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1.
Nataporn Chaipichit Janet Krska Thongchai Pratipanawatr Verawan Uchaipichat Narumol Jarernsiripornkul 《European journal of clinical pharmacology》2014,70(5):607-615
Purpose
To explore how Thai patients assess symptoms as adverse drug reactions (ADRs).Methods
Out-patients at two hospitals in Thailand previously reporting suspected ADRs to statins were purposively selected to cover factors relevant to the accuracy of ADR reports. Semi-structured interviews explored the mechanisms participants used to work out whether their symptoms were related to their statin. All interviews were audio-recorded, transcribed and independently thematically analyzed by two researchers.Results
One hundred interviews were suitable for analysis; 52 were male, age range was 36 to 77 years (mean?±?S.D.: 59.83?±?9.14) and most (92) were taking other medicines in addition to statins. Patient assessment of symptoms as ADRs fell into two major themes: medicine-related factors and external factors. Timing relationships were mentioned most frequently (74), followed by information received (55), seeing similar symptoms in others (7) and diagnosis through blood tests (4). Use of multiple medicines, consideration of the medicine versus diseases, symptoms occurring with more than one medicine or relieved through treatment reduced confidence in ADR attribution. Many participants proposed alternative explanations for symptoms, including old age. Lack of information and knowledge were obstacles to the assessment process.Conclusions
Patients assessed possible ADRs most often by considering timing relationships. While they also used medicine information, Thai patients received inadequate information to help them assess their symptoms. Patients expressed uncertainty and difficulties in deciding attribution when concomitant medicines and diseases were involved. The findings could support the development of a patient-friendly systematic tool for identifying and assessing possible ADRs. 相似文献2.
Uchaipichat V Galetin A Houston JB Mackenzie PI Williams JA Miners JO 《Molecular pharmacology》2008,74(4):1152-1162
Interactions between the UGT2B7-catalyzed glucuronidation of zidovudine (AZT), 4-methylumbelliferone (4MU), and 1-naphthol (1NP) were analyzed using multisite and empirical kinetic models to explore the existence of multiple substrate and effector binding sites within this important drug metabolizing enzyme. 4MU and 1NP glucuronidation by UGT2B7 exhibit sigmoidal kinetics characteristic of homotropic cooperativity (autoactivation), which may be modeled assuming the existence of two equivalent, interacting substrate binding sites. In contrast, UGT2B7-catalyzed AZT glucuronidation follows hyperbolic (Michaelis-Menten) kinetics. Although 4MU and 1NP decreased the binding affinity of AZT, the kinetics of AZT glucuronidation changed from hyperbolic to sigmoidal in the presence of both modifiers. Data were well described by a generic two-substrate binding site model in which there is no interaction between the sites in the absence of 4MU or 1NP, but heterotropic cooperativity results from the binding of modifier. Inhibition of 4MU and 1NP glucuronidation by AZT and interactions between 4MU and 1NP required more complex three-site models, where the modifier acts via a distinct effector site to alter either substrate binding affinity or Vmax without affecting the homotropic cooperativity characteristic of 4MU and 1NP glucuronidation. It is noteworthy that 1NP inhibited 4MU glucuronidation, whereas 4MU activated 1NP glucuronidation. The results are consistent with the existence of two "catalytic" sites for each substrate within the UGT2B7 active site, along with multiple effector sites. The multiplicity of binding and effector sites results in complex kinetic interactions between UGT2B7 substrates, which potentially complicates inhibition screening studies. 相似文献
3.
OBJECTIVES: Although dengue is one of the most common mosquito-borne viral diseases, few studies have investigated the relationship between the dengue virus and mosquito cells, and this study sought to describe the binding and propagation of the dengue viruses in C6/36 cells. METHODS: The internalization and production of the dengue virus was assayed by standard plaque assay methodologies, while dengue virus receptor proteins were examined by a virus overlay protein-binding assay and candidate gene analysis coupled with virus inhibition studies. RESULTS: All four serotypes were internalized linearly, and de novo virus production occurred 14-19 h postinfection. Virus overlay protein-binding assay identified a band of 50 kDa for dengue serotypes 2, 3 and 4 which comigrated with a protein that reacts with antibodies directed against the human 37/67-kDa high-affinity laminin receptor. Both antibodies directed against the human 37/67-kDa high-affinity laminin receptor protein and soluble laminin inhibited the binding and internalization of serotypes 3 and 4, but not serotypes 1 and 2. CONCLUSIONS: The results suggest that multiple receptors may be used by the dengue virus to enter into insect cells, and that one of these proteins may be a laminin-binding protein. 相似文献
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5.
Jarernsiripornkul N Senacom P Uchaipichat V Chaipichit N Krska J 《Epilepsy & behavior : E&B》2012,24(1):102-106
This study was aimed to assess the frequency and number of suspected ADRs reported by patients taking antiepileptic drugs (AEDs) and to explore the factors that may affect patients' symptom attribution accuracy. A validated questionnaire containing an extensively checklist of symptoms was distributed to outpatients prescribed one or more AEDs. Data on concomitant drugs and diseases were obtained from outpatient records. All symptoms identified were assessed for causality. Of 1388 questionnaires distributed to 1214 patients, 830 completed questionnaires were returned (59.8%) from 727 patients. In total, 7815 symptoms were identified on 757 questionnaires (91.2%). Symptom severity ratings were positively related to the number of symptoms reported (p=0.003). Causality assessment found that 71.9% of the symptoms were 'true' ADRs and 28.1% were 'false' ADRs. Attribution accuracy was primarily influenced by the number of symptoms identified and indication for AED therapy, fewer symptoms and use for non-epilepsy indications being associated with greater attribution accuracy. 相似文献
6.
OBJECTIVES: The mosquito-borne Japanese encephalitis virus is a leading cause of encephalitis worldwide. However, few studies have investigated the kinetics of Japanese encephalitis virus internalization and production in mosquito cells, and fewer still have investigated the nature of the molecules involved in the binding of the virus to mosquito cells. METHODS: Using the Aedes albopictus/Stegomyia albopicta-derived C6/36 cell line, Japanese encephalitis virus internalization and production were assayed by standard plaque assay, and virus binding was investigated through preinfection enzymatic treatment of cells and virus overlay protein-binding assay of membrane fractions in native and denaturing gels. RESULTS: The internalization of the virus was nonlinear, and intracellular infective viruses were detected 8 h after infection and exported to the medium 10 h after infection. The internalization of the virus was primarily mediated by protein elements, and several bands were observed after overlay assay to membrane proteins, although mass spectroscopy was unable to identify candidate proteins. Soluble laminin produced a marginal, but dose-dependent inhibition of infection. CONCLUSIONS: These results suggest that the mechanism of Japanese encephalitis entry, production, attachment and receptor usage are distinct from those employed by the dengue viruses. 相似文献
7.
Watson JN Addison PS Uchaipichat N Shah AS Grubb NR 《Computers in biology and medicine》2007,37(4):517-523
The aim of this study was to examine whether wavelet transform analysis of the electrocardiogram (ECG) can improve the prediction of the maintenance of sinus rhythm in patients with atrial fibrillation (AF) after external DC cardioversion. We examined a variety of wavelet transform-based statistical markers as potential candidates for the prediction of patient status post-cardioversion. Considering a 'success' as a patient who remains in normal sinus rhythm for one month post cardioversion and 'failure' as a patient who does not, it was shown the proposed non-parametric classification system can achieve 89% specificity at 100% sensitivity using a non-parametric classification method. 相似文献
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9.
Verawan Uchaipichat Peter I Mackenzie David J Elliot John O Miners 《Drug metabolism and disposition》2006,34(3):449-456
Relatively few selective substrate and inhibitor probes have been identified for human UDP-glucuronosyltransferases (UGTs). This work investigated the selectivity of trifluoperazine (TFP), as a substrate, and amitriptyline, androsterone, canrenoic acid, hecogenin, phenylbutazone, quinidine, quinine, and sulfinpyrazone, as inhibitors, for human UGTs. Selectivity was assessed using UGTs 1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B7, and 2B15 expressed in HEK293 cells. TFP was confirmed as a highly selective substrate for UGT1A4. However, TFP bound extensively to both HEK293 lysate and human liver microsomes in a concentration-dependent manner (fuinc 0.20-0.59). When corrected for nonspecific binding, Km values for TFP glucuronidation were similar for both UGT1A4 (4.1 microM) and human liver microsomes (6.1+/-1.2 microM) as the enzyme sources. Of the compounds screened as inhibitors, hecogenin, alone, was selective; significant inhibition was observed only for UGT1A4 (IC50 1.5 microM). Using phenylbutazone and quinine as "models," inhibition kinetics were variously described by competitive and noncompetitive mechanisms. Inhibition of UGT2B7 by quinidine was also investigated further, because the effects of this compound on morphine pharmacokinetics (a known UGT2B7 substrate) have been ascribed to inhibition of P-glycoprotein. Quinidine inhibited human liver microsomal and recombinant UGT2B7, with respective Ki values of 335+/-128 microM and 186 microM. In conclusion, TFP and hecogenin represent selective substrate and inhibitor probes for UGT1A4, although the extensive nonselective binding of the former should be taken into account in kinetic studies. Amitriptyline, androsterone, canrenoic acid, hecogenin, phenylbutazone, quinidine, quinine, and sulfinpyrazone are nonselective UGT inhibitors. 相似文献
10.
Quantitative prediction of in vivo inhibitory interactions involving glucuronidated drugs from in vitro data: the effect of fluconazole on zidovudine glucuronidation
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Uchaipichat V Winner LK Mackenzie PI Elliot DJ Williams JA Miners JO 《British journal of clinical pharmacology》2006,61(4):427-439
AIMS: Using the fluconazole-zidovudine (AZT) interaction as a model, to determine whether inhibition of UDP-glucuronosyltransferase (UGT) catalysed drug metabolism in vivo could be predicted quantitatively from in vitro kinetic data generated in the presence and absence bovine serum albumin (BSA). METHODS: Kinetic constants for AZT glucuronidation were generated using human liver microsomes (HLM) and recombinant UGT2B7, the principal enzyme responsible for AZT glucuronidation, as the enzyme sources with and without fluconazole. K(i) values were used to estimate the decrease in AZT clearance in vivo. RESULTS: Addition of BSA (2%) to incubations decreased the K(m) values for AZT glucuronidation by 85-90% for the HLM (923 +/- 357 to 91 +/- 9 microm) and UGT2B7 (478-70 microm) catalysed reactions, with little effect on V(max). Fluconazole, which was shown to be a selective inhibitor of UGT2B7, competitively inhibited AZT glucuronidation by HLM and UGT2B7. Like the K(m), BSA caused an 87% reduction in the K(i) for fluconazole inhibition of AZT glucuronidation by HLM (1133 +/- 403 to 145 +/- 36 microm) and UGT2B7 (529 to 73 microm). K(i) values determined for fluconazole using HLM and UGT2B7 in the presence (but not absence) of BSA predicted an interaction in vivo. The predicted magnitude of the interaction ranged from 41% to 217% of the reported AUC increase in patients, depending on the value of the in vivo fluconazole concentration employed in calculations. CONCLUSIONS: K(i) values determined under certain experimental conditions may quantitatively predict inhibition of UGT catalysed drug glucuronidation in vivo. 相似文献