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1.
Br Dent J ; 230(12): 790, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34172844
2.
Eur J Pharm Sci ; 111: 432-442, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-29032303

RESUMO

Although the term "personalized medicine" has been associated in many cases with pharmacogenomics, its definition embraces the use of specific biomarkers and covariates to help in the selection of medical treatments and procedures which are best for each patient. While several efforts have been performed for the tailored selection of therapies and dosing regimens in the general population, developing personalized medicine initiatives for elderly patients remains understudied. The personalized drug therapy for older patients requires the consideration of anatomical, physiological and functional alterations in a multimorbid setting requiring multiple medications. The present review focuses on currently employed qualitative and quantitative precision medicine approaches for elderly patients and discusses some of the associated challenges and limitations. Furthermore, the use of and confidence in physiologically-based approaches for optimal dose selection in this understudied yet clinically important patient population will be highlighted and discussed.


Assuntos
Tratamento Farmacológico/normas , Medicina de Precisão/normas , Idoso , Humanos , Farmacogenética
3.
J Clin Pharmacol ; 56(10): 1221-31, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27040602

RESUMO

FDA recommendations to manage polymorphic CYP-mediated drug-drug interactions (DDIs) and gene-drug interactions (GDIs) are typically similar. However, DDIs may not always reliably predict GDIs because the victim drug may have multiple metabolic pathways and the perpetrator drug may affect multiple enzymes or transporters. Consequently, it is of great interest to both the pharmaceutical industry and regulatory agencies to determine if DDI studies can be leveraged to inform GDIs or vice versa for dose adjustment and labeling. The objective of this study was to investigate under what circumstances DDIs can be used to predict GDIs for prototypical CYP2C9, CYP2C19, and CYP2D6 substrates. We investigated model substrates for CYP2D6 (metoprolol, dextromethorphan, atomoxetine, and vortioxetine), CYP2C9 (warfarin, flurbiprofen, and celecoxib), and CYP2C19 (omeprazole and clopidogrel). Data on drug exposure for poor metabolizers (GDI) and for DDIs mediated by strong/moderate inhibitors in extensive metabolizers were collected. The impact of DDIs and GDIs on drug exposure was compared using: (1) a descriptive and (2) a physiologically based pharmacokinetic convergence analysis. Results from both approaches indicate that information on DDIs can be used to reliably predict GDIs for CYP2D6 substrates. The situation is more complex for CYP2C9 and CYP2C19 substrates because dose of the inhibitor (CYP2C9) and potency of the inhibitor (CYP2C19) impact the extent to which perpetrator drugs phenotypically convert extensive metabolizers to poor(er) metabolizers.


Assuntos
Citocromos/genética , Citocromos/metabolismo , Interações Medicamentosas , Farmacogenética , Área Sob a Curva , Simulação por Computador , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C9/genética , Citocromo P-450 CYP2D6/genética , Inibidores Enzimáticos/farmacologia , Humanos , Farmacocinética , Especificidade por Substrato
4.
Antimicrob Agents Chemother ; 60(2): 946-54, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26621623

RESUMO

Levofloxacin (LEV) is a broad-spectrum fluoroquinolone used to treat pneumonia, urinary tract infections, chronic bacterial bronchitis, and prostatitis. Efflux transporters, primarily P-glycoprotein (P-gp), are involved in LEV's tissue penetration. In the present work, LEV free lung and prostate interstitial space fluid (ISF) concentrations were evaluated by microdialysis in Wistar rats after intravenous (i.v.) and intratracheal (i.t.) administration (7 mg/kg of body weight) with and without coadministration of the P-gp inhibitor tariquidar (TAR; 15 mg/kg administered i.v.). Plasma and tissue concentration/time profiles were evaluated by noncompartmental analysis (NCA) and population pharmacokinetics (popPK) analysis. The NCA showed significant differences in bioavailability (F) for the control group (0.4) and the TAR group (0.86) after i.t. administration. A four-compartment model simultaneously characterized total plasma and free lung (compartment 2) and prostate (compartment 3) ISF concentrations. Statistically significant differences in lung and prostate average ISF concentrations and levels of kidney active secretion in the TAR group from those measured for the control group (LEV alone) were observed. The estimated population means were as follows: volume of the central compartment (V1), 0.321 liters; total plasma clearance (CL), 0.220 liters/h; TAR plasma clearance (CLTAR), 0.180 liters/h. The intercompartmental distribution rate constants (K values) were as follows: K12, 8.826 h(-1); K21, 7.271 h(-1); K13, 0.047 h(-1); K31, 7.738 h(-1); K14, 0.908 h(-1); K41, 0.409 h(-1); K21 lung TAR (K21LTAR), 8.883 h(-1); K31 prostate TAR (K31PTAR), 4.377 h(-1). The presence of P-gp considerably impacted the active renal secretion of LEV but had only a minor impact on the efflux from the lung following intratracheal dosing. Our results strongly support the idea of a role of efflux transporters other than P-gp contributing to LEV's tissue penetration into the prostrate.


Assuntos
Levofloxacino/análise , Levofloxacino/farmacocinética , Pulmão/metabolismo , Próstata/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Administração Intravenosa , Animais , Antibacterianos/administração & dosagem , Antibacterianos/análise , Antibacterianos/sangue , Antibacterianos/farmacocinética , Calibragem , Vias de Administração de Medicamentos , Levofloxacino/administração & dosagem , Levofloxacino/sangue , Pulmão/efeitos dos fármacos , Masculino , Microdiálise , Próstata/efeitos dos fármacos , Ratos Wistar , Distribuição Tecidual
6.
AAPS J ; 17(6): 1388-94, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26112250

RESUMO

Clinical studies include occurrences of rare variables, like genotypes, which due to their frequency and strength render their effects difficult to estimate from a dataset. Variables that influence the estimated value of a model-based parameter are termed covariates. It is often difficult to determine if such an effect is significant, since type I error can be inflated when the covariate is rare. Their presence may have either an insubstantial effect on the parameters of interest, hence are ignorable, or conversely they may be influential and therefore non-ignorable. In the case that these covariate effects cannot be estimated due to power and are non-ignorable, then these are considered nuisance, in that they have to be considered but due to type 1 error are of limited interest. This study assesses methods of handling nuisance covariate effects. The specific objectives include (1) calibrating the frequency of a covariate that is associated with type 1 error inflation, (2) calibrating its strength that renders it non-ignorable and (3) evaluating methods for handling these non-ignorable covariates in a nonlinear mixed effects model setting. Type 1 error was determined for the Wald test. Methods considered for handling the nuisance covariate effects were case deletion, Box-Cox transformation and inclusion of a specific fixed effects parameter. Non-ignorable nuisance covariates were found to be effectively handled through addition of a fixed effect parameter.


Assuntos
Simulação por Computador , Modelos Biológicos , Farmacocinética , Humanos
7.
Ann Med Health Sci Res ; 4(Suppl 2): S144-6, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25184082

RESUMO

Tuberculosis (TB) is one of the major health problems in India. Genitourinary TB (GUTB) comprises 20% of all extrapulmonary TB, and is the most common extrapulmonary site to be affected by this disease. The spectrum of varied pathological changes occur in GUTB, hence a thorough knowledge is required to prevent complications related to GUTB. Diagnostic dilemma is a common problem faced as culture and polymerase chain reaction results vary in their sensitivity and specificity. A thorough knowledge of epidemiology, immunopathogenesis, and spectrum of the disease and importance of including liquid culture system for the diagnosis of this disease are presented in three cases.

8.
J Pharmacokinet Pharmacodyn ; 39(4): 383-92, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22767340

RESUMO

Population pharmacokinetic-pharmacodynamic analysis involves nonlinear hierarchical modelling where the mean response in a population and the variability in response from different sources are studied. It generally consists of two model hierarchies: a model for residual error and a model for heterogeneity termed between subject variance (BSV). The overall variability in a parameter within a population termed population parameter variance (PPV) consists of within subject variance (WSV) and BSV. Both these variances can further be split into random and predictable components. The predictable component of BSV (termed BSVP) is explained by covariates, individual characteristics e.g. weight. As BSVP increases, the remaining unpredictable (or random) between subject variability (BSVR) decreases since BSV = BSVP + BSVR, and BSV is a constant in any given data set. Since BSV and BSVR are estimated from the base and full covariate models, respectively, then BSVP = BSV-BSVR. The aim of this study was to explore the hypothesis, that a significant covariate may not always decrease BSVR. The specific aims were: (1) to explore circumstances where BSVR may not be reduced when adding a significantly correlated covariate and (2) to explore whether specific models for covariates may eliminate this anomaly when assessing BSVR. Simulations were performed using MATLAB (2011a) and estimation using NONMEM (ver 7.2) with FOCE and INTERACTION. A 1-compartment intravenous bolus PK model was used for simulation following a single unit dose (d = 1). The BSV of clearance [BSV(CL)] was described according to a log-normal distribution model with mean zero and variance ω². An additive random unexplained variability was assumed. Initially, we show through a simple simulation that BSVR can increase when a significantly correlated covariate is added to the model. We follow this with five simulation scenarios, A to E, that have various levels of correlation between the continuous covariate (Z) and CL ranging from 0 to 100 %. Each simulated scenario was replicated 100 times and estimated by a base model (i.e. without covariate addition) and six covariate models (M1-M6) which included non-nested (M1), nested (M2), and two types of interaction models for each of M1 and M2; non-nested interaction (M3, M5), nested interaction (M4, M6). Initially, through a motivating example we show that BSVR may not reduce even when there is 50 % correlation between the covariate Z and CL. It was found that with 0 % correlation M1, the non-nested covariate model (NNCM) resulted in negative BSVP (inflated BSVR) whereas M2, the nested covariate model (NCM), resulted in a calculated BSVP of zero. NNCM (M1) shows negative BSVP (BSVR > BSV) with correlation as high as 50 % and this model needs a minimum of 75 % correlation to show a positive BSVP. NCM (M2) shows positive but downwardly biased BSVP with 25, 50 and 75 % correlations. However, inclusion of a covariate-eta interaction term for both types of covariate models resulted in greater BSVP for 25, 50 and 75 % correlation scenarios compared to NNCM and NCM respectively. For 100 % correlation, it was found that covariate-eta interaction models show the same BSVP as the models without the interaction term, i.e. under perfect positive correlation all models perform similarly and correctly. It was found that a significantly correlated covariate may not reduce BSVR and in fact it may inflate the BSVR due to statistical misspecification of the covariate model. Incorporating statistical models that account for the covariate-eta interaction may be useful diagnostically in identifying the variability explained by covariates.


Assuntos
Análise de Variância , Modelos Biológicos , Farmacocinética , Simulação por Computador , Humanos , Individualidade
9.
J Pharmacokinet Pharmacodyn ; 39(1): 87-97, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22161222

RESUMO

Latent covariates are covariates that are known to exist but are either observable but unavailable or unobservable at the time of the clinical study. Designs to account for latent covariates must incorporate both uncertainty in the prevalence of the covariate and the data-type of the covariate. The informativeness of the covariate will then depend on whether the covariate data is continuous, ordinal or nominal. In this work we consider designs for latent covariates that may either directly influence the parameter of interest, or indirectly via actions on an observable covariate which then influences the parameter of interest. We consider a motivating example based on the effect of a genetic polymorphism on the influence of a continuous covariate (age) on drug clearance (CL). The polymorphism could take the case of a haplotype with many variant alleles, or a copy number variation in genes with different phenotypic expressions which could be treated as continuous data, or as a bi- or tri-allelic single nucleotide polymorphism that could form either an ordinal or nominal covariate on drug CL. The aim of this study was to investigate designs for clinical studies for latent covariates that accommodate both unknown prevalence and unknown data-type. Initially, the informativeness of a covariate was explored using linear regression assuming the three data-types continuous, ordinal and nominal. The linear covariate model was then considered within a nonlinear mixed effects modelling framework. Two simulation scenarios were considered: (1) the influence of the latent covariate directly on the parameter of interest and (2) the influence of the latent covariate on an observable non-latent continuous covariate, which was assumed to follow a normal or stratified distribution, and the effect of this covariate on the parameter of interest. A power analysis for population PK modelling (1) where the latent covariate had direct influence on the parameter also showed similar behaviour to the linear regression solution. When the influence of the latent covariate was mediated via another observable non-latent continuous covariate, the power for the continuous model was highest but the power of the ordinal model was indistinguishable from that of the nominal model. Stratification of the observable non-latent continuous covariate did not appreciably change the power to identify the latent covariate from that when we assumed the observable covariate conformed to a normal distribution. It was found that parameter estimation is generally at least 1.5 to 7 fold more precise for continuous models than for categorical models.


Assuntos
Projetos de Pesquisa Epidemiológica , Modelos Estatísticos , Farmacocinética , Fatores Etários , Algoritmos , Viés , Simulação por Computador , Humanos , Modelos Lineares , Taxa de Depuração Metabólica/fisiologia , Dinâmica não Linear , Polimorfismo de Nucleotídeo Único/fisiologia , RNA/genética , Tamanho da Amostra , Telomerase/genética
10.
Am J Respir Crit Care Med ; 183(1): 59-66, 2011 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-20693377

RESUMO

RATIONALE: significant progress has been made in understanding the pathogenesis of acute respiratory distress syndrome (ARDS). Recent advances in hospital practice may have reduced the incidence of this lethal syndrome. OBJECTIVES: to observe incidence trends and associated outcomes of ARDS. METHODS: this population-based cohort study was conducted in Olmsted County, Minnesota. Using a validated screening protocol, investigators identified intensive care patients with acute hypoxemia and bilateral pulmonary infiltrates. The presence of ARDS was independently confirmed according to American-European Consensus Conference criteria. The incidence of ARDS and associated outcomes were compared over the 8-year study period (2001-2008). MEASUREMENTS AND MAIN RESULTS: over the 8-year period, critically ill Olmsted County residents presented with increasing severity of acute illness, a greater number of comorbidities, and a higher prevalence of major predisposing conditions for ARDS. The ARDS incidence decreased significantly from 82.4 to 38.9 per 100,000 person-years during the study period (P < 0.001). A decline in hospital-acquired ARDS (P < 0.001) was responsible for the fall in the incidence density with no change on admission (P = 0.877). Overall, mortality and hospital and intensive care unit lengths of stay decreased over time (P < 0.001), whereas the ARDS case-fatality did not change significantly. CONCLUSIONS: despite an increase in patients' severity of illness, number of comorbidities, and prevalence of major ARDS risk factors, the incidence of ARDS in this suburban community decreased by more than half. Correlation of the observed findings with changes in health care delivery may have important implications for the planning of acute care services in other regions.


Assuntos
Vigilância da População , Síndrome do Desconforto Respiratório/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Minnesota/epidemiologia , Morbidade/tendências , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo
11.
Indian J Pharmacol ; 40(3): 121-5, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20040939

RESUMO

OBJECTIVE: To evaluate the anti-inflammatory activity of exogenously administered polyamines on experimentally induced acute and chronic inflammation in wistar rats and to elucidate their possible mechanism of action. MATERIALS AND METHODS: The in vivo anti-inflammatory activity of polyamines was studied using acute (carrageenin paw edema), sub-acute (cotton pellet granuloma) and chronic (Freund's adjuvant induced arthritis) models of inflammation. The biochemical parameters like liver lipid peroxides, SGOT and SGPT were also measured. RESULTS: Polyamines exhibited significant anti-inflammatory activity in acute, sub-acute and chronic models of inflammation. Polyamines treatment inhibited the increase in lipid peroxides in liver and the serum concentration of marker enzymes (glutamate oxaloacetate transferase and glutamate pyruvate transferase) during inflammation. CONCLUSION: Polyamines possess anti-inflammatory activity in acute and chronic inflammation which can be attributed to their anti-oxidant and /or lysosomal stabilization properties.

12.
BMC Complement Altern Med ; 7: 29, 2007 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-17892543

RESUMO

BACKGROUND: The MCE, Momordica charantia fruit extract Linn. (Cucurbitaceae) have been documented to elicit hypoglycemic activity on various occasions. However, due to lack of standardization of these extracts, their efficacy remains questionable. The present study was undertaken by selecting a well standardised MCE. This study reports hypoglycemic and antilipidemic activities of MCE employing relevant animal models and in vitro methods. METHODS: Diabetes was induced in Wistar rats by a s.c., subcutaneous injection of alloxan monohydrate (100 mg/kg) in acetate buffer (pH 4.5). MCE and glibenclamide were administered orally to alloxan diabetic rats at doses of 150 mg/kg, 300 mg/kg & 600 mg/kg, and 4 mg/kg respectively for 30 days, blood was withdrawn for glucose determination on 0, 7, 14, 21 and 30th days. On the 31st day, overnight fasted rats were sacrificed and blood was collected for various biochemical estimations including glycosylated haemoglobin, mean blood glucose, serum insulin, cholesterol, triglcerides, protein and glycogen content of liver. The hemidiaphragms and livers were also isolated, carefully excised and placed immediately in ice cooled perfusion solution and processed to study the glucose uptake/transfer processes. Hypolipidemic activity in old obese rats was evaluated by treating two groups with MCE (150 mg/kg & 300 mg/kg) orally for 30 days and determining total cholesterol, triglyceride and HDL-CH, LDL-CH and VLDL-CH levels from serum samples. RESULTS: Subchronic study of MCE in alloxan induced diabetic rats showed significant antihyperglycemic activity by lowering blood glucose and GHb%, percent glycosylated haemoglobin. Pattern of glucose tolerance curve was also altered significantly. MCE treatment enhanced uptake of glucose by hemidiaphragm and inhibited glycogenolysis in liver slices in vitro. A significant reduction in the serum cholesterol and glyceride levels of obese rats following MCE treatment was also observed. CONCLUSION: Our experimental findings with respect to the mechanism of action of MCE in alloxan diabetic rats suggest that it enhances insulin secretion by the islets of Langerhans, reduces glycogenesis in liver tissue, enhances peripheral glucose utilisation and increases serum protein levels. Furthermore, MCE treatment restores the altered histological architecture of the islets of Langerhans. Hence, the biochemical, pharmacological and histopathological profiles of MCE clearly indicate its potential antidiabetic activity and other beneficial effects in amelioration of diabetes associated complications. Further, an evaluation of its antilipidemic activity in old obese rats demonstrated significant lowering of cholesterol and triglyceride levels while elevating HDL-cholesterol levels. Also, the extract lowered serum lipids in alloxan diabetic rats, suggesting its usefulness in controlling metabolic alterations associated with diabetes.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Frutas , Hipoglicemiantes/administração & dosagem , Hipolipemiantes/administração & dosagem , Momordica charantia , Fitoterapia , Administração Oral , Aloxano , Animais , Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Relação Dose-Resposta a Droga , Fígado/efeitos dos fármacos , Masculino , Modelos Animais , Extratos Vegetais/administração & dosagem , Ratos , Ratos Wistar , Triglicerídeos/sangue
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