A model of hypertension and proteinuria in cancer patients treated with the anti-angiogenic drug E7080

Hypertension and proteinuria are commonly observed side-effects for anti-angiogenic drugs targeting the VEGF pathway. In most cases, hypertension can be controlled by prescription of anti-hypertensive (AH) therapy, while proteinuria often requires dose reductions or dose delays. We aimed to construct a pharmacokinetic–pharmacodynamic (PK–PD) model for hypertension and proteinuria following treatment with the experimental VEGF-inhibitor E7080, which would allow optimization of treatment, by assessing the influence of anti-hypertensive medication and dose reduction or dose delays in treating and avoiding toxicity. Data was collected from a phase I study of E7080 (n = 67), an inhibitor of multiple tyrosine kinases, among which VEGF. Blood pressure and urinalysis data were recorded weekly. Modeling was performed in NONMEM, and direct and indirect response PK–PD models were evaluated. A previously developed PK model was used. An indirect response PK–PD model described the increase in BP best, while the probability of developing proteinuria toxicity in response to exposure to E7080, was best described by a Markov transition model. This model may guide clinical interventions and provide treatment recommendations for E7080, and may serve as a template model for other drugs in this class

Prognostic value of echocardiographically assessed right ventricular dysfunction in patients with pulmonary embolism

Background: Echocardiographically assessed right ventricular dysfunction is increasingly used to guide more aggressive therapy in hemodynamically stable patients with acute pulmonary embolism (PE). However, the prognostic value of right ventricular dysfunction in these patients is still unclear. Methods: We systemically reviewed the literature to assess the prevalence of echocardiographic right ventricular dysfunction and the association with adverse outcomes in patients with PE who had this condition. The methodologic quality of each study was scored. Absolute risks of the outcome events were calculated for each study separately, and positive predictive values of PE-related mortality were determined for normotensive patients. Results: Seven studies were included. All had methodologic shortcomings, but they suggested an at least 2-fold increased risk of PE-related mortality in patients with right ventricular dysfunction, the prevalence of which varied from 40% to 70%. However, this seems to be less convincing in hemodynamically stable patients. The only 2 studies that allowed for an estimation of the accuracy in normotensive patients showed low positive predictive values of echo cardiographic right ventricular dysfunction for PE-related in-hospital mortality (positive predictive value, 4% and 5% in the 2 studies). Conclusion: It remains unclear whether echocardiographic right ventricular dysfunction is a prevalent and reliable predictor of adverse outcomes in hemodynamically stable patients with acute P

Travel and the risk of symptomatic venous thromboembolism

Whether long-distance travel and symptomatic venous thromboembolism (VTE) are associated is debated. On the basis of the available literature a fair risk estimate cannot be obtained. We estimated an accurate odds ratio for the relationship between recent travelling and symptomatic VTE. From three case-control studies consisting of 788 and 170 patients with clinically suspected deep vein thrombosis (DVT) and 989 patients with clinically suspected pulmonary embolism (PE) referred for diagnostic work-up, a pooled odds ratio for the relation between travel and symptomatic VTE was calculated. Cases were patients in whom the diagnosis was confirmed according to a diagnostic management strategy, whereas controls were patients in whom the diagnosis was excluded and who had an uneventful clinical follow-up. Patients were seen in the period April 1997 to September 2000. Travel history was recorded prior to diagnostic work-up. The pooled odds ratio for the association between any travel and symptomatic venous thromboembolism was 0.5 (95% Cl: 0.6-1.4). The median travel time was 7 h (quartile range 4 to 10 h). Separate analyses performed for different types of transport (plane, car, bus or train) yielded comparable odds ratios. The analysis for duration of travelling showed an increased odds ratio of 2.5 (95% Cl: 1.0-6.2) in the category of 10-15 h of travelling. This study shows that the average traveller does not have an increased risk for symptomatic venous thromboembolism. Only very long travelling (more than 10 h) may be associated with venous thromboembolic diseas

Large and medium-sized pulmonary artery obstruction does not play a role of primary importance in the etiology of sickle-cell disease-associated pulmonary hypertension

Background: Pulmonary hypertension (PHT) occurs in approximately 30% of adult patients with sickle-cell disease (SCD) and is a risk factor for early death. The potential role of pulmonary artery obstruction, whether due to emboli or in situ thrombosis, in the etiology of SCD-related PHT is unknown. Methods: Consecutive SCD patients were screened for PHT (defined as a tricuspid regurgitant jet flow velocity ≥ 2.5 m/s) employing echocardiography and were evaluated for pulmonary artery obstruction with ventilation-perfusion (VQ) scintigraphy. Results: Fifty-three HbSS, 6 HbSβ0-thalassemia, 20 HbSC, and 6 HbSβ+-thalassemia patients were included. The overall prevalence of PHT was 41% in HbSS/HbSβ0-thalassemia patients and 13% in HbSC/HbSβ+-thalassemia patients. High-probability VQ defects (Prospective Investigation of Pulmonary Embolism Diagnosis criteria) were detected in two patients, one of whom had PHT. In HbSS/HbSβ0-thalassemia patients with PHT, 19 patients (86%), 2 patients (9%), and 1 patient (5%) had low-, intermediate-, or high-probability scan results as compared to 30 patients (97%), 1 patient (3%), and 0 patients (0%) in HbSS/HbSβ0-thalassemia patients without PHT (p = 0.31). In HbSC/HbSβ+-thalassemia patients with PHT, 3 patients (100%), 0 patients (0%), and 0 patients (0%) had low-, intermediate-, and a high-probability scan as compared to 19 patients (90%), 1 patient (5%), and 1 patient (5%) in HbSC/HbSβ+-thalassemia patients without PHT (p = 0.86). There were no statistical differences in irregular distribution of the radiopharmaceutical or nonspecific signs associated with PHT between patients with and without PHT. Conclusions: Although small pulmonary artery obstruction cannot be excluded, large to medium-sized pulmonary artery obstruction is an unlikely primary causative factor in SCD-related PHT

Cardiopulmonary imaging, functional and laboratory studies in sickle cell disease associated pulmonary hypertension

Pulmonary hypertension (PHT) occurs in approximately 30% of adults with sickle cell disease (SCD) and is an independent risk factor for early death. In this study, we aimed to determine the value of general laboratory testing, plain chest radiography, electrocardiography (ECG), high-resolution computer tomography (HRCT) of the thorax, pulmonary function testing, and plasma N-terminal brain natriuretic peptide (NT-proBNP) and brain natriuretic peptide (BNP) in patients with SCD-related PHT. A cohort of 85 ambulatory sickle cell patients were prospectively screened for PHT with echocardiography (defined as a tricuspid regurgitation flow velocity of >= 2.5 ml All patients were systematically evaluated by the aforementioned diagnostic tests comparing patients with and without PHT. The prevalence of PHT was 41% in HbSS/HbS beta(0)-thalassemia patients and 13% in HbSC/HbS beta(+)-thalassemia patients. No statistically significant differences were detected in ECG, chest radiography, HRCT, and pulmonary function testing between patients with and without PHT. The degree of anemia and renal dysfunction, but not the presence of PHT, were the most important determinants of plasma (NT pro)BNP levels. The performed imaging and functional studies do not seem to be of value in identifying etiological conditions (such as airflow obstruction or parenchymal lung disease) nor do they offer clues to the presence of mild PHT in SCD. Am. J. Hematol. 83:850-854, 2008. (C) 2008 Wiley-Liss, Inc

Dengue disease severity in Indonesian children: an evaluation of the World Health Organization classification system.

Contains fulltext : 65629.pdf ( ) (Open Access