Lymphoma is the most common hematological cancer in dogs. Canine diffuse large B cell lymphoma shows a relatively good response to treatment with multi-agent cyclophosphamide, doxorubicin, ...vincristine, and prednisone (CHOP) chemotherapy; however, the 2-year survival rate is as low as 20%. For human B cell type lymphoma, the anti-CD20 chimeric antibody, rituximab, was developed two decades ago. The combination of rituximab and CHOP chemotherapy was highly successful in improving patient prognosis. However, no anti-canine CD20 antibody is available for the treatment of canine lymphoma. During this study, a rat anti-canine CD20 monoclonal antibody was established. We also generated a rat-canine chimeric antibody against canine CD20 designed for clinical application. This chimeric antibody (4E1-7-B) showed in vitro antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) against the canine B cell lymphoma cell line CLBL-1. Moreover, to obtain stronger ADCC activity, a defucosylated 4E1-7-B antibody (4E1-7-B_f) was also generated, and it showed tenfold stronger ADCC activity compared with 4E1-7-B. 4E1-7-B_f as well as 4E1-7-B suppressed the growth of CLBL-1 tumors in an immunodeficient xenotransplant mouse model. Finally, a single administration of 4E1-7-B_f induced considerable peripheral B cell depletion in healthy beagles. Thus, 4E1-7-B_f is a good antibody drug candidate for canine B cell type lymphoma.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Cilostazol and L-carnitine have been used as a first-line drug and supplement, respectively, in patients with peripheral arterial disease with intermittent claudication. In this study, the effect of ...the combination of cilostazol and L-carnitine has been investigated in rats with unilateral hindlimb ischemia. For 28 days, cilostazol and L-carnitine were administrated separately or as a combination. The distance walked before gait disturbance developed was measured using a treadmill for 5 days a week. The capillary density of the ischemic hindlimb was evaluated by immunohistochemical staining at days 7, 14, 21, and 28. Angiogenic gene expression was measured by real-time RT-PCR at days 7 and 28. The greatest increase in the distance was observed in the combination therapy group when compared to the other groups. The capillary density in the adductor muscles of rats treated with cilostazol alone and combination therapy increased at day 28. Angiopoietin-2/Angiopoietin-1 expression ratios were higher, suggesting the promotion of angiogenesis, with cilostazol alone and combination therapy at day 7. This is the first study to show functional improvement of the hind limb following combination therapy with cilostazol and L-carnitine in experimental animals. This study also revealed that cilostazol promotes angiogenesis, and L-carnitine additively contributes to functional improvement via a non-angiogenic mechanism.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
4.
Pharmacodynamics of alacepril in healthy cats Sugimoto, Keisuke; Fujii, Yoko; Takubo, Izumi ...
Journal of feline medicine and surgery,
06/2017, Volume:
19, Issue:
6
Journal Article
Peer reviewed
Objectives
The aims of this study were to investigate the pharmacodynamics of alacepril and to determine the appropriate dose for clinical usage in cats.
Methods
Six experimental cats were used. Each ...cat received alacepril orally at a single dose of 1 mg/kg, 2 mg/kg and 3 mg/kg. Blood samples were collected before administration and at 2, 4, 6, 8, 12, 24, 36, 48 and 72 h after administration to measure serum angiotensin converting enzyme (ACE) activity. Systolic blood pressure was also measured at the same time point.
Results
Dose-dependent inhibition of ACE activity was observed. Doses of 2 mg/kg and 3 mg/kg alacepril were considered to effectively inhibit ACE activity. There were no significant differences in systolic blood pressue among groups at any time point.
Conclusions and relevance
Alacepril 2–3 mg/kg q24h may be an appropriate dosage for clinical use in cats.
Refractory pheochromocytoma and paraganglioma (PPGL) have a poor prognosis and the treatment strategy remains to be established. This multi-institutional phase I study was performed to determine the ...safety, dose-limiting toxicity (DLT), and efficacy of
I-meta-iodobenzylguanidine (
I-mIBG) therapy for refractory PPGLs. Twenty patients with refractory PPGL were enrolled in this study. We administered fixed doses of
I-mIBG to all patients, delivering a second and third course of
I-mIBG to eight and three patients, respectively. During the 20 weeks after
I-mIBG injection, the authors surveyed the adverse events in accordance with the Common Terminology Criteria for Adverse Events. All patients experienced adverse events and adverse reactions, but none experienced a grade 4 adverse event. Twelve weeks after
I-mIBG injection, examinations for the evaluation of therapeutic effects was performed in accordance with the Response Evaluation Criteria in Solid Tumours (RECIST). The best overall response rates (based on RECIST categories) were 10% (complete response), 65% (stable disease), 15% (progressive disease), and 10% (not all evaluated). The efficacy and safety of
I-mIBG therapy was shown in patients with refractory PPGL, and DLT was observed in neither single nor repeated
I-mIBG therapy, indicating a tolerability for
I-mIBG therapy.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Digoxin is an important treatment option for reducing the ventricular rate in patients with atrial fibrillation (AF) and heart failure (HF). Digoxin has a narrow therapeutic window and large ...interindividual variability. A low target blood concentration, especially ≤0.9 ng/mL, is recommended for patients with HF who are taking digoxin. This study aimed to develop a population pharmacokinetic model and to identify clinical factors that affect digoxin exposure and an optimal digoxin dosing regimen in Japanese patients with AF and HF.
A population pharmacokinetic analysis was performed by using a nonlinear mixed effects model based on 3465 concentration points from 391 patients (>18 years) who were receiving oral digoxin. Using trough serum digoxin concentrations and clinical data, a population pharmacokinetic model was developed for determining covariates of clearance. A 1-compartment model was used to examine the interindividual variability of the oral clearance (CL/F) of digoxin. An appropriate dosage of digoxin was identified using Monte Carlo simulation.
The final model demonstrated that creatinine clearance (CL
) and the use of amiodarone were factors that contributed to the CL/F of digoxin. Monte Carlo simulation results showed that with a daily maintenance dose of 0.25 mg, the intoxication risk window of a trough serum concentration of ≥0.9 ng/mL could be reached in more than half of patients regardless of renal function category or concurrent use of amiodarone. The appropriate maintenance dosage was 0.125 mg daily for most Japanese patients with AF and HF. However, with a daily dose of 0.125 mg, a trough serum concentration of ≥0.9 ng/mL could be reached in more than half of patients with renal impairments (CL
30 mL/min) or concurrent use of amiodarone. A daily maintenance dose of 0.0625 mg was acceptable for these patients.
CL
and the use of amiodaron were found to contribute to digoxin clearance using a population pharmacokinetic methodology. For Japanese patients with AF and HF, 0.125 mg is an appropriate daily digoxin maintenance dose, but a dose reduction is required for patients with CL
<30 mL/min or concurrent amiodarone use.
The aim of this study was to determine an appropriate equation for estimating renal function to dose regulate the serum digoxin trough concentration to a target of <0.9 ng/ml in patients with atrial ...fibrillation (AF) and heart failure (HF). All patients received 0.125 mg oral digoxin daily. The estimated glomerular filtration rate by the Modification of Diet in Renal Disease (eGFRMDRD) equation deindexed based on body surface area had the highest correlation with digoxin trough concentrations (r = −0.450) compared to the Cockcroft‐Gault equation (r = −0.415) or deindexed eGFR based on the Chronic Kidney Disease Epidemiology Collaboration (eGFRCKD‐EPI) equation (r = −0.416). The median digoxin trough concentrations were 0.60, 0.77, 0.97 and 1.30 ng/ml in patients with a deindexed eGFRMDRD ≥ 60, 45–59, 30–44 and < 30 ml/min, respectively. The deindexed eGFRMDRD is an appropriate equation for digoxin dose adjustment in patients with AF and HF.
The estimated glomerular filtration rate by the Modification of Diet in Renal Disease (eGFRMDRD) equation deindexed based on body surface area had the highest correlation with digoxin trough concentrations (r = −0.450) compared to the Cockcroft‐Gault (r = −0.415) or deindexed eGFR based on the Chronic Kidney Disease Epidemiology Collaboration (eGFRCKD‐EPI) equation (r = −0.416).
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
A whitish mass approximately 30 mm in diameter was noted in the anterior mediastinum of a 67-week-old female Fischer 344 rat. Histopathologically, two types of tumor cells were identified on the ...basis of morphologic features: epithelial tumor cells with a tubular or cord-like growth pattern and rhabdomyosarcomatous tumor cells characterized by the presence of cross-striations. Immunohistochemically, the epithelial tumor cells reacted positively for cytokeratin AE1/AE3, and some reacted positively for p63, which is expressed in normal thymic epithelial cells. The rhabdomyosarcomatous tumor cells stained positively for desmin, sarcomeric actin, and S-100 protein, which coincides with the stainability of normal thymic myoid cells. Since the tumor was also found to have malignant features such as high proliferative activity, cytologic atypia, and necrotic behavior, it was diagnosed as a malignant myoid thymoma. We believe that this is the first case report of such a tumor in a rodent.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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