ABSTRACT
Lower urinary tract symptoms (LUTS) induced by anticholinergic drug action impair the QOL of patients and are associated with a poor prognosis. Therefore, it is expedient to develop methods of predicting the anticholinergic side effects of drugs, which we aimed to achieve in this study using a quantitative structure-activity relationship (QSAR) and docking study with molecular operations environment (MOE; Molecular Simulation Informatics Systems [MOLSIS], Inc.) In the QSAR simulation, the QSAR model built using the partial least squares regression (PLS) and genetic algorithm-multiple linear regression (GA-MLR) methods showed remarkable coefficient of determination (R2) and XR2 values. In the docking study, a specific relationship was identified between the adjusted docking score (-S) and bioactivity (pKi) values. In conclusion, the methods developed could be useful for in silico risk assessment of LUTS, and plans are potentially applicable to numerous drugs with anticholinergic activity that induce serious side effects, limiting their use.
Subject(s)
Cholinergic Antagonists/chemistry , Molecular Docking Simulation , Quantitative Structure-Activity Relationship , Algorithms , Binding Sites , Cholinergic Antagonists/therapeutic use , Humans , Least-Squares Analysis , Linear Models , Lower Urinary Tract Symptoms/drug therapy , Lower Urinary Tract Symptoms/pathology , Receptor, Muscarinic M3/chemistry , Receptor, Muscarinic M3/metabolismABSTRACT
BACKGROUND: Effect of statin therapy has been reported to be associated with patient's adherence. Atorvastatin was available in Japan as a brand-name product beginning in 2000. The first atorvastatin generics were introduced in Japan in November 2011. The objective of this study was to analyze whether changing from a brand-name atorvastatin to a generic product would affect patient adherence. METHODS: We conducted a retrospective cohort study that included adult patients who received newly prescribed brand-name atorvastatin between June 1, 2011 and May 31, 2012, using a health insurance claims database in Japan. Patients were classified by the presence or absence of changing to a generic during the 6 months from December 1, 2011 to May 31, 2012 (the index period). The first prescription date for the generic or brand product during the index period was defined as the index date. Adherence to therapy was assessed by the proportion of days covered (PDC) and persistence of treatment by time to discontinuation. RESULTS: There were 135 patients changing to generic atorvastatin and 147 continuing with the brand-name product. There was no significant difference in decrease of PDC from pre- to post-index date between the changed cohort and continued cohort (-8.6% vs -10.3%, respectively; P = 0.443). After adjusting for baseline covariates, including adherence in pre-index date, no statistically significant differences were observed in the adjusted odds of adherence between the cohorts (adjusted odds ratio = 0.83, 95% confidence interval (CI) = 0.46-1.53). There was also no significant difference in persistence between two cohorts in the 180-day after post-index date. After analysis of a Cox proportional hazard regression model controlling for baseline covariates, including adherence in pre-index date, no statistically significant differences were observed for the hazard of non-persistence between the cohorts (adjusted hazard ratio = 0.96, 95% CI = 0.60-1.53). CONCLUSIONS: Changing from a brand-name atorvastatin to generic product did not affect adherence for patients newly treated with atorvastatin.
ABSTRACT
BACKGROUND: The "zero death from asthma strategy" in the medical treatment for bronchial asthma has been promoted by the Ministry of Health, Labour, and Welfare from 2006, and it indicates that medical and non-medical specialists, as well as pharmacists, should cooperate, and strives to build cooperation which is suited the actual conditions of an area. It is also important for COPD. Although hospitals in some areas cooperate with clinics and pharmacies, the overall concept of cooperation appears to be absent in most Japanese hospitals. METHOD: A questionnaire was administered in early March, 2012 to 477 allergology institutions, and was authorized by an educational establishment. RESULT: Among 246 replies from the institutions, cooperation between hospitals and clinics was carried out by 98 institutions (39.8%) specializing in bronchial asthma, and in 64 institutions (37.2%) specializing in COPD. However, cooperation tools were used in only 37 of these institutions (15.0%). The ability to fill prescriptions outside the hospital was available in 209 institutions (85.0%). One-hundred and seventeen institutions (47.6%) replied that they have no tools for hospital-pharmacy cooperation. Direct indications were written in prescriptions by 82 institutions (33.3). CONCLUSION: In order to build inter-regional association and to equalize medical treatment, we suggest that developing tools and organization for cooperation between health professionals who treat patients with bronchial asthma and COPD is necessary.
Subject(s)
Ambulatory Care Facilities , Asthma/drug therapy , Hospitals , Interdisciplinary Communication , Pharmacy , Administration, Inhalation , Anti-Asthmatic Agents/administration & dosage , Asthma/mortality , Humans , Japan/epidemiology , Patient Education as Topic/statistics & numerical data , Prescriptions/statistics & numerical data , Pulmonary Disease, Chronic Obstructive/drug therapy , Surveys and QuestionnairesABSTRACT
In this study we report the pharmacokinetics and severe adverse effects of sunitinib in a woman with a gastrointestinal stromal tumor (GIST). A 60-year-old woman with small intestinal GIST developed severe thrombocytopenia (1.7×10(4)/µl) following 1 week of treatment with sunitinib at 50 mg/day. Although the dose of sunitinib was reduced to 25 mg/day, platelet levels remained low. On day 7, the trough concentration of sunitinib plus SU12662 was 46.1 ng/ml and the area under the curve (AUC) was 1,393.0 ng·h/l. The dose was again reduced to 12.5 mg/day. However, the day after resumption of treatment, the patient developed symptoms of left heart failure due to myocardosis caused by sunitinib. Sunitinib has been reported to inhibit platelet-derived growth factor receptor (PDGFR) phosphorylation at concentrations over the range of 50-100 ng/ml (sunitinib plus SU12662) in vivo. In this case, the plasma concentration was sufficient to inhibit PDGFR at 25 or 50 mg/day. However, thrombocytopenia appeared at both dosages. Although the results in this case did not suggest a correlation between thrombocytopenia and plasma concentration, the degree of thrombocytopenia was decreased by reduction of the dose. In conclusion, the findings reported here indicate that the plasma concentration of sunitinib plus SU12662 is an important indicator to reduce adverse effects.
ABSTRACT
We investigated the effects of embryoid body (EB) forming conditions on the expression of hepatocyte marker genes such as alpha-fetoprotein, albumin and CYP7A1 in cells cultured on Matrigel-coated plates for 15 d. The expression levels of hepatocyte marker genes in the cells cultured for 2 d for EB formation from cynomolgus monkey embryonic stem (cmES) cells was higher than those in cells cultured for 5 d. However, the fragment-size of cmES colonies did not markedly affect the expression levels. The expression levels of hepatocyte marker genes, and CYP1A1 and CYP2C43 in cells cultured on Matrigel were considerably higher than those on Matrigel reduced and collagen I. CYP1A1 and CYP3A8 mRNAs were significantly induced by 3-methylcholanthrene and rifampicin, respectively. However, CYP2C43 and CYP2D17 were not induced by these compounds. These results suggested that the differentiation into hepatocytes is affected by the incubation period for EB formation, and that Matrigel successfully promoted in vitro differentiation of cmES cells to hepatocytes.
Subject(s)
Cell Differentiation/physiology , Cytochrome P-450 Enzyme System/biosynthesis , Embryonic Development/physiology , Embryonic Stem Cells/physiology , Hepatocytes/physiology , Pharmaceutical Preparations/metabolism , RNA, Messenger/biosynthesis , Animals , Biocompatible Materials , Collagen/pharmacology , Collagen Type I/pharmacology , DNA Primers , Drug Combinations , Laminin/pharmacology , Macaca fascicularis , Proteoglycans/pharmacology , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
Hepatocyte differentiation markers were expressed in the cells differentiated from mouse embryonic stem (ES) cells. In the differentiating ES cells, Cyp1a1 mRNA was highly expressed during the early to middle stage; Cyp2c29, Cyp2e1, Cyp3a11 and Cyp7a1 mRNAs were expressed only at the late stage; Cyp7b1 mRNA was expressed throughout all stages. Alpha-fetoprotein and albumin were co-expressed with Cyp3a and Cyp1a, respectively. Aryl hydrocarbon receptor, aryl hydrocarbon receptor nuclear translocator and glucocorticoid receptor mRNAs were detected in differentiating ES cells throughout the culture period. Pregnane X receptor mRNA was detected only in cells cultured for more than 24 days. The expression levels of Cyp2c29, Cyp3a11 and Cyp7a1 and G6p mRNAs were increased in embryoid bodies that were cultured with culture medium containing acid fibroblast growth factor, hepatocyte growth factor (HGF) and oncostatin M for 12 or 18 days, then the medium was replaced by that without HGF. These findings suggested that the expression levels of Cyp genes in hepatocytes differentiated from ES cells were markedly changed in individual enzymes during the course of differentiation, and that the duration of incubation with the addition of HGF affected the expression of Cyps and hepatocytes marker proteins.