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1.
Bone Joint J ; 103-B(9): 1514-1525, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34465156

RESUMO

AIMS: The aims of this study were to investigate the ability to kneel after total knee arthroplasty (TKA) without patellar resurfacing, and its effect on patient-reported outcome measures (PROMs). Secondary aims included identifying which kneeling positions were most important to patients, and the influence of radiological parameters on the ability to kneel before and after TKA. METHODS: This prospective longitudinal study involved 209 patients who underwent single radius cruciate-retaining TKA without patellar resurfacing. Preoperative EuroQol five-dimension questionnaire (EQ-5D), Oxford Knee Score (OKS), and the ability to achieve four kneeling positions were assessed including a single leg kneel, a double leg kneel, a high-flexion kneel, and a praying position. The severity of radiological osteoarthritis (OA) was graded and the pattern of OA was recorded intraoperatively. The flexion of the femoral component, posterior condylar offset, and anterior femoral offset were measured radiologically. At two to four years postoperatively, 151 patients with a mean age of 70.0 years (SD 9.44) were included. Their mean BMI was 30.4 kg/m2 (SD 5.36) and 60 were male (40%). They completed EQ-5D, OKS, and Kujala scores, assessments of the ability to kneel, and a visual analogue scale for anterior knee pain and satisfaction. RESULTS: The ability to kneel in the four positions improved in between 29 (19%) and 53 patients (35%) after TKA, but declined in between 35 (23%) and 46 patients (30%). Single-leg kneeling was most important to patients. After TKA, 62 patients (41%) were unable to achieve a single-leg kneel, 76 (50%) were unable to achieve a double-leg kneel, 102 (68%) were unable to achieve a high-flexion kneel and 61 (40%) were unable to achieve a praying position. Posterolateral cartilage loss significantly affected preoperative deep flexion kneeling (p = 0.019). A postoperative inability to kneel was significantly associated with worse OKS, Kujala scores, and satisfaction (p < 0.05). Multivariable regression analysis identified significant independent associations with the ability to kneel after TKA (p < 0.05): better preoperative EQ-5D and flexion of the femoral component for single-leg kneeling; the ability to achieve it preoperatively and flexion of the femoral component for double-leg kneeling; male sex for high-flexion kneeling; and the ability to achieve it preoperatively, anterior femoral offset, and patellar cartilage loss for the praying position. CONCLUSION: The ability to kneel was important to patients and significantly influenced knee-specific PROMs, but was poorly restored by TKA with equal chances of improvement or decline. Cite this article: Bone Joint J 2021;103-B(9):1514-1525.


Assuntos
Artroplastia do Joelho , Articulação do Joelho/fisiopatologia , Articulação do Joelho/cirurgia , Idoso , Fenômenos Biomecânicos , Feminino , Humanos , Articulação do Joelho/diagnóstico por imagem , Estudos Longitudinais , Masculino , Osteoartrite do Joelho/diagnóstico por imagem , Osteoartrite do Joelho/cirurgia , Medição da Dor , Dor Pós-Operatória/diagnóstico , Articulação Patelofemoral/diagnóstico por imagem , Articulação Patelofemoral/fisiopatologia , Articulação Patelofemoral/cirurgia , Medidas de Resultados Relatados pelo Paciente , Estudos Prospectivos , Amplitude de Movimento Articular/fisiologia , Inquéritos e Questionários
2.
Knee ; 31: 54-63, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34116435

RESUMO

BACKGROUND: The aim of this study was to determine if radiographic severity, extent or pattern of knee osteoarthritis was associated with pain and function before total knee arthroplasty (TKA) or improvement therein one year after TKA. METHODS: A prospective study of 259 patients undergoing unilateral TKA for Kellgren-Lawrence (KL) grade ≥ 3 knee osteoarthritis was conducted: mean age 69.8 ± 9.7 (44-91); mean BMI 31.0 ± 5.8 (17-52); 152/259 (58.7%) female. Preoperative radiographs were assessed using the KL and Ahlback systems. Preoperatively and 1 year postoperatively patients completed Oxford Knee Scores, VAS-Pain and EQ-5D scores. Full thickness cartilage loss was recorded intraoperatively. RESULTS: Median radiographic severity was Ahlback 2, KL 4: 51/259 (19.7%) hypertrophic; 23/259 (8.8%) atrophic. Neither Ahlback nor Kellgren-Lawrence OA grade was associated with OKS, VAS Pain or EQ-5D prior to TKA (p > 0.05). The extent and pattern of cartilage loss did not affect preoperative PROMs. Radiographic OA severity, compartment involvement, and pattern of cartilage loss were not significantly associated with PROMs or improvements therein following TKA (p > 0.05). Hypertrophic OA was associated with less pain before TKA (difference 6.8, 0.23-13.9 95%CI, p = 0.044), and worse improvement in OKS following TKA (difference -3.41, -6.8 to -0.05 95%CI, p = 0.047). Better preoperative OKS and hypertrophic OA were independently associated with poorer improvement in OKS 1 year following TKA (R2 = 0.208). CONCLUSION: Provided at least one compartment has KL grade ≥ 3 changes, further radiographic severity, pattern or extent of cartilage loss did not affect PROMs before or after TKA: multicompartmental was no worse than unicompartmental disease.


Assuntos
Artroplastia do Joelho , Osteoartrite do Joelho , Idoso , Cartilagem , Feminino , Humanos , Articulação do Joelho/diagnóstico por imagem , Articulação do Joelho/cirurgia , Osteoartrite do Joelho/diagnóstico por imagem , Osteoartrite do Joelho/cirurgia , Medidas de Resultados Relatados pelo Paciente , Estudos Prospectivos , Índice de Gravidade de Doença
3.
Knee ; 28: 194-201, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33418395

RESUMO

BACKGROUND: The aim of this study was to compare the outcomes and cost economics of TKA without patella resurfacing in patients with and without patellar cartilage loss. METHODS: Prospective case control study of 209 consecutive patients undergoing TKA without patella resurfacing. Patella cartilage status was documented intra-operatively: 108 patients had patella cartilage loss (mean age 70 ± 9.7, mean BMI 31 ± 6.2, 72 (67%) female) and 101 control patients did not (age 68 ± 9.2, BMI 31 ± 5.6, 52 (51%) female). The primary outcome measure was Oxford Knee Score (OKS) improvement at one year. Secondary outcomes included OKS, EQ-5D, anterior knee pain (AKP), Kujala scores and reoperation at 2-4 years. The cost to prevent secondary patella resurfacing was calculated. RESULTS: There were more women in the patella cartilage loss group (67% Vs 51%, p = 0.037), but no other preoperative characteristics differed. There was no difference in OKS improvement between those with and without patella cartilage loss at 1 year (mean difference -1.03, -3.68 to 1.62 95%CI, p = 0.446) or 2-4 years (mean difference 1.52, -1.43 to 4.45 95%CI, p = 0.310). At 2-4 years there was no difference in AKP (14/87 with vs 17/80 without, p = 0.430) nor Kujala score (mean difference 2.66, -3.82 to 9.13 95%CI, p = 0.418). Routine patella resurfacing would have cost £58,311 to prevent one secondary resurfacing. CONCLUSION: There was no difference in OKS, anterior knee pain, reoperation or Kujala scores up to 2-4 years between patients with and without patellar cartilage loss following TKA without patella resurfacing. Resurfacing for this indication would not have been a cost effective intervention.


Assuntos
Artroplastia do Joelho , Cartilagem Articular/fisiopatologia , Articulação do Joelho/fisiopatologia , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Medidas de Resultados Relatados pelo Paciente , Estudos Prospectivos , Reoperação
4.
J Knee Surg ; 34(5): 526-532, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31569257

RESUMO

Prosthetic joint infections provide a complex challenge for management, owing to their often difficult diagnoses, need for multiple surgeries, and increased technical and financial requirements. The '2 in 1' single-stage approaches have been recently advocated in the field of arthroplasty on account of their reduction in risks, costs, and complications. The aim of our study was to investigate the outcomes of this variant of single-stage revision, which is used in the setting of infection following primary total knee replacement (TKR) and associated bone loss. Prospective data were collected from all patients presenting with an infection following primary TKR over an 8-year period (2009-2017). We examined revision procedures that were undertaken as a single-stage procedure and had bone loss present. Patients were followed-up for evidence of recurrent infection. Functional assessments were conducted using range of motion, Oxford Knee Score (OKS), American Knee Society Score (AKSS), and Short Form-12 (SF-12) survey. Twenty-six patients were included in the analysis, two of whom had previously failed 2 stage revision; another three among them had failed debridement, antibiotics, irrigation, and implant retention procedures. The mean age was 72.5 years, mean body mass index was 33.4, and median American Society of Anesthesiologists (ASA) physical status classification was 2. The mean time to revision was 3.5 years (3 months to 12 years). Six patients had actively been discharging sinuses at the time of surgery. Only 4/26 patients possessed no positive microbiological cultures from deep tissue samples or joint aspirates. One patient was afflicted with a recurrence of infection. This patient did not require further surgery and was successfully treated with the help of long-term antibiotic suppression. There were statistically significant improvements in both the pain component of AKSS scores (preoperative 4.3 to postoperative 32.4) and the functional component of AKSS scores (preoperative 10.7 to postoperative 15.7). There was no significant improvement in flexion; however, mean extension (increased from 18.5 to 6.9 postoperative) and total range of motion (increased from 69.2 preoperative to 90.3 postoperative) both showed statistically significant improvements. The use of "2-in-1" single-stage revision can be considered as an effective option for treating infection following TKR and associated bone loss.


Assuntos
Artrite Infecciosa/cirurgia , Artroplastia do Joelho , Reabsorção Óssea/cirurgia , Infecções Relacionadas à Prótese/cirurgia , Reoperação/métodos , Idoso , Antibacterianos/uso terapêutico , Artrite Infecciosa/etiologia , Artroplastia do Joelho/efeitos adversos , Artroplastia do Joelho/métodos , Reabsorção Óssea/etiologia , Desbridamento , Remoção de Dispositivo , Feminino , Seguimentos , Humanos , Articulação do Joelho/cirurgia , Prótese do Joelho , Masculino , Período Pós-Operatório , Infecções Relacionadas à Prótese/etiologia , Amplitude de Movimento Articular , Resultado do Tratamento
5.
Bone Jt Open ; 1(6): 182-189, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33225287

RESUMO

Aims: This study aims to define the epidemiology of trauma presenting to a single centre providing all orthopaedic trauma care for a population of ∼ 900,000 over the first 40 days of the COVID-19 pandemic compared to that presenting over the same period one year earlier. The secondary aim was to compare this with population mobility data obtained from Google. Methods: A cross-sectional study of consecutive adult (> 13 years) patients with musculoskeletal trauma referred as either in-patients or out-patients over a 40-day period beginning on 5 March 2020, the date of the first reported UK COVID-19 death, was performed. This time period encompassed social distancing measures. This group was compared to a group of patients referred over the same calendar period in 2019 and to publicly available mobility data from Google. Results: Orthopaedic trauma referrals reduced by 42% (1,056 compared to 1,820) during the study period, and by 58% (405 compared to 967) following national lockdown. Outpatient referrals reduced by 44%, and inpatient referrals by 36%, and the number of surgeries performed by 36%. The regional incidence of traumatic injury fell from 5.07 (95% confidence interval (CI) 4.79 to 5.35) to 2.94 (95% CI 2.52 to 3.32) per 100,000 population per day. Significant reductions were seen in injuries related to sports and alcohol consumption. No admissions occurred relating to major trauma (Injury Severity Score > 16) or violence against the person. Changes in population mobility and trauma volume from baseline correlated significantly (Pearson's correlation 0.749, 95% CI 0.58 to 0.85, p < 0.001). However, admissions related to fragility fractures remained unchanged compared to the 2019 baseline. Conclusion: The profound changes in social behaviour and mobility during the early stages of the COVID-19 pandemic have directly correlated with a significant decrease in orthopaedic trauma referrals, but fragility fractures remained unaffected and provision for these patients should be maintained.Cite this article: Bone Joint Open 2020;1-6:182-189.

6.
Bone Joint J ; 102-B(6): 716-726, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32475247

RESUMO

AIMS: This study aims to determine the proportion of patients with end-stage knee osteoarthritis (OA) possibly suitable for partial (PKA) or combined partial knee arthroplasty (CPKA) according to patterns of full-thickness cartilage loss and anterior cruciate ligament (ACL) status. METHODS: A cross-sectional analysis of 300 consecutive patients (mean age 69 years (SD 9.5, 44 to 91), mean body mass index (BMI) 30.6 (SD 5.5, 20 to 53), 178 female (59.3%)) undergoing total knee arthroplasty (TKA) for Kellgren-Lawrence grade ≥ 3 knee OA was conducted. The point of maximal tibial bone loss on preoperative lateral radiographs was determined as a percentage of the tibial diameter. At surgery, Lachman's test and ACL status were recorded. The presence of full-thickness cartilage loss within 16 articular surface regions (two patella, eight femoral, six tibial) was recorded. RESULTS: According to articular cartilage loss and ACL status, 195/293 (67%) were suitable for PKA or CPKA: medial unicompartmental knee arthroplasty (UKA) 97/293 (33%); lateral UKA 25 (9%); medial bicompartmental arthroplasty 31 (11%); lateral bicompartmental arthroplasty 12 (4%); bicondylar-UKA 23 (8%); and patellofemoral arthroplasty (PFA) seven (2%). The ACL was intact in 166 (55%), frayed in 82 (27%), disrupted in 12 (4%), and absent in 33 (11%). Lachman testing was specific (97%) but poorly sensitive (38%) for disrupted/absent ACLs. The point of maximal tibial bone loss showed good interclass correlation (ICC 0.797, 0.73 to 0.85 95% confidence interval (CI); p < 0.001) and was more posterior when the ACL was absent. Maximum tibial bone loss occurring at > 55% of the anterior to posterior distance predicted ACL absence with 93% sensitivity and 91% specificity (area under the curve 0.97 (0.94 to 0.99 95% CI; p < 0.001). CONCLUSION: ACL status can be reliably determined from a lateral radiograph using the location of maximal tibial bone loss. According to regions of cartilage loss and ACL status, two-thirds of patients with end-stage knee OA could potentially be treated with PKA or CPKA. Cite this article: Bone Joint J 2020;102-B(6):716-726.


Assuntos
Ligamento Cruzado Anterior/patologia , Artroplastia do Joelho , Cartilagem Articular/patologia , Osteoartrite do Joelho/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Ligamento Cruzado Anterior/diagnóstico por imagem , Cartilagem Articular/diagnóstico por imagem , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/complicações , Osteoartrite do Joelho/diagnóstico por imagem , Radiografia , Índice de Gravidade de Doença
7.
Bone Joint J ; 102-B(3): 301-309, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32114823

RESUMO

AIMS: Although knee osteoarthritis (OA) is diagnosed and monitored radiologically, actual full-thickness cartilage loss (FTCL) has rarely been correlated with radiological classification. This study aims to analyze which classification system correlates best with FTCL and to assess their reliability. METHODS: A prospective study of 300 consecutive patients undergoing unilateral total knee arthroplasty (TKA) for OA (mean age 69 years (44 to 91; standard deviation (SD) 9.5), 178 (59%) female). Two blinded examiners independently graded preoperative radiographs using five common systems: Kellgren-Lawrence (KL); International Knee Documentation Committee (IKDC); Fairbank; Brandt; and Ahlbäck. Interobserver agreement was assessed using the intraclass correlation coefficient (ICC). Intraoperatively, anterior cruciate ligament (ACL) status and the presence of FTCL in 16 regions of interest were recorded. Radiological classification and FTCL were correlated using the Spearman correlation coefficient. RESULTS: Knees had a mean of 6.8 regions of FTCL (SD 3.1), most common medially. The commonest patterns of FTCL were medial ± patellofemoral (143/300, 48%) and tricompartmental (89/300, 30%). ACL status was associated with pattern of FTCL (p = 0.023). All radiological classification systems demonstrated moderate ICC, but this was highest for the IKDC: whole knee 0.68 (95% confidence interval (CI) 0.60 to 0.74); medial compartment 0.84 (95% CI 0.80 to 0.87); and lateral compartment 0.79 (95% CI 0.73 to 0.83). Correlation with actual FTCL was strongest for Ahlbäck (Spearman rho 0.27 to 0.39) and KL (0.30 to 0.33) systems, although all systems demonstrated medium correlation. The Ahlbäck score was the most discriminating in severe knee OA. Osteophyte presence in the medial compartment had high positive predictive value (PPV) for FTCL, but not in the lateral compartment. CONCLUSION: The Ahlbäck and KL systems had the highest correlation with confirmed cartilage loss at TKA. However, the IKDC system displayed the best interobserver reliability, with favourable correlation with FTCL in medial and lateral compartments, although it was less discriminating in more severe disease. Cite this article: Bone Joint J 2020;102-B(3):301-309.


Assuntos
Cartilagem Articular/diagnóstico por imagem , Articulação do Joelho/diagnóstico por imagem , Osteoartrite do Joelho/classificação , Radiografia/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Artroplastia do Joelho , Feminino , Seguimentos , Humanos , Articulação do Joelho/cirurgia , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/diagnóstico , Osteoartrite do Joelho/cirurgia , Estudos Prospectivos , Curva ROC , Reprodutibilidade dos Testes , Índice de Gravidade de Doença
8.
AJR Am J Roentgenol ; 199(5): 1149-52, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23096192

RESUMO

OBJECTIVE: The purpose of this study is to compare technical success and complications of percutaneous transhepatic cholangiography (PTC) and percutaneous transhepatic biliary drainage (PTBD) between patients with and without transplanted liver. MATERIALS AND METHODS: Between 2007 and 2011, 89 PTCs, including 34 PTBDs, in 87 patients with transplanted liver were attempted, and 131 PTCs, including 118 PTBDs, in 126 patients without transplanted liver were attempted. Technical success, diameters of the bile ducts, fluoroscopy time, and complications were statistically compared between the two groups. RESULTS: The technical success rate of PTC for transplanted liver was significantly lower than that for nontransplanted liver (88.8% vs 98.5%; p = 0.004). Consequently, the technical success rate of PTBD for transplanted liver was also significantly lower than that for nontransplanted liver (75.0% vs 95.8%; p < 0.001). The average diameters of the first branches and second branches of the bile ducts of transplanted liver were significantly smaller than those of nontransplanted liver (5.8 ± 3.4 mm vs 8.7 ± 3.9 mm for the first branches [p < 0.001]; and 3.7 ± 1.7 mm vs 5.8 ± 2.4 mm for the second branches [p < 0.001]). No significant difference of fluoroscopy time of unilateral successful PTBD was observed (21.8 ± 11.7 vs 19.3 ± 12.9 min; p = 0.372), and no significant difference of overall complication rates was observed (8.0% vs 8.7%; p = 1.000) between transplanted and nontransplanted liver. CONCLUSION: The technical success rates of PTC and PTBD for transplanted liver are slightly lower than those for nontransplanted liver because the bile ducts are smaller. There is no significant difference in complication rate.


Assuntos
Colangiografia/métodos , Drenagem/métodos , Transplante de Fígado , Complicações Pós-Operatórias/diagnóstico por imagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Fluoroscopia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
10.
J Med Chem ; 53(9): 3618-25, 2010 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-20405948

RESUMO

Glucokinase (GK) is a glucose sensor that couples glucose metabolism to insulin release. The important role of GK in maintaining glucose homeostasis is illustrated in patients with GK mutations. In this publication, identification of the hit molecule 1 and its SAR development, which led to the discovery of potent allosteric GK activators 9a and 21a, is described. Compound 21a (RO0281675) was used to validate the clinical relevance of targeting GK to treat type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucoquinase/efeitos dos fármacos , Hipoglicemiantes/química , Sulfonas/farmacologia , Tiazóis/farmacologia , Animais , Glicemia , Linhagem Celular , Citotoxinas , Relação Dose-Resposta a Droga , Descoberta de Drogas , Humanos , Insulina , Masculino , Camundongos , Farmacocinética , Relação Estrutura-Atividade , Sulfonas/química , Sulfonas/toxicidade , Tiazóis/química , Tiazóis/toxicidade
11.
J Chem Inf Model ; 47(4): 1395-404, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17569522

RESUMO

In this work, two reliable aqueous solubility models, ASMS (aqueous solubility based on molecular surface) and ASMS-LOGP (aqueous solubility based on molecular surface using ClogP as a descriptor), were constructed by using atom type classified solvent accessible surface areas and several molecular descriptors for a diverse data set of 1708 molecules. For ASMS (without using ClogP as a descriptor), the leave-one-out q(2) and root-mean-square error (RMSE) were 0.872 and 0.748 log unit, respectively. ASMS-LOGP was slightly better than ASMS (q(2) = 0.886, RMSE = 0.705). Both models were extensively validated by three cross-validation tests and encouraging predictability was achieved. High throughput aqueous solubility prediction was conducted for a number of data sets extracted from several widely used databases. We found that real drugs are about 20-fold more soluble than the so-called druglike molecules in the ZINC database, which have no violation of Lipinski's "Rule of 5" at all. Specifically, oral drugs are about 16-fold more soluble, while injection drugs are 50-60-fold more soluble. If the criterion of a molecule to be soluble is set to -5 log unit, about 85% of real drugs are predicted as soluble; in contrast only 50% of druglike molecules in ZINC are soluble. We concluded that the two models could be served as a rule in druglike analysis and an efficient filter in prioritizing compound libraries prior to high throughput screenings (HTS).


Assuntos
Modelos Moleculares , Preparações Farmacêuticas/química , Desenho de Fármacos , Ligação de Hidrogênio , Reprodutibilidade dos Testes , Solubilidade
12.
Radiology ; 243(3): 885-93, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17446521

RESUMO

PURPOSE: To prospectively assess patient response (after 12 months) to magnetic resonance (MR) imaging-guided focused ultrasound surgery in treatment of uterine leiomyomas by using two treatment protocols. MATERIALS AND METHODS: This prospective clinical trial was approved by institutional review boards and was HIPAA compliant. After giving informed consent, patients with symptomatic leiomyomas were consecutively enrolled and treated at one of five U.S. centers by using an original or a modified protocol. Outcomes were assessed with the symptom severity score (SSS) obtained at baseline and 3, 6, and 12 months after treatment. Adverse events (AEs) were recorded. Statistical analysis included Student t test, Fisher exact test, analysis of covariance, Spearman correlation, and logistic regression. RESULTS: One hundred sixty patients had a mean SSS of 62.1 +/- 16.3 (standard deviation) at baseline, which decreased to 35.5 +/- 19.5 at 3 months (P<.001) and to 32.3 +/- 19.8 at 6 months (P<.001) and was 32.7 +/- 21.0 at 12 months (P<.001). Ninety-six patients (mean age, 46.0 years +/- 4.6) were treated with an original protocol, and 64 (mean age, 45.9 years +/- 3.9) were treated with a modified protocol. Patients in the modified group had a significantly greater SSS decrease at 3 months (P=.037) than those in the original group, and 73% of those in the original group and 91% of those in the modified group reported a significant decrease in SSS (of 10 points or greater) at 12 months. No serious AEs were recorded. Fewer AEs were reported in the modified group than in the original group (25% vs 13% reporting no event). Of evaluable patients, fewer in the modified group chose alternative treatment (28%) than in the original group (37%). CONCLUSION: MR imaging-guided focused ultrasound surgery results in symptomatic improvement, sustained to 12 months after treatment. Treatment with a modified protocol results in greater clinical effectiveness and fewer AEs.


Assuntos
Leiomioma/diagnóstico , Leiomioma/terapia , Imageamento por Ressonância Magnética/métodos , Terapia Assistida por Computador/métodos , Terapia por Ultrassom/métodos , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/terapia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
13.
J Chem Inf Model ; 46(6): 2674-83, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-17125207

RESUMO

In this work, a genetic algorithm (GA) was applied to build up a set of QSPR (quantitative structure-property relationship) models for human absolute oral bioavailability, plasma protein binding, and urinary excretion using the counts of molecular fragments as descriptors. For a pharmacokinetic property, the consensus score of a set of models (20 or 30) was found to improve the correlation coefficient and reduce the standard error significantly. Key fragments that may boost or reduce pharmacokinetic properties were also identified. Databases searches were performed for a set of key fragments identified by bioavailability models. The percentage of hit rates of bioavailability-boosting fragments were significantly higher than those of bioavailability-reducing fragments for MDDR (MDL Drug Data Report), a database of drugs and drug leads entered or entering development. On the other hand, the opposite trend was observed for ACD (Available Chemicals Directory), a database of all kinds of available compounds.


Assuntos
Administração Oral , Disponibilidade Biológica , Química Farmacêutica/métodos , Desenho de Fármacos , Modelos Genéticos , Preparações Farmacêuticas/química , Tecnologia Farmacêutica/métodos , Algoritmos , Transporte Biológico , Humanos , Modelos Químicos , Modelos Teóricos , Estrutura Molecular
14.
J Med Chem ; 47(8): 1969-86, 2004 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-15055997

RESUMO

Sitaxsentan (1) (Wu et al. J. Med. Chem. 1997, 40, 1690) is our first endothelin antagonist being evaluated in clinical trials. It has demonstrated biological effects in an acute hemodynamic study in CHF (Givertz et al. Circulation 2000, 101, 2922), an open-label 20-patient pulmonary hypertension trial (Barst et al. Chest 2002, 121, 1860-1868), and a 31-patient trial in essential hypertension (Calhoun et al. AHA Scientific Sessions 2000). In a phase 2b/3 pulmonary arterial hypertension trial, once a day treatment of 100 mg of sitaxsentan statistically significantly improved 6-min walk distance and NYHA class at 12 weeks (Barst et al. Am. J. Respir. Crit. Care Med. 2004, 169, 441). We have since reported on our efforts in generating follow-up compounds (Wu et al. J. Med. Chem. 1999, 42, 4485) and recently communicated that an ortho acyl group on the anilino ring enhanced oral absorption in this category of compounds (Wu et al. J. Med. Chem. 2001, 44, 1211). Here we report an expansion of this work by substituting a variety of electron-withdrawing groups at the ortho position and evaluating their effects on oral bioavailability as well as structure-activity relationships. As a result, TBC3711 (7z) was identified as our second endothelin antagonist to enter the clinic due to its good oral bioavailability (approximately 100%) in rats, high potency (ET(A) IC(50) = 0.08 nM), and optimal ET(A)/ET(B) selectivity (441 000-fold). Compound 7z has completed phase-I clinical development and was well tolerated with desirable pharmacokinetics in humans (t(1/2) = 6-7 h, oral availability > 80%).


Assuntos
Anti-Hipertensivos/síntese química , Antagonistas do Receptor de Endotelina A , Isoxazóis/síntese química , Sulfonas/síntese química , Administração Oral , Animais , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacocinética , Disponibilidade Biológica , Relação Dose-Resposta a Droga , Método Duplo-Cego , Humanos , Isoxazóis/química , Isoxazóis/farmacologia , Ligantes , Masculino , Modelos Moleculares , Ratos , Ratos Sprague-Dawley , Receptor de Endotelina A/metabolismo , Relação Estrutura-Atividade , Sulfonas/química , Sulfonas/farmacologia
15.
Pulm Pharmacol Ther ; 17(1): 1-10, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-14643165

RESUMO

Airway inflammation is a hallmark of respiratory diseases such as asthma and chronic obstructive pulmonary disease. Cell adhesion molecules play critical roles in the recruitment and migration of cells to sites of inflammation. Not surprisingly, these receptors have garnered the attention of the pharmaceutical industry as targets for the development of drugs to treat inflammatory and autoimmune diseases. Although several potential cell adhesion targets exist, development of compounds for pulmonary indications has centered around the selectins and the integrin VLA-4. In vitro and in vivo studies have implicated these receptors in the recruitment of inflammatory cells to the lung as well as to key cellular activation pathways. Several first generation compounds are currently in clinical development for asthma. Positive data from a phase II clinical trial using an inhaled formulation of a selectin antagonist has recently been reported. Initial results from clinical trials using first generation VLA-4 antagonists have been less promising but additional trials with more fully optimized compounds are underway. Results from these trials will provide insight into what the future holds for this exciting new class of drugs to treat pulmonary diseases.


Assuntos
Asma/tratamento farmacológico , Moléculas de Adesão Celular/antagonistas & inibidores , Fenilalanina/análogos & derivados , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Animais , Compostos de Bifenilo/uso terapêutico , Química Farmacêutica , Ensaios Clínicos como Assunto , Humanos , Integrina alfa4beta1/antagonistas & inibidores , Manose/análogos & derivados , Manosídeos/uso terapêutico , Fenilalanina/uso terapêutico , Selectinas/efeitos dos fármacos
16.
J Magn Reson Imaging ; 18(4): 449-60, 2003 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-14508782

RESUMO

PURPOSE: To determine the diagnostic performance of functional magnetic resonance cholangiography (fMRC) for the evaluation of anatomic and functional biliary disorders. MATERIALS AND METHODS: At 1.5 T, 39 MR examinations with conventional MRC and mangafodipir trisodium-enhanced fMRC were retrospectively reviewed by three observers who recorded anatomic (duct dilation, stricture, filling defects) and functional (cholecystitis, obstruction) abnormalities in three modes: MRC alone, fMRC alone, and MRC and fMRC images together (combined-MRC). Performance was determined by comparing findings with each mode to findings of invasive cholangiography (IC) and surgery. RESULTS: Among 75 biliary segments (correlated with IC), the sensitivity/specificity for diagnosing dilation (N = 41) with MRC was 95%/97%; with fMRC, 90%/100%; with combined-MRC, 100%/97%. For stricture (N = 7), the sensitivity/specificity of MRC was 86%/98%; of fMRC, 43%/100%; of combined-MRC, 86%/100%. For filling defects (N = 9), the sensitivity/specificity of MRC was 91%/98%; of fMRC, 82%/100%; of combined-MRC, 91%/100%. For diagnosing obstruction (N = 9), the sensitivity/specificity of MRC, fMRC, and combined-MRC were 89%/100%, 100%/100%, and 100%/100%, respectively. For surgically proven cholecystitis (N = 13), positive predictive values for diagnosing acute/chronic cholecystitis for MRC were 33%/40%; for fMRC, 100%/50%; for combined-MRC, 100%/50%. CONCLUSION: Although single-shot fast spin echo (SSFSE)-MRC is valuable, the addition of fMRC increased diagnostic performance for functional biliary disorders.


Assuntos
Doenças Biliares/diagnóstico , Sistema Biliar/patologia , Ácido Edético/análogos & derivados , Vesícula Biliar/patologia , Imageamento por Ressonância Magnética/métodos , Fosfato de Piridoxal/análogos & derivados , Colecistite/diagnóstico , Meios de Contraste , Feminino , Humanos , Masculino , Manganês , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Sensibilidade e Especificidade
17.
Radiology ; 228(2): 457-64, 2003 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12893904

RESUMO

PURPOSE: To compare the safety and effectiveness of an undiluted direct injection of ferumoxides with those of a diluted slow infusion of ferumoxides during 30 minutes in patients with known liver lesions or in those suspected of having them. MATERIALS AND METHODS: Two hundred thirty-three patients at 16 institutions were randomized to receive either an undiluted direct injection of 0.56 mg of iron per kilogram of body weight of ferumoxides administered during 2 minutes (2 mL/min) or a diluted slow infusion administered during 30 minutes. Safety was assessed with monitoring for adverse events and laboratory tests. For sensitivity, specificity, and accuracy analysis, two independent blinded observers identified and classified lesions as benign or malignant with precontrast images and with pre- and postcontrast images combined. RESULTS: There was no statistically significant difference in adverse events in the group with direct injection compared with those in the group with infusion (21 [18%] of 114 patients vs 19 [17%] of 112 patients, respectively). No serious adverse events were observed. The most common adverse events in the group with direct injection versus the group with infusion were headache (five [4%] of 114 vs three [3%] of 112, respectively) and back pain (five [4%] of 114 vs three [3%] of 112, respectively). Overall, in 68 (62%) of 109 patients with direct injection and 71 (66%) of 108 patients with infusion, additional magnetic resonance (MR) imaging information was obtained after ferumoxides administration (P =.67). Sensitivity, specificity, and accuracy for the diagnosis of malignancy were significantly improved by adding images obtained after ferumoxides administration to the images obtained before contrast agent administration (P <.05 for all comparisons). CONCLUSION: Direct injection of ferumoxides has safety and effectiveness profiles similar to those of slow infusion of the agent. Further findings indicate that the addition of ferumoxides increases the sensitivity and specificity of hepatic MR evaluation when compared with unenhanced MR imaging.


Assuntos
Meios de Contraste/administração & dosagem , Ferro/administração & dosagem , Neoplasias Hepáticas/diagnóstico , Imageamento por Ressonância Magnética , Óxidos/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Meios de Contraste/efeitos adversos , Dextranos , Feminino , Óxido Ferroso-Férrico , Humanos , Infusões Intravenosas , Injeções , Ferro/efeitos adversos , Nanopartículas de Magnetita , Masculino , Pessoa de Meia-Idade , Óxidos/efeitos adversos , Sensibilidade e Especificidade , Estatísticas não Paramétricas
18.
IDrugs ; 6(3): 232-9, 2003 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12789612

RESUMO

Endothelins (ET-1, 2 and 3) are 21-residue peptides with two disulfide bridges and a highly conserved carboxy terminal. ET-1, the most significant isoform, is a potent vasoconstrictor and mitogen that exerts its biological effects through binding to its two G protein-coupled receptors: ET(A) and ET(B). ET(A) receptors are expressed on vascular smooth muscle cells and mediate vasoconstrictive and proliferative responses to ET-1. ET(B) receptors are mainly located on endothelial cells where they clear ET-1 from circulation and mediate vasodilation via the release of nitric oxide. ET-1 has been associated with a variety of serious diseases such as pulmonary hypertension, heart failure, prostate cancer and renal dysfunction.


Assuntos
Ácidos Carboxílicos/química , Antagonistas dos Receptores de Endotelina , Sulfonamidas/química , Animais , Ácidos Carboxílicos/farmacologia , Ácidos Carboxílicos/uso terapêutico , Humanos , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Doenças Vasculares/tratamento farmacológico
19.
J Magn Reson Imaging ; 17(1): 86-94, 2003 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-12500277

RESUMO

PURPOSE: To assess whether measuring the pattern of pancreatic enhancement on gadolinium chelate dynamic magnetic resonance imaging (MRI) is helpful for diagnosis of suspected early or mild chronic pancreatitis. MATERIALS AND METHODS: In this retrospective study, 24 patients with suspected early or mild chronic pancreatitis, classified by imaging criteria of equivocal chronic pancreatitis (ultrasound, computed tomography [CT] or ERCP) grading, had dynamic MRI that included unenhanced, arterial dominant, early venous, and late venous phases of contrast enhancement. Twenty patients without pancreatic diseases also had the dynamic sequence as a control group. The signal intensity was measured at the pancreatic head, body, and tail on all phases, and for each, the signal intensity ratio (SIR, the signal intensity in postcontrast divided by that in precontrast) was calculated. Two radiologists independently reviewed the images of the patients with suspected early or mild chronic pancreatitis for pancreatic morphologic abnormalities without knowing the results of signal intensity measurements. RESULTS: On unenhanced images, there was no significant difference of signal intensity between control and pancreatitis groups (P < 0.05). In the pancreatitis group, but not in the control group, the unenhanced signal intensity of the pancreatic head and body were significantly higher than that of the tail (P < 0.05). In the control group, the greatest enhancement (highest SIR) after injection was in the arterial phase (1.89 +/- 0.31), significantly higher than that in the early venous phase (1.68 +/- 0.17, P < 0.01) and in the late venous phase (1.61 +/- 0.15, P < 0.001). The pancreatitis group, however, had an arterial phase SIR (1.65 +/- 0.23) that was significantly lower than its early venous phase SIR (1.75 +/- 0.22, P < 0.05) and lower than the arterial phase SIR of the control group (P < 0.01). The presence of an SIR less than 1.73 in the arterial phase and/or a delayed peak enhancement after contrast agent administration had a sensitivity and specificity of diagnosing early or mild chronic pancreatitis of 92% and 75%, respectively. This sensitivity was significantly higher than the sensitivity of 50% for diagnosis based on morphologic abnormalities (P < 0.05). CONCLUSION: Measuring pancreatic signal intensity on gadolinium chelate dynamic MRI is helpful for diagnosing early or mild chronic pancreatitis, especially before apparent pancreatic morphologic or signal intensity changes are present.


Assuntos
Gadolínio , Aumento da Imagem , Pancreatite/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Doença Crônica , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Tempo
20.
Radiology ; 224(3): 769-74, 2002 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12202712

RESUMO

PURPOSE: To determine whether a modified caudate-right lobe ratio (C/RL) with use of the right portal vein to set the lateral boundary (C/RL-r) is more accurate for diagnosing cirrhosis and evaluating its clinical severity than is the previously described C/RL with use of the main portal vein to set the lateral boundary (C/RL-m). MATERIALS AND METHODS: Two hundred thirty-six patients (121 with pathologically proved cirrhosis and 115 without history of chronic hepatic diseases) underwent magnetic resonance (MR) imaging. Two independent observers measured C/RL-r and compared it with C/RL-m. Results were compared by using receiver operating characteristic (ROC) curves and accuracy measures at various thresholds. RESULTS: The area below the ROC curve was greater for C/RL-r (0.797) than for C/RL-m (0.731; P =.040). By using a C/RL-r greater than 0.90, the sensitivity, specificity, and accuracy for the MR imaging diagnosis of cirrhosis were 71.7%, 77.4%, and 74.2%, respectively. The highest accuracy of the C/RL-m was 65.7%, when the C/RL-m was greater than 0.55. Interobserver agreement was statistically confirmed for both measurements by using kappa analysis. Significant differences were found among the three Child-Pugh classes by using C/RL-r (P =.0105) but not by using C/RL-m. CONCLUSION: C/RL-r is more accurate for diagnosing cirrhosis and evaluating its clinical severity than is C/RL-m.


Assuntos
Cirrose Hepática/diagnóstico , Imageamento por Ressonância Magnética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Cirrose Hepática/patologia , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Veia Porta/anatomia & histologia , Curva ROC , Sensibilidade e Especificidade
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