Teorema de Bayes , Interpretação Estatística de Dados , Demografia/normas , Humanos , Cadeias de Markov , Método de Monte Carlo , Processos EstocásticosRESUMO
PURPOSE: We evaluated the psychometric properties of the Korean version of the European Organization for Research and Treatment of Cancer high-dose chemotherapy specific quality of life questionnaire module (EORTC QLQ-HDC29) when implemented with Korean patients by conducting a multicenter, longitudinal study in three Korean hospitals. METHODS: A total of 226 patients who scheduled to receive the HDC followed by hematopoietic stem cell transplantation (HSCT) were enrolled. The patients were asked to complete three questionnaires [the EORTC Core Questionnaire (QLQ-C30), QLQ-HDC29, and the Functional Assessment of Cancer Therapy-Bone Marrow Transplantation] at four points in time: before HSCT and 100, 180, and 365 days after HSCT. Standard validity and reliability analyses were performed. RESULTS: Internal consistency of the QLQ-HDC29 was generally acceptable, as tested by Cronbach's α, except for the scales body image and the inpatient issues. Cronbach's α values for the Korean version of the QLQ-HDC29 were almost in accordance with results of the original version, except for the scales body image (lower to the original QLQ-HDC29, α = 0.73) and impact on family (higher to the original QLQ-HDC29, α = 0.52). Known-group comparison analyses showed significantly higher symptom burdens in patients with poor performance status or graft versus host disease (similar to the original QLQ-HDC29). The QLQ-HDC29 indicated good convergent and discriminant validity and showed responsiveness to changes in line with a clinical course over time after HSCT. CONCLUSIONS: The QLQ-HDC29 is generally reliable and adequate to assess QoL in Korean patients undergoing HDC followed by HSCT.
Assuntos
Antineoplásicos/administração & dosagem , Relação Dose-Resposta a Droga , Qualidade de Vida/psicologia , Inquéritos e Questionários , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Psicometria , Reprodutibilidade dos Testes , República da Coreia , Perfil de Impacto da Doença , Centros de Atenção TerciáriaRESUMO
Glutamate carboxypeptidase II (GCPII) is a zinc metalloprotease on the surface of astrocytes which cleaves N-acetylaspartylglutamate to release N-acetylaspartate and glutamate. GCPII inhibitors can decrease glutamate concentration and play a protective role against apoptosis or degradation of brain neurons. Herein, we report the synthesis and structural analysis of novel carborane-based GCPII inhibitors. We determined the X-ray crystal structure of GCPII in complex with a carborane-containing inhibitor at 1.79Å resolution. The X-ray analysis revealed that the bulky closo-carborane cluster is located in the spacious entrance funnel region of GCPII, indicating that the carborane cluster can be further structurally modified to identify promising lead structures of novel GCPII inhibitors.
Assuntos
Compostos de Boro/síntese química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Glutamato Carboxipeptidase II/antagonistas & inibidores , Ureia/análogos & derivados , Compostos de Boro/química , Compostos de Boro/farmacologia , Cristalografia por Raios X , Inibidores Enzimáticos/química , Glutamato Carboxipeptidase II/ultraestrutura , Humanos , Ureia/síntese química , Ureia/química , Ureia/farmacologiaRESUMO
Oral mucositis (OM) is one of the most common and debilitating complications in patients undergoing intensive chemotherapy followed by hematopoietic stem cell transplantation (HSCT). The aim of this study was to evaluate the efficacy and safety of recombinant human epidermal growth factor (rhEGF) oral spray for OM induced by intensive chemotherapy followed by HSCT. Patients were randomly assigned to either the rhEGF group or placebo group. The severity of OM and self-reported quality of life (QOL) were assessed daily. A total of 58 patients were analyzed. Baseline characteristics were similar between the two groups. The incidence of NCI grade ≥ 2 OM was higher in the rhEGF group (78.6% vs. 50%, P = 0.0496). However, the duration of OM in patients with NCI grade ≥ 2 tended to be shorter in the rhEGF group (8.5 days vs. 14.5 days, P = 0.262). The QOL analysis in patients with World Health Organization (WHO) grade ≥ 3 OM showed that rhEGF significantly reduced limitations in swallowing (P = 0.039) and drinking (P = 0.042). The duration of hospitalization (P = 0.047), administration of total parenteral nutrition (P = 0.012), and the usage of opioid analgesics (P = 0.018) were significantly shorter in the rhEGF group with WHO grade ≥ 3 OM. Adverse events were mild and similar between the two groups. In conclusion, this analysis showed that rhEGF did not reduce the incidence of NCI grade ≥ 2 OM. However, the patients with WHO grade ≥ 3 OM in the rhEGF group showed better results compared to the placebo group for several secondary endpoints.
Assuntos
Fator de Crescimento Epidérmico/uso terapêutico , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Estomatite/tratamento farmacológico , Condicionamento Pré-Transplante/efeitos adversos , Adolescente , Adulto , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/uso terapêutico , Transtornos de Deglutição/etiologia , Transtornos de Deglutição/prevenção & controle , Método Duplo-Cego , Fator de Crescimento Epidérmico/administração & dosagem , Fator de Crescimento Epidérmico/efeitos adversos , Feminino , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Sprays Orais , Nutrição Parenteral , Qualidade de Vida , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Índice de Gravidade de Doença , Estomatite/induzido quimicamente , Estomatite/fisiopatologia , Estomatite/prevenção & controle , Adulto JovemRESUMO
OBJECTIVE: We examined the differences in allele frequencies for pharmacogenes among the Korean (KOR), Chinese (CHB), Japanese (JPT), Caucasian (CEU), and Nigerian (YRI) populations. METHODS: Fifty-seven pharmacogenes were selected from the imputed Korean Association REsource and HapMap databases. Minor allele frequencies were analyzed using the sample size-modified single nucleotide polymorphism-specific fixation index (FST) and the χ-test with Bonferroni's correction. Geneset analysis was also carried out to identify pharmacogenes that have significantly different allele frequencies among the various populations tested. RESULTS: The KOR population was the most divergent group from the YRI population (FST: 0.079) but very similar to the CHB and JPT populations (FST: 0.003). VKORC1 showed a large population divergence in the KOR-YRI (0.439) comparison. CYP3A4 was also highly divergent in the KOR-YRI (FST: 0.361) comparison. The calcium signaling pathway gene set was divergent in all pairwise population comparisons. CONCLUSION: In terms of the 57 pharmacogenes studied, there were no significant differences among the KOR, CHB, and JPT populations. However, the YRI and CEU populations were significantly differentiated from the three Eastern Asian groups. Future pharmacogenomics studies can utilize the polymorphisms identified in this study, as these variants may have important implications for the selection of highly informative single nucleotide polymorphisms for future clinical trials.
Assuntos
Povo Asiático , Farmacogenética , Polimorfismo Genético , Alelos , População Negra , Frequência do Gene , Humanos , Desequilíbrio de Ligação , População BrancaRESUMO
BACKGROUND: The second-generation serotonin 5-HT(3) receptor antagonist palonosetron has shown improved efficacy in the prevention of both acute and delayed chemotherapy-induced nausea and vomiting (CINV). However, there have been no randomized controlled trials supporting the preferential use of palonosetron in triple antiemetic regimens for patients receiving multiday highly emetogenic chemotherapy (HEC). OBJECTIVE: To compare the effectiveness of palonosetron-based and first-generation 5-HT(3) receptor antagonist-based triple antiemetic regimens in cancer patients receiving multiday HEC. METHODS: This was a review and analysis of medical record data. A total of 115 patients who had received multiday HEC were included and grouped into a palonosetron-based antiemetic group (n = 73) or a first-generation 5-HT(3) receptor antagonist-based antiemetic group (n = 42). Data on CINV were collected in 24-hour intervals for 120 hours after the start of chemotherapy. RESULTS: Complete response rates did not differ significantly between the 2 groups during any of the 3 phases: acute (0-24 hours), p = 0.877; overlap (24-120 hours), p = 0.997; and overall (0-120 hours), p = 0.723. The proportion of patients with complete control was similar between the groups during each phase: acute, p = 0.862; overlap, p = 0.838; and overall, p = 0.828. There was also no significant difference in other end points between the 2 groups. Among all patients, females experienced significantly more acute nausea (p = 0.040) and vomiting (p = 0.046) than males. Compared with nondrinkers, patients who consumed alcohol had a lower overall incidence of vomiting (p = 0.020). CONCLUSIONS: Within a triple antiemetic regimen, a palonosetron-based antiemetic regimen was not significantly different from regimens based on first-generation 5-HT(3) receptor antagonists in preventing CINV during multiday HEC.
Assuntos
Antieméticos/uso terapêutico , Antineoplásicos/efeitos adversos , Isoquinolinas/uso terapêutico , Náusea/prevenção & controle , Quinuclidinas/uso terapêutico , Vômito/prevenção & controle , Adulto , Idoso , Consumo de Bebidas Alcoólicas/epidemiologia , Antieméticos/administração & dosagem , Antineoplásicos/administração & dosagem , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Palonossetrom , Estudos Retrospectivos , Antagonistas do Receptor 5-HT3 de Serotonina/administração & dosagem , Antagonistas do Receptor 5-HT3 de Serotonina/uso terapêutico , Fatores Sexuais , Resultado do Tratamento , Vômito/induzido quimicamenteRESUMO
PURPOSE: The purpose of this study was to characterize the effects of clinical and genetic variables on the pharmacokinetics and complications of tacrolimus during the first year after kidney transplantation. METHODS: One hundred and thirty-two Korean kidney recipients who received tacrolimus were genotyped for ABCB1 (exons 12, 21, and 26) and CYP3A5 (intron 3). Tacrolimus trough levels, dose, or dose-adjusted trough levels and complications were compared among patients during the early stage (3, 7, 14, 30, and 90 days) and up to 1 year according to the genotypes. RESULTS: A donor source-adjusted linear mixed model with multilevel analysis adjusting for age, body weight, hematocrit, and serum creatinine showed that CYP3A5 genotype is associated with dose-adjusted level of tacrolimus (p < 0.001). The influence of ABCB1 polymorphisms on the pharmacokinetics or complications of tacrolimus was less certain in our study. The incidence of acute rejections was significantly higher in recipients of cadaveric donor kidney (p < 0.05). CONCLUSIONS: A generalized estimating equation model analysis showed that alopecia and hyperlipidemia were associated with dose-adjusted level of tacrolimus (p < 0.001). Genotype of CYP3A5 variants along with significant clinical covariates may be useful in individualizing tacrolimus therapy in kidney transplantation patients.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Citocromo P-450 CYP3A/genética , Rejeição de Enxerto/prevenção & controle , Imunossupressores/farmacocinética , Transplante de Rim/imunologia , Polimorfismo Genético , Tacrolimo/farmacocinética , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Adulto , Idoso , Alopecia/induzido quimicamente , Inibidores de Calcineurina , Citocromo P-450 CYP3A/metabolismo , Monitoramento de Medicamentos , Feminino , Estudos de Associação Genética , Rejeição de Enxerto/epidemiologia , Rejeição de Enxerto/imunologia , Humanos , Hiperlipidemias/induzido quimicamente , Imunossupressores/efeitos adversos , Imunossupressores/sangue , Imunossupressores/uso terapêutico , Incidência , Transplante de Rim/efeitos adversos , Masculino , Pessoa de Meia-Idade , República da Coreia/epidemiologia , Estudos Retrospectivos , Tacrolimo/efeitos adversos , Tacrolimo/sangue , Tacrolimo/uso terapêutico , Adulto JovemRESUMO
The effects of acidic polysaccharides purified from Gastrodia rhizome on blood pressure and serum lipid levels in spontaneously hypertensive rats (SHR) fed a high-fat diet were investigated. Acidic polysaccharides were purified from crude polysaccharides by DEAE-Sepharose CL-6B. Thirty-six male SHR were randomly divided into three groups: Gastrodia rhizome crude polysaccharide (A), acidic polysaccharide (B) groups, and a control group (C). A 5-week oral administration of all treatment groups was performed daily in 3- to 8-week-old SHRs with a dose of 6 mg/kg of body weight/day. After 5 weeks of treatment, total cholesterol in the acidic polysaccharide group, at 69.7 ± 10.6 mg/dL, was lower than in the crude polysaccharide group (75.0 ± 6.0 mg/dL) and the control group (89.2 ± 7.4 mg/dL). In addition, triglyceride and low-density lipoprotein cholesterol levels in the acidic polysaccharide group were lower than in the crude polysaccharide and control groups. The atherogenic index of the acidic polysaccharide group was 46.3% lower than in the control group. Initial blood pressure after the initial three weeks on the high-fat diet averaged 195.9 ± 3.3 mmHg among all rats. Compared with the initial blood pressure, the final blood pressure in the control group was increased by 22.8 mmHg, whereas it decreased in the acidic polysaccharide group by 14.9 mmHg. These results indicate that acidic polysaccharides from Gastrodia rhizome reduce hypertension and improve serum lipid levels.
Assuntos
Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Gastrodia/metabolismo , Lipídeos/sangue , Polissacarídeos/farmacologia , Animais , Anti-Hipertensivos/análise , Anti-Hipertensivos/uso terapêutico , Peso Corporal/efeitos dos fármacos , LDL-Colesterol/sangue , Cromatografia em Camada Fina , Dieta Hiperlipídica , Hipertensão/tratamento farmacológico , Hipertensão/etiologia , Hipertensão/metabolismo , Masculino , Polissacarídeos/análise , Polissacarídeos/uso terapêutico , Ratos , Ratos Endogâmicos SHR , Rizoma/metabolismo , Triglicerídeos/sangueRESUMO
STUDY OBJECTIVES: To evaluate the efficacy of a single, low-dose injection of botulinum toxin type A in relieving pain in Korean patients with piriformis syndrome resistant to conventional therapy, and to assess the drug's influence on these patients' quality of life. DESIGN: Prospective, single-site, open-label trial. SETTING: Rehabilitation medicine clinic in Seoul, Korea. PATIENTS: Twenty-nine patients with a confirmed diagnosis of chronic piriformis syndrome and 82 age- and sex-matched healthy subjects were enrolled from April 1, 2003-February 28, 2004. Intervention. In 20 of the patients, botulinum toxin type A 150 U was injected using computed tomographic guidance into the affected unilateral piriformis muscle. The other nine patients served as active controls and received an injection of dexamethasone 5 mg and 1% lidocaine. The healthy subjects did not receive any injection. MEASUREMENTS AND MAIN RESULTS: The patients' pain at baseline and at 4, 8, and 12 weeks after treatment was rated by using a numeric rating scale. Health-related quality of life was assessed by using the validated Korean version of the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) at baseline and at 4 weeks of treatment. Healthy subjects also completed the SF-36 at baseline. Pain intensity scores were significantly lower at 4, 8, and 12 weeks after treatment than at baseline (p<0.0001). Baseline scores from the SF-36 subscales, including those for physical functioning (p<0.0001), role physical (p<0.0001), bodily pain (p<0.0001), general health (p<0.0001), vitality (p<0.0001), and social functioning (p<0.002), were significantly lower in the patients than in the healthy subjects. Four weeks after treatment, physical functioning (p=0.003), role physical (p=0.021), bodily pain (p=0.016), general health (p=0.013), vitality (p=0.031) and social functioning (p=0.035) improved significantly from baseline in the patients. However, at 4 weeks, patients in the active control group were withdrawn from the study because their pain did not improve, and continuation without further medical care was considered unethical. CONCLUSION: A low dose of botulinum toxin type A relieved pain and improved quality of life in patients with refractory piriformis syndrome.
Assuntos
Toxinas Botulínicas Tipo A/uso terapêutico , Músculo Esquelético/efeitos dos fármacos , Fármacos Neuromusculares/uso terapêutico , Dor/tratamento farmacológico , Adulto , Anestésicos Locais/uso terapêutico , Povo Asiático , Toxinas Botulínicas Tipo A/efeitos adversos , Dexametasona/uso terapêutico , Feminino , Glucocorticoides/uso terapêutico , Humanos , Coreia (Geográfico) , Lidocaína/uso terapêutico , Masculino , Pessoa de Meia-Idade , Contração Muscular/efeitos dos fármacos , Exercícios de Alongamento Muscular , Fármacos Neuromusculares/efeitos adversos , Medição da Dor , Estudos Prospectivos , Qualidade de Vida , Centros de Reabilitação , Nervo Isquiático/fisiopatologia , Síndrome , Tomografia Computadorizada por Raios XRESUMO
The purpose of this study is to characterize a meta-signature of differentially expressed mRNA in chronic kidney disease (CKD) to predict putative microRNA (miRNA) in CKD-mineral bone disorder (CKD-MBD) and confirm the changes in these genes and miRNA expression under uremic conditions by using a cell culture system. PubMed searches using MeSH terms and keywords related to CKD, uremia, and mRNA arrays were conducted. Through a computational analysis, a meta-signature that characterizes the significant intersection of differentially expressed mRNA and expected miRNAs associated with CKD-MBD was determined. Additionally, changes in gene and miRNA expressions under uremic conditions were confirmed with human Saos-2 osteoblast-like cells. A statistically significant mRNA meta-signature of upregulated and downregulated mRNA levels was identified. Furthermore, miRNA expression profiles were inferred, and computational analyses were performed with the imputed microRNA regulation based on weighted ranked expression and putative microRNA targets (IMRE) method to identify miRNAs associated with CKD occurrence. TLR4 and miR-146b levels were significantly associated with CKD-MBD. TLR4 levels were significantly downregulated, whereas primiR- 146b and miR-146b were upregulated in the presence of uremic toxins in human Saos-2 osteoblast-like cells. Differentially expressed miRNAs associated with CKD-MBD were identified through a computational analysis, and changes in gene and miRNA expressions were confirmed with an in vitro cell culture system.
Assuntos
MicroRNAs/genética , Insuficiência Renal Crônica/complicações , Receptor 4 Toll-Like/genética , Uremia/genética , Doenças Ósseas Metabólicas/complicações , Linhagem Celular Tumoral , Perfilação da Expressão Gênica , Humanos , Metanálise como Assunto , Análise de Sequência com Séries de Oligonucleotídeos , Uremia/metabolismoRESUMO
Patient-reported outcome (PRO) measures and validated instruments have become integral in assessing the quality of healthcare delivery, including pharmaceutical care services. The Pharmacy Services Questionnaire (PSQ) measures patient satisfaction with pharmaceutical care. In this study, we developed a modified Korean version of the PSQ (PSQ-K) and evaluated its validity and reliability. The PSQ-K was developed using a strict translation and cultural-adaptation procedure. A validation study was performed in six community pharmacies in Korea. A total of 300 respondents completed three questionnaires (a brief questionnaire for social demographics and clinical characteristics, the PSQ-K, and the 5-level EuroQoL Group's 5-dimension [EQ-5D-5L]). Standard validity and reliability analyses were performed. The internal consistency of the PSQ-K was high for all scales (Cronbach's α > 0.9). The PSQ-K indicated good discriminant and divergent validity. Known-group comparisons revealed that the PSQ-K was able to distinguish between respondents differing in socio-demographic characteristics, such as gender, level of education, and household income. In conclusion, the PSQ-K is a highly reliable and valid PRO instrument for assessing the level of satisfaction with community pharmacy services.
Assuntos
Serviços Comunitários de Farmácia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Satisfação do Paciente , Farmácias , República da Coreia , Inquéritos e Questionários , Traduções , Adulto JovemRESUMO
The aim of this study was to evaluate the efficacy and safety of recombinant human epidermal growth factor (rhEGF) oral spray for oral mucositis (OM) induced by intensive chemotherapy with hematopoietic stem cell transplantation. In this phase 2 study, patients were randomized to either rhEGF (50 microg/mL) or placebo in a 1:1 ratio. The primary endpoint was incidence of National Cancer Institute (NCI) grade ≥2 OM. A total of 138 patients were enrolled in this study. In the intention-to-treat analysis, rhEGF did not reduce the incidence of NCI grade ≥2 OM (p = 0.717) nor reduce its duration (p = 0.725). Secondary endpoints including the day of onset and duration of NCI grade ≥2 OM, the incidence of NCI grade ≥3 OM and its duration, and patient-reported quality of life were also similar between the two groups. In the per-protocol analysis, however, the duration of opioid analgesic use was shorter in the rhEGF group (p = 0.036), and recipients in the rhEGF group required a lower cumulative dose of opioid analgesics than those in the placebo group (p = 0.046), among patients with NCI grade ≥2 OM. Adverse events were mild and transient. This study found no evidence to suggest that rhEGF oral spray reduces the incidence of OM. However, further studies are needed to investigate the effect of rhEGF on OM-induced pain reduction after intensive chemotherapy.
Assuntos
Fator de Crescimento Epidérmico/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Proteínas Recombinantes/administração & dosagem , Estomatite/tratamento farmacológico , Administração Tópica , Adolescente , Adulto , Idoso , Analgésicos Opioides/uso terapêutico , Antineoplásicos/uso terapêutico , Método Duplo-Cego , Fator de Crescimento Epidérmico/uso terapêutico , Feminino , Neoplasias Hematológicas/terapia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Proteínas Recombinantes/uso terapêutico , Adulto JovemRESUMO
In the present study, we systematically investigated population differentiation of drug-related (DR) genes in order to identify common genetic features underlying population-specific responses to drugs. To do so, we used the International HapMap project release 27 Data and Pharmacogenomics Knowledge Base (PharmGKB) database. First, we compared four measures for assessing population differentiation: the chi-square test, the analysis of variance (ANOVA) F-test, Fst, and Nearest Shrunken Centroid Method (NSCM). Fst showed high sensitivity with stable specificity among varying sample sizes; thus, we selected Fst for determining population differentiation. Second, we divided DR genes from PharmGKB into two groups based on the degree of population differentiation as assessed by Fst: genes with a high level of differentiation (HD gene group) and genes with a low level of differentiation (LD gene group). Last, we conducted a gene ontology (GO) analysis and pathway analysis. Using all genes in the human genome as the background, the GO analysis and pathway analysis of the HD genes identified terms related to cell communication. "Cell communication" and "cell-cell signaling" had the lowest Benjamini-Hochberg's q-values (0.0002 and 0.0006, respectively), and "drug binding" was highly enriched (16.51) despite its relatively high q-value (0.0142). Among the 17 genes related to cell communication identified in the HD gene group, five genes (STX4, PPARD, DCK, GRIK4, and DRD3) contained single nucleotide polymorphisms with Fst values greater than 0.5. Specifically, the Fst values for rs10871454, rs6922548, rs3775289, rs1954787, and rs167771 were 0.682, 0.620, 0.573, 0.531, and 0.510, respectively. In the analysis using DR genes as the background, the HD gene group contained six significant terms. Five were related to reproduction, and one was "Wnt signaling pathway," which has been implicated in cancer. Our analysis suggests that the HD gene group from PharmGKB is associated with cell communication and drug binding.
Assuntos
Variação Genética , Genoma Humano , Farmacogenética , Bases de Dados Genéticas , Genética Populacional , HumanosRESUMO
Rhodiola rosea is a perennial plant which grows in the alpine regions of Europe and Asia. Although the protective effects of R. rosea extract from fatigue due to exercise stress have been reported, studies on fermented R. rosea extract remain insufficient to date. Therefore, this study was conducted to examine the protective effects of fermented R. rosea extract against fatigue and exercise stress. As a result, fermented R. rosea extract was found to significantly increase swimming time, hepatic superoxide dismutase content, and serum lactate dehydrogenase in mice, while decreasing serum blood urea nitrogen content compared to R. rosea extract. Given the above results, it is considered that fermented R. rosea extract effectively protects against fatigue caused by strenuous exercise.
RESUMO
Cytarabine arabinoside (ara-C) is the key agent for treating acute myeloid leukaemia (AML). Here, we genotyped 139 single nucleotide polymorphisms (SNPs) within the ara-C transport and metabolic pathway using the Illumina Golden Gate Assay in 97 patients with previously non-treated de novo AML other than M3. DCK rs4694362 (CC genotype) was a significant poor prognostic factor for overall survival (OS) (hazard ratio [HR], 33.202 [95% confidence interval (CI), 4.937-223.273], P<0.0001, P(Bonferroni)=0.017). SLC29A1 rs3734703 (AA or AC genotype) in combination with TYMS rs2612100 (AA genotype) was significantly associated with shorter relapse free survival (RFS) (HR, 17.630 [95% CI, 4.829-64.369], P<0.0001, P(Bonferroni)=0.021). These SNPs showed moderate or large inter ethnic divergence in allele frequencies from African or Caucasian populations. The results of our study suggest that a single SNP and SNP-SNP interactions may help to predict the drug response and provide a guide in developing individualised chemotherapy for AML patients receiving ara-C based chemotherapy.
Assuntos
Citarabina/farmacocinética , Loci Gênicos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Citarabina/administração & dosagem , Feminino , Genótipo , Humanos , Leucemia Mieloide Aguda/metabolismo , Masculino , Redes e Vias Metabólicas/genética , Pessoa de Meia-Idade , Tipagem de Sequências Multilocus , Polimorfismo de Nucleotídeo Único , Resultado do Tratamento , Adulto JovemRESUMO
Anthracyclines play a major role in chemotherapeutic regimens for a variety of pediatric cancers, but produce undesirable dose-related cardiotoxicity. Dexrazoxane reduces early myocardial injury during anthracycline treatment, but data remain insufficient to fully understand its cardioprotective effectiveness in treating pediatric cancers and additional research is necessary to find efficient methods of dexrazoxane administration. Therefore, we retrospectively evaluated the cardioprotective effect of dexrazoxane against anthracyclines in 258 pediatric cancer patients who had received any anthracyclines from January 1997 to May 2005 at a tertiary teaching hospital in Korea. The results of this study suggest that the early use of dexrazoxane protects against the development of cardiotoxicity during anthracycline treatment in pediatric cancer patients. Further studies involving larger pediatric cancer patients are needed to evaluate the cardioprotective effect of dexrazoxane at higher cumulative doses of anthracyclines and on late-onset cardiotoxicity in long-term survivors.
Assuntos
Antraciclinas/efeitos adversos , Fármacos Cardiovasculares/administração & dosagem , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/prevenção & controle , Razoxano/administração & dosagem , Adolescente , Fatores Etários , Antraciclinas/uso terapêutico , Fármacos Cardiovasculares/uso terapêutico , Criança , Pré-Escolar , Feminino , Testes de Função Cardíaca , Hospitais de Ensino , Humanos , Lactente , Masculino , Neoplasias/tratamento farmacológico , Razoxano/uso terapêutico , República da Coreia , Estudos RetrospectivosRESUMO
Copy number variation (CNV) has been reported to be associated with chemotherapy response, which affects disease prognosis. Here, we determined the frequency of genome-wide cytogenetic CNV aberrations in Korean patients with normal karyotype (NK) acute myeloid leukaemia (AML) and tested whether these genomic variations contribute to differences in Ara-C and anthracycline-based chemotherapy responses. Bone marrow aspirates and blood from 30 previously untreated de novo NK-AML patients were provided at the time of diagnosis for copy number analysis. Possible associations between cytogenetic aberrations and clinical parameters were analysed. CNVs were identified in 23 (76.7%) of the 30 cases tested. Multivariate analyses controlled for other clinical co-variates showed that patients having copy number loss had a decreased probability of complete remission (OR, 0.015 [95% CI, 0-0.737], p = 0.035). Patients who had a copy number gain of more than four regions tended to have shorter event-free survival (EFS) (p = 0.083) with multivariate analysis showing that CNV increase is an independent predictive factor for shorter EFS (HR, 22.104 [95% CI, 1.644-297.157], p = 0.020). In addition, we identified candidate genes that may be involved in Ara-C and anthracycline drug response in Korean patients with NK-AML. These results suggest that CNVs may affect the success of Ara-C and anthracycline-based chemotherapy in Korean patients with NK-AML.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Variações do Número de Cópias de DNA , Resistencia a Medicamentos Antineoplásicos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Citarabina/administração & dosagem , Citarabina/uso terapêutico , Feminino , Estudo de Associação Genômica Ampla , Humanos , Idarubicina/administração & dosagem , Idarubicina/uso terapêutico , Quimioterapia de Indução , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/metabolismo , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , República da Coreia , Análise de Sobrevida , Adulto JovemRESUMO
STUDY OBJECTIVE: To estimate the population pharmacokinetic parameters of cyclosporine in Korean adults undergoing living-donor kidney transplantation, and to identify clinical factors affecting cyclosporine pharmacokinetics. DESIGN: Retrospective cohort study. SETTING: Single, 1600-bed, tertiary care academic medical center in Seoul, South Korea. PATIENTS: Seventy-four living-donor kidney transplant recipients (mean age 42 yrs) receiving oral cyclosporine microemulsion as an immunosuppressant between January 1, 2001, and August 31, 2006. MEASUREMENTS AND MAIN RESULTS: Using nonlinear mixed-effects modeling (NONMEM) with first-order absorption and elimination, a total of 2394 whole-blood cyclosporine concentrations from the 74 patients were analyzed. The effects of several clinical covariates on cyclosporine pharmacokinetic parameters were evaluated over 12 months after transplantation. The absorption rate constant was fixed at 1.28 hour(-1), and the following population pharmacokinetic estimates were calculated: cyclosporine clearance 43.6 L/hour, apparent volume of distribution 1990 L, and interpatient variability for clearance (coefficient of variation) 17.69%. The clinical factors (covariates) that significantly affected cyclosporine pharmacokinetics were postoperative days, prednisolone dose (in mg/day), total bilirubin level (mg/dl), current body weight (in kg), and concurrent use of amlodipine. CONCLUSION: This population pharmacokinetic model identified important sources of variability in cyclosporine pharmacokinetics. The model will help calculate cyclosporine dose requirements in renal transplant recipients according to specific clinical factors affecting cyclosporine clearance, and it will also be useful for therapeutic drug monitoring.
Assuntos
Ciclosporina/farmacocinética , Imunossupressores/farmacocinética , Transplante de Rim/métodos , Modelos Biológicos , Centros Médicos Acadêmicos , Adulto , Idoso , Povo Asiático , Estudos de Coortes , Ciclosporina/administração & dosagem , Ciclosporina/uso terapêutico , Relação Dose-Resposta a Droga , Emulsões , Feminino , Glucocorticoides/administração & dosagem , Glucocorticoides/uso terapêutico , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/uso terapêutico , Doadores Vivos , Masculino , Pessoa de Meia-Idade , Dinâmica não Linear , Prednisolona/administração & dosagem , Prednisolona/uso terapêutico , República da Coreia , Estudos Retrospectivos , Distribuição Tecidual , Adulto JovemRESUMO
To characterize the molecular mechanisms involved in the transition from the chronic phase to blast crisis in chronic myelogenous leukemia (CML), gene expression profiles of leukemic cells from patients in the chronic and blast crisis phases were analyzed using an 8.7K cDNA chip and real-time PCR. A transient transfection analysis was conducted to evaluate the role of FLT3, which was significantly upregulated in the blast crisis patients. Abl and c-Kit induction was detected in K562 cells transfected with FLT3 cDNA (K562/FLT3), and Abl and c-Kit levels were reduced in K562/FLT3 cells transfected with FLT3-siRNA (K562/FLT3-siRNA). The induction of FLT3 in CML cells attenuated imatinib-induced apoptosis. The opposite effect was observed in K562/FLT3-siRNA cells. An increased level of cleaved PARP and decreased level of pro-caspase 3 were noted when K562/FLT3-siRNA cells were treated with imatinib. These findings indicate that FLT3 is associated with disease progression, despite imatinib therapy. These results may help in the prediction of disease progression in CML patients and the development of more appropriate therapeutic modalities.