Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 16 de 16
Filtrar
Mais filtros

Base de dados
País/Região como assunto
Tipo de documento
Intervalo de ano de publicação
1.
Kidney Int ; 101(3): 626-634, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34481803

RESUMO

Primary hyperoxaluria (PH) is a family of ultra-rare autosomal recessive inherited disorders of hepatic glyoxylate metabolism characterized by oxalate overproduction. Nedosiran is an RNA interference agent that inhibits hepatic lactate dehydrogenase, the enzyme responsible for the common, final step of oxalate production in all three genetic subtypes of PH. Here, we assessed in a two-part, randomized, single-ascending-dose, phase 1 study (PHYOX1) the safety, pharmacokinetics, pharmacodynamics, and exposure-response of subcutaneous nedosiran in 25 healthy participants (Group A) and 18 patients with PH1 or PH2 (Group B). Group A received nedosiran (0.3, 1.5, 3.0, 6.0, then 12.0 mg/kg) or placebo, and Group B received open-label nedosiran (1.5, 3.0, or 6.0 mg/kg). No significant safety concerns were identified. Injection site reactions (four or more hours post dose) occurred in 13.3% of participants in Group A and 27.8% of participants in Group B. Mean maximum reduction in 24-hour urinary oxalate excretion from baseline to day 57 (end of study) across Group B dose cohorts was 55% (range: 22%-100%) after single-dose nedosiran, with 33% participants reaching normal 24-hour urinary oxalate excretion. Based on the available modeling and simulation data, a fixed monthly dose of nedosiran 160 mg (free acid; equivalent to 170 mg sodium salt) in adults was associated with the highest proportion of simulated individuals achieving normal or near-normal 24-hour urinary oxalate excretion and fewest fluctuations in urinary oxalate response. Thus, single-dose nedosiran demonstrated acceptable safety and evidence of a pharmacodynamic effect in both PH1 and PH2 subpopulations consistent with its mechanism of action.


Assuntos
Hiperoxalúria Primária , Adulto , Humanos , Hiperoxalúria Primária/tratamento farmacológico , Hiperoxalúria Primária/genética , Oxalatos/urina , Interferência de RNA
2.
Transpl Infect Dis ; 19(1)2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27875016

RESUMO

BACKGROUND: The aim of this research paper was to determine the incidence, risk factors, and clinical outcome of solid organ transplant (SOT) recipients diagnosed and treated for cryptococcosis at our institution. METHODS: Retrospective analysis of all patients with SOT diagnosed and treated for cryptococcal infection occurring between January 2001 and December 2015. RESULTS: Of 102 patients diagnosed with cryptococcal infection, 23 were SOT recipients. Renal transplant accounted for 22/23 cases, of which 13 had meningitis. The annual incidence of infection has risen significantly, and is now greater than 2/1000 prevalent renal transplant recipients. As expected, biochemical factors associated with meningitis include lower glucose on cerebrospinal fluid (CSF) analysis, median 2.4 vs 4.5 mmol/L (P=.02); CSF white blood cell median 50 vs 1/µL (P<.001); CSF protein, median 950 vs 335 mg/L (P=.04). Serum cryptococcal antigen titers were higher in the meningitis cohort, median 512 vs 32 (P=.03). Clinically, headache on admission (odds ratio: 9 [1.29-63.03], P=.03) and a prolonged length of stay (median of 36 vs 13 days) in the meningitis cohort (P=.02) were significant. CONCLUSION: Cryptococcal infection in SOT recipients remains rare; however, there has been a marked increase in cases since 2014. This study reveals a need for increased vigilance for a potential emerging infectious disease. It furthermore highlights the need for ongoing research to further aid early diagnosis, prognostication, management, and screening cost-effectiveness.


Assuntos
Antígenos de Fungos/sangue , Criptococose/epidemiologia , Cryptococcus neoformans/isolamento & purificação , Terapia de Imunossupressão/efeitos adversos , Transplante de Rim/efeitos adversos , Adulto , Idoso , Antibacterianos/uso terapêutico , Criptococose/sangue , Criptococose/tratamento farmacológico , Criptococose/microbiologia , Feminino , Humanos , Hospedeiro Imunocomprometido , Terapia de Imunossupressão/métodos , Incidência , Masculino , Meningite Criptocócica/sangue , Meningite Criptocócica/tratamento farmacológico , Meningite Criptocócica/epidemiologia , Meningite Criptocócica/microbiologia , Pessoa de Meia-Idade , Transplante de Órgãos/efeitos adversos , Estudos Retrospectivos , Fatores de Risco
3.
J Pharmacokinet Pharmacodyn ; 43(2): 165-77, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26676909

RESUMO

Model based personalised dosing (MBPD) is a sophisticated form of individualised therapy, where a population pharmacokinetic (PK) or pharmacodynamic model is utilised to estimate the dose required to reach a target exposure or effect. The choice of which model to implement in MBPD is a subjective decision. By choosing one model, information from the remaining models is ignored, as well as the rest of the literature base. This manuscript describes a methodology to develop a 'hybrid' model for voriconazole that incorporated information from prior models in a biologically plausible manner. Voriconazole is a triazole antifungal with difficult to predict PK, although it does have a defined exposure-response relationship. Nine population PK models of voriconazole were identified from the literature. The models differed significantly in structural components. The hybrid model contained a two-compartment disposition model with mixed linear and nonlinear time-dependent clearance. The parameters for the hybrid model were determined using simulation techniques. Validation of the hybrid model was assessed via visual predictive checks, which indicated the majority of the variability in the literature models was captured by the hybrid model. The predictive performance was assessed using four different sampling strategies of limited concentrations from ten richly PK sampled subjects to predict future concentrations. Overall, the hybrid model predicted future concentrations with good precision. Further prospective and retrospective validation of the hybrid model is required before it could be used in clinical practice.


Assuntos
Antifúngicos/farmacocinética , Medicina de Precisão/métodos , Voriconazol/farmacocinética , Humanos , Modelos Teóricos
4.
Scand J Infect Dis ; 46(5): 361-7, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24588565

RESUMO

BACKGROUND: Bloodstream infections (BSIs) are a well-recognized complication of parenteral nutrition (PN). However, their epidemiology and clinical consequences are incompletely described. METHODS: A retrospective cohort study was performed, from 2002 to 2009, of all hospital inpatients who were administered PN, outside the intensive care setting, at a major tertiary hospital in Queensland, Australia. RESULTS: In 780 episodes of PN administration, 120 BSIs occurred, giving an incidence of 10.0/1000 PN-days. The majority of PN-associated BSIs were classified as central line-associated (n = 98, 81.7%). Candida spp. were the most frequent pathogens. Observed BSI management revealed that over 8% of intravascular devices were inappropriately retained, over 30% of empirical antibiotic therapy was inappropriate, and 62% of antifungal therapy was delayed ≥ 48 h. All-cause hospital mortality was over 2-fold greater in patients with a PN-associated BSI compared to those without (17.9% vs 8.3%, crude odds ratio (OR) 2.4, 95% confidence interval (CI) 1.29-4.35, p = 0.002). BSI was identified as an independent risk factor for mortality (adjusted OR 3.54, 95% CI 1.76-7.12, p < 0.001). Low baseline albumin levels and a requirement for intravenous insulin infusion (a marker of sustained hyperglycaemia) were independent risk factors for the development of PN-associated BSIs. CONCLUSIONS: PN-associated BSI in hospital inpatients is common and is associated with mortality. The implementation of standardized evidence-based infection prevention strategies, particularly targeting IVD maintenance, is a priority. PN-associated BSI management pathways require optimization, with timely IVD removal and appropriate antimicrobial therapy. Depending on local epidemiology patterns, empirical antifungal therapy should be considered.


Assuntos
Bacteriemia/epidemiologia , Candidemia/epidemiologia , Infecções Relacionadas a Cateter/epidemiologia , Infecção Hospitalar/epidemiologia , Nutrição Parenteral/estatística & dados numéricos , Adulto , Idoso , Austrália/epidemiologia , Bacteriemia/mortalidade , Candidemia/mortalidade , Infecções Relacionadas a Cateter/mortalidade , Infecção Hospitalar/mortalidade , Feminino , Hospitais de Ensino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Nutrição Parenteral/efeitos adversos , Estudos Retrospectivos
5.
Clin Transl Sci ; 17(6): e13831, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38808564

RESUMO

The systemic exposure at the no-observed-adverse-effect-level (NOAEL) estimated from animals is an important criterion commonly applied to guard the safety of participants in clinical trials of investigational drugs. However, the discrepancy in toxicity profile between species is widely recognized. The objective of the work reported here was to assess, via simulation, the level of uncertainty in the NOAEL estimated from an animal species and the effectiveness of applying its associated exposure value to minimizing the toxicity risk to human. Simulations were conducted for dose escalation of an investigational new chemical entity with hypothetical exposure-response models for the dose-limiting toxicity under a variety of conditions, in terms of between-species relative sensitivity to the toxicity and the between-subject variability in the key parameters determining the sensitivity and pharmacokinetics. Results show a high uncertainty in the NOAEL estimation. Notably, even when the animal species and humans are assumed to have the same sensitivity, which may not be realistic, limiting clinical dose to the exposure at the NOAEL that has been identified in the animals carries a high risk of either causing toxicity or under-dosing, hence undermining the therapeutic potential of the drug candidate. These findings highlight the importance of understanding the mechanism of the toxicity profile and its cross-species translatability, as well as the importance of understanding the dose requirement for achieving adequate pharmacology.


Assuntos
Relação Dose-Resposta a Droga , Nível de Efeito Adverso não Observado , Humanos , Animais , Incerteza , Simulação por Computador , Especificidade da Espécie , Medição de Risco , Drogas em Investigação/administração & dosagem , Drogas em Investigação/farmacocinética , Drogas em Investigação/efeitos adversos , Pesquisa Translacional Biomédica
6.
J Clin Pharmacol ; 64(6): 685-696, 2024 06.
Artigo em Inglês | MEDLINE | ID: mdl-38337106

RESUMO

Pralsetinib is a highly potent oral kinase inhibitor of oncogenic RET (rearranged during transfection) fusions and mutations. Pralsetinib received approval from the United States Food and Drug Administration for the treatment of patients with metastatic RET fusion-positive non-small cell lung cancer (NSCLC), and received accelerated approval for the treatment of patients with RET fusion-positive thyroid cancer. Exposure-response (ER) analyses of efficacy were performed separately in patients with thyroid cancer and in patients with NSCLC, but data for all patients were pooled for the safety analysis. ER models were developed with time-varying exposure; the effect of covariates was also examined. For patients with NSCLC, a higher starting dose was associated with improved progression-free survival (PFS), but this improvement did not correlate with a higher exposure overall. Significant covariates included sex and baseline Eastern Cooperative Oncology Group (ECOG) score. For patients with thyroid cancer, a higher exposure was associated with improved PFS. Significant covariates included prior systemic cancer therapy and ECOG score. For safety, higher exposure was associated with a greater risk of grade ≥3 anemia, pneumonia, and lymphopenia. Patients with an ECOG score of ≥1 had an increased risk of grade ≥3 pneumonia. Non-White patients had a lower risk of grade ≥3 lymphopenia. ER analysis revealed that higher pralsetinib exposure was associated with improved PFS in thyroid cancer, but not in NSCLC. However, a higher starting dose (ie, 400 vs ≤300 mg daily) was correlated with better PFS for all indications. Higher exposure was also associated with an increased risk of grade ≥3 adverse events (AEs); however, the overall incidence of these events was acceptably low (≤20%). This analysis supports the use of a 400 mg starting dose of pralsetinib, allowing for dose reduction in the event of AEs.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Proteínas Proto-Oncogênicas c-ret , Neoplasias da Glândula Tireoide , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Proteínas Proto-Oncogênicas c-ret/genética , Proteínas Proto-Oncogênicas c-ret/antagonistas & inibidores , Feminino , Masculino , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/genética , Pessoa de Meia-Idade , Idoso , Adulto , Relação Dose-Resposta a Droga , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinonas/uso terapêutico , Pirimidinonas/administração & dosagem , Pirimidinonas/efeitos adversos , Antineoplásicos/uso terapêutico , Antineoplásicos/efeitos adversos , Antineoplásicos/administração & dosagem , Intervalo Livre de Progressão , Idoso de 80 Anos ou mais , Pirazóis , Piridinas , Pirimidinas
7.
J Antimicrob Chemother ; 68(2): 457-60, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23027714

RESUMO

OBJECTIVES: The objective of this study was to determine the association between ertapenem and antipseudomonal carbapenem use and carbapenem resistance in Pseudomonas aeruginosa in 12 hospitals in Queensland, Australia. METHODS: Data on usage of ertapenem and other antipseudomonal carbapenems, measured in defined daily doses per 1000 occupied bed-days, were collated using statewide pharmacy dispensing and distribution software from January 2007 until June 2011. The prevalence of unique carbapenem-resistant P. aeruginosa isolates derived from statewide laboratory information systems was collected for the same time period. Mixed-effects models were used to determine any relationship between ertapenem and antipseudomonal carbapenem usage and carbapenem resistance among P. aeruginosa isolates in the 12 hospitals analysed. RESULTS: No relationship between ertapenem usage and P. aeruginosa carbapenem resistance was observed. The introduction of ertapenem did not replace antipseudomonal carbapenem prescribing to any significant extent. However, an association between greater usage of antipseudomonal carbapenems and greater P. aeruginosa carbapenem resistance was demonstrated. CONCLUSIONS: It is likely that the only mechanism by which ertapenem can improve P. aeruginosa resistance patterns is by being used as a substitute for, rather than in addition to, antipseudomonal carbapenems.


Assuntos
Antibacterianos/uso terapêutico , Carbapenêmicos/uso terapêutico , Pseudomonas aeruginosa/efeitos dos fármacos , Resistência beta-Lactâmica , beta-Lactamas/uso terapêutico , Uso de Medicamentos/estatística & dados numéricos , Ertapenem , Hospitais , Humanos , Pseudomonas aeruginosa/isolamento & purificação , Queensland
8.
AJR Am J Roentgenol ; 201(3): 483-95, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23971440

RESUMO

OBJECTIVE: This imaging-based article systematically reviews traumatic knee dislocations. After completion, the reader should be familiar with the definition, epidemiology, cause, and classification schemes associated with these injuries, as well as the importance of timely diagnostic imaging and an accurate, detailed description of findings, particularly as it relates to MRI interpretation. Finally, information our orthopedic surgical colleagues consider critical for the preoperative planning and reconstruction of the multiple ligament knee injury will be discussed. CONCLUSION: Although uncommon, traumatic knee dislocations are an important potentially limb-threatening injury, which if not emergently recognized and appropriately managed, can result in significant patient morbidity, joint dysfunction, chronic pain, and long-term disability. A radiologist familiar with the imaging appearance and potential neurovascular complications associated with these injuries can play an integral role in the multidisciplinary team that manages this increasingly recognized clinical entity.


Assuntos
Diagnóstico por Imagem , Luxação do Joelho/diagnóstico , Humanos , Imageamento Tridimensional , Luxação do Joelho/classificação , Luxação do Joelho/epidemiologia , Luxação do Joelho/etiologia
9.
Malar J ; 11: 214, 2012 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-22727113

RESUMO

BACKGROUND: Relapsing Plasmodium vivax infection results in significant morbidity for the individual and is a key factor in transmission. Primaquine remains the only licensed drug for prevention of relapse. To minimize relapse rates, treatment guidelines have recently been revised to recommend an increased primaquine dose, aiming to achieve a cumulative dose of ≥6 mg/kg, i.e. ≥420 mg in a 70 kg patient. The aims of this study were to characterize the epidemiology of P. vivax infection imported into Queensland Australia, to determine the rates of relapse, to investigate the use of primaquine therapy, and its efficacy in the prevention of relapse. METHODS: A retrospective study was undertaken of laboratory confirmed P. vivax infection presenting to the two major tertiary hospitals in Queensland, Australia between January 1999 and January 2011.Primaquine dosing was classified as no dose, low dose (<420 mg), high dose (≥420 mg), or unknown. The dose of primaquine prescribed to patients who subsequently relapsed that prescribed to patients who did not relapse. RESULTS: Twenty relapses occurred following 151 primary episodes of P. vivax infection (13.2%). Relapses were confirmed among 3/21 (14.2%), 9/50 (18.0%), 1/54 (1.9%) and 7/18 (38.9%) of patients administered no dose, low dose, high dose and unknown primaquine dose respectively. High dose primaquine therapy was associated with a significantly lower rate of relapse compared to patients who were prescribed low dose therapy (OR 11.6, 95% CI 1.5-519, p = 0.005). CONCLUSIONS: Relapse of P. vivax infection is more likely in patients who received low dose primaquine therapy. This study supports the recommendations that high dose primaquine therapy is necessary to minimize relapse of P. vivax malaria.


Assuntos
Antimaláricos/administração & dosagem , Malária Vivax/tratamento farmacológico , Malária Vivax/epidemiologia , Primaquina/administração & dosagem , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Plasmodium vivax/isolamento & purificação , Queensland/epidemiologia , Estudos Retrospectivos , Prevenção Secundária , Adulto Jovem
10.
Br J Clin Pharmacol ; 72(2): 338-49, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21426371

RESUMO

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Prescribing errors are common and are caused by multiple factors. Standard medication charts have been recommended by British and Australian Health services. A study of a standard medication chart in five hospitals in one state of Australia significantly reduced prescribing errors. WHAT THIS STUDY ADDS: A standard medication chart developed in one area can be adopted through a collaborative process and successfully implemented across a diverse country resulting in similar reductions in prescribing errors. Three of the four stages of the prescribing process (information gathering, decision making and communication of instructions) can be improved by the use of an improved standard medication chart. The introduction of a standard medication chart has enabled development of standard prescribing education programmes. AIMS: To establish whether a standard national inpatient medication chart (NIMC) could be implemented across a range of sites in Australia and reduce frequency of prescribing errors and improve the completion of adverse drug reaction (ADR) and warfarin documentation. METHODS: A medication chart, which had previously been implemented in one state, was piloted in 22 public hospitals across Australia. Prospective before and after observational audits of prescribing errors were undertaken by trained nurse and pharmacist teams. The introduction of the chart was accompanied by local education of prescribers and presentation of baseline audit findings. RESULTS After the introduction of the NIMC, prescribing errors decreased by almost one-third, from 6383 errors in 15,557 orders, a median (range) of 3 (0-48) per patient to 4293 in 15,416 orders, 2 (0-45) per patient (Wilcoxon Rank Sum test, P < 0.001). The documentation of drugs causing previous ADRs increased significantly from 81.9% to 88.9% of drugs (χ(2) test, P < 0.001). The documentation of the indication for warfarin increased from 12.1 to 34.3% (χ(2) test, P= 0.001) and the documentation of target INR increased from 10.8 to 70.0% (χ(2) test, P < 0.001) after implementation of the chart. CONCLUSIONS: National implementation of a standard medication chart is possible. Similar reduction in the rate of prescribing errors can be achieved in multiple sites across one country. The consequent benefits for patient care and training of staff could be significant.


Assuntos
Controle de Formulários e Registros/normas , Erros de Medicação/prevenção & controle , Sistemas de Medicação no Hospital/normas , Programas Nacionais de Saúde , Serviço de Farmácia Hospitalar/normas , Austrália , Prescrições de Medicamentos/normas , Hospitais de Ensino/normas , Humanos , Projetos Piloto
11.
AAPS J ; 23(4): 82, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34100149

RESUMO

The single-tablet regimen darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg has undergone phase III studies AMBER (NCT02431247) and EMERALD (NCT02269917) in HIV-infected patients. An existing population pharmacokinetic (PopPK) model for cobicistat-boosted darunavir (DRV) was updated to describe DRV PK in AMBER and EMERALD. For TAF, a PopPK model was developed using richly sampled phase I/II data and updated with sparsely sampled AMBER data. Individual exposure metrics for DRV and TAF in patients receiving D/C/F/TAF were derived (AMBER, n=356; EMERALD, n=750). The DRV PopPK model is a two-compartment model with sequential zero-order, first-order input. TAF PK is described by a one-compartment model with dual parallel input for absorption (slow and fast pathway). DRV covariates were α1-acid-glycoprotein and body weight. TAF covariates were lean body weight and α1-acid-glycoprotein. DRV and TAF PK were unaffected by age, race, or gender. Estimated DRV mean (SD) C0h and AUC24h, respectively, were 1899 (759) ng/mL and 87,909 (20,232) ng*h/mL in AMBER; 1813 (859) ng/mL and 85,972 (22,413) ng*h/mL in EMERALD. Estimated TAF mean (SD) AUC24h was 132 (41) ng*h/mL. These PK parameters were in line with historical data. No apparent relationships of DRV or TAF exposure with efficacy (virologic response) or safety (metabolic, cardiac, liver, gastrointestinal, skin, bone, renal, pancreas, lipid events) parameters were seen. Additionally, our findings demonstrate that in patients with low plasma concentrations, there is no risk of decreased virologic response or virologic rebound. This supports the use of a once-daily, single-tablet regimen of D/C/F/TAF 800/150/200/10 mg for the treatment of HIV-1-infected subjects.


Assuntos
Alanina/farmacocinética , Fármacos Anti-HIV/farmacocinética , Cobicistat/farmacocinética , Darunavir/farmacocinética , Emtricitabina/farmacocinética , Infecções por HIV/tratamento farmacológico , Tenofovir/análogos & derivados , Adulto , Idoso , Alanina/administração & dosagem , Alanina/efeitos adversos , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Variação Biológica da População , Cobicistat/administração & dosagem , Cobicistat/efeitos adversos , Darunavir/administração & dosagem , Darunavir/efeitos adversos , Combinação de Medicamentos , Emtricitabina/administração & dosagem , Emtricitabina/efeitos adversos , Feminino , Infecções por HIV/sangue , Infecções por HIV/diagnóstico , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/isolamento & purificação , Humanos , Masculino , Pessoa de Meia-Idade , Comprimidos , Tenofovir/administração & dosagem , Tenofovir/efeitos adversos , Tenofovir/farmacocinética , Resultado do Tratamento , Carga Viral/efeitos dos fármacos , Adulto Jovem
13.
AAPS J ; 18(5): 1244-1253, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27306545

RESUMO

Model Based Personalised Dosing (MBPD) requires a population pharmacokinetic (PK) or pharmacodynamic model to determine the optimal dose of medication for an individual. Often several models are published, and the decision of which model is implemented in MBPD may have a large impact on its clinical utility. As quoted by Box, "all models are wrong, the practical question is how wrong can they be and still be useful". Voriconzole, a triazole antifungal and the example used in this manuscript, currently has nine population PK models published. To assess the impact of model-misspecification on MBPD, five structurally mis-specified models for voriconazole were developed. Intensive plasma concentrations were simulated for 100 virtual subjects. The dose adjustments required to reach a target exposure were determined by using the empirical Bayes estimates of the PK parameters under each of the mis-specified models. The predicted plasma concentrations and the probability of clinical outcomes, upon following the dose recommendations, were determined. Models that did not contain non-linear clearance performed poorly, with a median dose recommendation 155-310 mg higher than appropriate doses, when only one plasma concentration was available. Removal of body weight and CYP2C9 genotype as covariates had no clinically significant impact on outcomes. In summary, the removal of important structural components, such as non-linear clearance in the case of voriconazole, had a large impact on the clinical utility of MBPD. The removal of patient covariates, even highly influential covariates such as CYP2C9 genotype for voriconazole, had no clinical impact.


Assuntos
Antifúngicos/sangue , Citocromo P-450 CYP2C9/metabolismo , Modelos Biológicos , Medicina de Precisão/métodos , Voriconazol/sangue , Adolescente , Adulto , Antifúngicos/administração & dosagem , Criança , Citocromo P-450 CYP2C9/genética , Formas de Dosagem , Relação Dose-Resposta a Droga , Humanos , Voriconazol/administração & dosagem
14.
J Rheumatol ; 43(1): 232-8, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26077400

RESUMO

OBJECTIVE: To develop and validate a knowledge transfer (KT) module aimed at enhancing feasibility and reliability of semiquantitative assessment of bone marrow lesions (BML) and synovitis-effusion using the Hip Inflammation Magnetic Resonance Imaging Scoring System (HIMRISS). METHODS: Three radiologists naive to the HIMRISS method reviewed the manuscript describing the method and then scored MRI scans from 16 patients with hip OA obtained at baseline and 8 weeks after intraarticular injection of corticosteroid. Readers then reviewed a KT module comprising an instructional presentation and 8 reference DICOM (digital imaging and communications in medicine) cases scored by 3 readers with expertise in the HIMRISS method, and then used electronic overlay software to score scans from 23 patients with OA. The same format was followed with a second group of 3 readers naive to HIMRISS using a KT module revised to incorporate the overlay with a Web-based DICOM viewer to enhance feasibility. Interobserver reliability was assessed with the intraclass correlation coefficient (ICC). RESULTS: In both exercises, reliability for baseline scores was excellent for femoral BML, very good for acetabular BML, and good for synovitis-effusion (overall ICC = 0.91, 0.89, 0.62, respectively) even without prior calibration using the KT module. However, reliability for detecting change was substantially worse than for expert readers, especially for acetabular BML and synovitis-effusion (overall ICC = 0.59 vs 0.19, and 0.42 vs 0.25, respectively). Reliability improved for detection of change in these lesions, especially after reader calibration with the revised KT module. CONCLUSION: Development and validation of a systematic method for KT may enhance external validation of certain imaging instruments.


Assuntos
Interpretação de Imagem Assistida por Computador , Imageamento por Ressonância Magnética/métodos , Osteoartrite do Quadril/patologia , Índice de Gravidade de Doença , Idoso , Educação Médica/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade
15.
J Infect ; 70(6): 585-91, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25583208

RESUMO

OBJECTIVES: Urinary catheter associated bloodstream infection (UCABSI) causes significant morbidity, mortality and healthcare costs. We aimed to define the risk factors for UCABSI. METHODS: A case-control study was conducted at two Australian tertiary hospitals. Patients with urinary source bloodstream infection associated with an indwelling urinary catheter (IDC) were compared to controls with an IDC who did not develop urinary source bloodstream infection. RESULTS: There were 491 controls and 67 cases included in the analysis. Independent statistically significant risk factors for the development of UCABSI included insertion of the catheter in operating theatre, chronic kidney disease, age-adjusted Charlson comorbidity index, accurate urinary measurements as reason for IDC insertion and dementia. IDCs were inserted for valid reasons in nearly all patients, however an appropriate indication at 48 h post-insertion was found in only 44% of patients. Initial empiric antibiotics were deemed inappropriate in 23 patients (34%). CONCLUSION: To our knowledge, this is the first study to look specifically at the risk factors for bloodstream infection in urinary catheterised patients. Several risk factors were identified. IDC management and empiric management of UCABSI could be improved and is likely to result in a decreased incidence of infection and its complications.


Assuntos
Infecções Relacionadas a Cateter/epidemiologia , Cateterismo Urinário/efeitos adversos , Cateteres Urinários/efeitos adversos , Infecções Urinárias/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/uso terapêutico , Austrália/epidemiologia , Bacteriemia , Estudos de Casos e Controles , Infecções Relacionadas a Cateter/tratamento farmacológico , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Infecções Urinárias/tratamento farmacológico
16.
Clin Neurol Neurosurg ; 112(6): 467-9, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20227821

RESUMO

OBJECTIVE: Risk factors for adverse events in intravenous immunoglobulin (IVIG) therapy are uncertain. We sought to determine the associations of IVIG-related adverse events in patients with neuromuscular disorders. PATIENTS AND METHODS: We determined the prevalence of adverse events with the use of different forms of IVIG in a tertiary care patient population with neuromuscular diseases. A retrospective assessment for over two decades of patient care was performed. RESULTS: Adverse events occurred in 43% of patients over time and during 10% of infusions. Prevalence of adverse events, especially headache, was higher for lyophilized forms of IVIG, and increased with cumulative IVIG delivery. Fortunately, serious adverse events were rare for all IVIG preparations. Discontinuation of IVIG therapy occurred most commonly due to perceived inefficacy or adverse events with lyophilized forms of IVIG. CONCLUSION: IVIG is generally well tolerated and only rarely associated with serious adverse events, but lyophilized forms of IVIG may be associated with greater prevalence of adverse events in patients with neuromuscular diseases.


Assuntos
Imunização Passiva/efeitos adversos , Imunoglobulinas Intravenosas/efeitos adversos , Doenças Neuromusculares/complicações , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Autoimunes/terapia , Química Farmacêutica , Feminino , Liofilização , Síndrome de Guillain-Barré/complicações , Síndrome de Guillain-Barré/terapia , Humanos , Imunoglobulina A/análise , Imunoglobulinas Intravenosas/administração & dosagem , Imunoglobulinas Intravenosas/química , Modelos Lineares , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Miastenia Gravis/complicações , Miastenia Gravis/terapia , Doenças Neuromusculares/terapia , Estudos Retrospectivos , Fatores de Risco , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA