Homocysteine concentration-time courses with and without co-administration of folinate.

<p>Excerpt of 1000 per-protocol simulations each of the low-risk (A) and standard/high-risk (B) study population. The solid grey line represents the median of the simulations without folinate with the 90% prediction interval (PI) as solid grey area, the solid black line represents the median of the simulations under influence of folinate with the 90% PI as shaded area.</p

Patients characteristics.

<p>WIN = window phase; CONS = consolidation phase LR = low risk; SHR = standard/high risk.</p

Visual predictive check of the pharmacokinetic model for all patients of the evaluation dataset receiving a 24 h MTX infusion with a dose of 2500±20 mg/m² (A) and 5000±20 mg/m² (B), respectively.

<p>The black circles represent the measured methotrexate concentrations. The solid line represents the median predicted concentration, the dashed lines represent the 90% prediction interval of 10000 simulations.</p

Scheme of the PK/PD model (CL = total body clearance; Q = intercompartmental clearance; V1 = volume of the central compartment; V2 = volume of the peripheral compartment; HCY = homocysteine; k_in = HCY formation rate constant; k_out

<p> = <b>HCY elimination rate constant).</b></p

Visual predictive check of the pharmacodynamic model for low-risk (A) and standard/high-risk (B) patients from the evaluation dataset.

<p>The black circles represent the measured homocysteine concentrations relative to baseline. The solid line represents the median predicted concentration, the dashed lines represent the 90% prediction interval of 1000 simulations.</p

Pharmacokinetic and pharmacodynamic model parameters.

<p>CI_90% = 90% confidence interval.</p><p>(CI_90% by bootstrapping).</p

Histology of osteonecrosis and arteriopathy.

<p>H&E staining of representative stifle joints from mice negative for osteonecrosis (ON) and arteriopathy (Art, top panel), negative for osteonecrosis but positive for arteriopathy (middle panel), and positive for both osteonecrosis and arteriopathy (bottom panel). All mice received dexamethasone and PEG-asparaginase for 6 weeks. (A) Normal arteriole (arrow), marrow and trabecular bone. (B) Magnified cross-section of the arteriole in A. The inset shows the normal endothelial cells (dashed arrows) with elongated nuclei and smooth muscle cells (solid arrows) with round nuclei. (C) Magnification of boxed area in A, showing healthy osteocytes in lacunae (arrows) and healthy hematopoietic cells in marrow (asterisk). (D) Vessel with arteriopathy (arrow) and healthy bone with slightly decreased hematopoietic cells (asterisk). (E) Magnification of the arteriole in D, showing thickened, occluded blood vessel (arrow) and loss of endothelium and smooth muscle cells. (F) Magnification of boxed area in D, showing healthy osteocytes in lacunae (arrows) and decreased hematopoietic cells (asterisk). (G) Vessel with arteriopathy (arrow) and necrotic marrow and trabecular bone. (H) Magnification of the arteriole in G, showing thickened, occluded blood vessel (arrow) and loss of endothelium and smooth muscle cells. (I) Magnification of boxed area in G, showing empty lacunae and dead osteocytes (arrows) and necrotic marrow (asterisk). Scale bars are 500 microns in the left panel and 50 microns in the middle and right panels.</p

Osteonecrosis was associated with higher plasma dexamethasone and asparaginase levels in mice receiving both dexamethasone and asparaginase treatment.

<p>BALB/cJ males received dexamethasone (4 mg/L) and PEG-asparaginase (1200 IU/kg i.p. twice weekly) for 6 weeks. Blood samples were collected at the end of week 6 (approximately 3.5 days after last asparaginase injection).</p

Asparaginase treatment potentiated osteonecrosis and arteriopathy in dexamethasone-treated mice.

<p>Chi-square P values were calculated between dexamethasone (DEX)-treated mice that received vs. those that did not receive asparaginase (ASP).</p

Dexamethasone and asparaginase treatment regimens.

<p>Horizontal arrows represent dexamethasone treatment (2 or 4 mg/L in drinking water) and vertical arrows represent PEG-asparaginase (Oncaspar) treatment (1200 or 1500 IU/kg twice weekly via i.p. injection). Dashed lines and arrows indicate continuous dexamethasone and twice weekly asparaginase treatment after week 2. The dose of dexamethasone in drinking water and dose and number of asparaginase injections are shown.</p