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Selected AbstractsCoat colour changes associated with cabergoline administration in bitchesJOURNAL OF SMALL ANIMAL PRACTICE, Issue 8 2003C. Gobello Cabergoline or bromocriptine were administered orally to 60 bitches at doses of 5 ,g/kg and 15 ,g/kg daily, respectively, for two to 45 days for the treatment of pseudopregnancy or for oestrus induction. Seven of the dogs which received cabergoline for more than 14 days developed coat colour changes from the second week of administration to the next coat shedding. Of these, fawn-coloured bitches developed a yellowish coat colour while Argentine boar hounds became black spotted, mainly on their extremities. In previous untreated oestrous periods, these bitches had shown no coat colour changes. It is concluded that a colour shift in certain haircoats of particular breeds could be mediated through the inhibition of the secretion of melanocyte-stimulating hormone by the administration of the dopaminergic agonist cabergoline for more than two weeks. Transient coat colour changes should be considered a possible side effect when planning long-term treatment with dopaminergic agonists in dogs. [source] ORIGINAL ARTICLE: Can Sulfasalazine Prevent Infection-Mediated Pre-Term Birth in a Murine Model?AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 2 2010Carl A. Nath Citation Nath CA, Ananth CV, Smulian JC, Peltier MR. Can sulfasalazine prevent infection-mediated pre-term birth in a murine model? Am J Reprod Immunol 2010; 63: 144,149 Problem, Sulfasalazine (SASP) blocks activation of nuclear factor-kappa B (NF-,B) in gestational tissues in vitro, one of the earliest signals in the inflammatory response. We hypothesized that the administration of SASP would reduce the rate of infection-mediated pre-term birth in a murine model. Method of study, CD-1 mice (n = 40) were assigned on gestational day (gd) 14.5 to 1 of 3 treatments: (1) Sham infection and vehicle; (2) 104 CFU Escherichia coli and vehicle; or (3) 104 CFU E. coli and SASP (150 mg/Kg daily). Mice were observed twice daily and deliveries prior to gd 18.5 were considered pre-term. Results, Significantly more mice delivered prior to gd 18.5 when infected with 104 CFU E. coli than sham-infected mice (P < 0.001) and this effect was significantly reduced in mice also treated with SASP (P = 0.002). SASP also tended to increase litter size (P = 0.060) and significantly increased weight of pups born to dams with intrauterine infections (P = 0.001). Conclusion, SASP reduced rates of pre-term delivery and improved pregnancy outcomes for mice infected with 104 CFU E. coli. This suggests that SASP has the potential to play a role in strategies to prevent pre-term birth in women. [source] Vorinostat enhances the antimyeloma effects of melphalan and bortezomibEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 3 2010Richard A. Campbell Abstract Objectives:, Examine the antitumor activity of the histone deacetylase inhibitor vorinostat's antitumor activity against multiple myeloma (MM) using cell lines and a murine xenograft model. Methods:, RPMI8226, U266, and MM1S cells were cultured for 48 h in the presence of media, vorinostat, melphalan, or bortezomib alone, or combinations of vorinostat with melphalan or bortezomib. Cell proliferation was measured using the MTS [3-(4,5-dimethylthiazol-2yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfphophenyl)-2H-tetrazolium, inner salt] assay. Severe combined immunodeficient mice bearing LAG,-1B tumors were treated with vorinostat [30, 60, or 100 mg/kg daily for five consecutive days per week (qd×5d), 100 or 300 mg/kg daily for 2 d/wk (qd×2d)], melphalan (1, 3, or 10 mg/kg qd×1d), bortezomib (0.25 or 0.5 mg/kg qd×2d), or combinations thereof for 35 d. Tumor growth was determined via measurement of human immunoglobulin G (hIgG) levels and tumor volume. Results and Conclusions:, Vorinostat enhanced the anti-MM effects of melphalan and bortezomib in vitro. Synergism was observed with vorinostat and melphalan in RPMI8226 and U266 cell lines. Vorinostat 100 mg/kg in combination with melphalan 3 mg/kg resulted in significant inhibition of tumor growth in vivo, compared with control (tumor volume P = 0.0001; hIgG P = 0.0001), single-agent vorinostat (tumor volume P = 0.0025; hIgG P = 0.0137), and single-agent melphalan (tumor volume P = 0.0043; hIgG P = 0.0426). Vorinostat also enhanced the antimyeloma effects of bortezomib in vivo. Vorinostat enhances the anti-MM activity of melphalan and bortezomib in vitro and in vivo. This study provides rationale for further evaluation of vorinostat in combination with chemotherapeutic agents and bortezomib for the treatment of MM. [source] Potent Antiarrhythmic Effects of Chronic Amiodarone in Canine Pulmonary Vein Sleeve PreparationsJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 7 2009SERGE SICOURI M.D. Objectives: To examine the effects of chronic amiodarone on the electrophysiology of canine pulmonary vein (PV) sleeve preparations and left ventricular wedge preparation. Background: Amiodarone is commonly used for the treatment of ventricular and supraventricular arrhythmias. Ectopic activity arising from the PV plays a prominent role in the development of atrial fibrillation (AF). Methods: Standard microelectrode techniques were used to evaluate the electrophysiological characteristics of superfused PV sleeve (left superior or inferior) and arterially perfused left ventricular (LV) wedge preparations isolated from untreated and chronic amiodarone-treated dogs (amiodarone, 40 mg/kg daily for 6 weeks). Results: In PV sleeves, chronic amiodarone (n = 6) induced a significant increase in action potential duration at 90% repolarization (APD90) and a significant use-dependent reduction in Vmax leading to 1:1 activation failure at long cycle lengths (basic cycle length of 124 ± 15 ms in control vs 420 ± 320 ms after chronic amiodarone [P < 0.01]). Diastolic threshold of excitation increased from 0.3 ± 0.2 to 1.8 ± 0.7 mA (P < 0.01). Delayed and late phase 3 early afterdepolarizations and triggered activity could be induced in PV sleeve preparations using acetylcholine (ACh, 1 ,M), high calcium ([Ca2+]o= 5.4 mM), isoproterenol (Iso, 1 ,M), or their combination in 6 of 6 untreated PV sleeves, but in only 1 of 5 chronic amiodarone-treated PV sleeve preparations. Vmax, conduction velocity, and 1:1 activation failure were much more affected in PV sleeves versus LV wedge preparations isolated from amiodarone-treated animals. Conclusions: The results point to potent effects of chronic amiodarone to preferentially suppress arrhythmogenic substrates and triggers arising from the PV sleeves of the dog. [source] 5-aminoisoquinolin-1(2H)-one, a water-soluble poly (ADP-ribose) polymerase (PARP) inhibitor reduces the evolution of experimental periodontitis in ratsJOURNAL OF CLINICAL PERIODONTOLOGY, Issue 2 2007Rosanna Di Paola Abstract Background: Poly (ADP-ribose) polymerase (PARP), a nuclear enzyme activated by strand breaks in DNA, plays an important role in the tissue injury associated with ischaemia-reperfusion and inflammation. Recent studies have demonstrated that PARP activation plays a crucial role in the pathogenesis of acute periodontal injury. Aim: We have investigated the effect of 5-aminoisoquinolin-1(2H)-one (5-AIQ), a water-soluble PARP inhibitor, in a rat model of periodontitis. Materials and Methods: Periodontitis was induced in rats by placing a 2/0 braided silk ligature around the lower left first molar. At day eight, the gingivomucosal tissue encircling the mandibular first molar was removed for biochemical and histological analysis. Results and Conclusions: Ligation significantly induced an increased neutrophil infiltration and a positive staining for PARP activation. Ligation significantly increased Evans blue extravasation in gingivomucosal tissue and alveolar bone destruction. Intraperitonial injection of 5-aminoisoquinolin-1(2H)-one (5-AIQ) (5 mg/kg daily for eight days) significantly decreased all of the parameters of inflammation as described above. This suggests that inhibition of PARP may represent a novel approach for the treatment of periodontal disease. [source] Hypercholesterolaemia induces early renal lesions characterized by upregulation of MMP-9 and iNOS and ETAR: alleviated by a dual endothelin receptor antagonist CPU0213 and simvastatinJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 6 2009Lu Luo Abstract Objectives We aimed to investigate hypercholesterolaemia-induced early renal lesions which result in abnormal expression of endothelin A receptor (ETAR), induced nitric oxide synthase (iNOS) and matrix metalloproteinase 9 (MMP-9). We hypothesized that this is due to an upregulated endothelin (ET) pathway consequent to hypercholesterolaemia and that CPU0213, a dual ET antagonist, could mitigate these changes. Methods Rats were randomly divided into four groups: (1), control; (2), high-fat diet for 60 days (HFD); HFD rats medicated in the last 15 days with either (3) CPU0213 (30 mg/kg daily, s.c.) or (4) simvastatin (4 mg/kg daily, p.o.). Key findings Body weight, serum triglycerides, total cholesterol and low-density-lipoprotein cholesterol were significantly increased, whereas high-density lipoprotein cholesterol decreased in the HFD group, relative to normal. Meanwhile, these changes were associated with upregulation of mRNA and protein of ETAR, iNOS and MMP-9 in the kidney. The lipid-lowering effect of simvastatin was predominant, lessening abnormal expression of these molecules in the kidney dramatically. Interestingly, CPU0213 significantly normalized expression of mRNA and protein of ETAR, iNOS and MMP-9, comparable with simvastatin, leaving no changes in hyperlipidaemia. Conclusions CPU0213 relieves renal lesions by blunting hypercholesterolaemia caused by the upregulated ET system, iNOS and MMP-9 in the kidney. This indicates that CPU0213 is promising in treating patients with end stage renal disease. [source] Melatonin attenuates ifosfamide-induced Fanconi syndrome in ratsJOURNAL OF PINEAL RESEARCH, Issue 1 2004Goksel Sener Abstract:, Regarding the mechanisms of ifosfamide (IFO)-induced nephrotoxicity and hemorrhagic cystitis, several hypotheses have been put forward, among which oxidative stress and depletion of glutathione (GSH) are suggested. This investigation elucidates the role of free radicals in IFO-induced toxicity and the protection by melatonin. Wistar albino rats were injected intraperitoneally with saline (0.9% NaCl; control-C group), melatonin (Mel group; 10 mg/kg daily for 5 days) or ifosfamide (50 mg/kg daily for 5 days; IFO group) or IFO + Mel. On the 5th day (120 hr) after the first IFO dose, animals were killed by decapitation and trunk blood was collected. Kidney and bladder tissues were obtained for biochemical and histological analysis. Urine was collected 24 hr before the rats were killed. The results demonstrated that IFO induced a Fanconi syndrome (FS) characterized by wasting of sodium, phosphate, and glucose, along with increased serum creatinine and urea. Melatonin markedly ameliorated the severity of renal dysfunction induced by IFO with a significant decrease in urinary sodium, phosphate, and glucose and increased creatinine excretion. Moreover, melatonin significantly improved the IFO-induced GSH depletion, malondialdehayde accumulation and neutrophil infiltration in both renal and bladder tissues. In the kidney, Na+,K+ -ATPase activity which was significantly reduced by IFO, was increased with melatonin treatment. Increased collagen contents of the kidney and bladder tissues by IFO treatment were reversed back to the control levels with melatonin. Our results suggest that IFO causes oxidative damage in renal and bladder tissues and melatonin, via its antioxidant effects, protects these tissues. These data suggest that melatonin may be of therapeutic use in preventing acquired FS due to IFO toxicity. [source] Protective effect of a polyherbal formulation (Immu-21) against cyclophosphamide-induced mutagenicity in mice,PHYTOTHERAPY RESEARCH, Issue 4 2003G. B. Jena Abstract The object was to evaluate the effects of a polyherbal formulation, Immu-21, against cyclophosphamide (CP)-induced chromosomal aberrations (CA) and micronuclei (MN) in mice. CP alone (40 mg/kg, i.p.) produced classical as well as non-classical chromosomal aberrations in mice, and the incidence of CA was signi,cantly more in the CP treated group when compared with that of the control group. Immu-21, which contains extracts of Ocimum sanctum, Withania somnifera, Emblica officinalis and Tinospora cordifolia, was given at 100 mg/kg, daily, over 7 days, and 30 mg/kg daily over 14 days and inhibited both CP-induced classical and non-classical chromosomal aberrations (,40%,60% of control). A significant increase in MN was also observed in bone marrow erythrocytes of mice treated with CP, and pretreatment with Immu-21 also signi,cantly reduced these. Cytotoxicity was evaluated by estimating the ratio of polychromatic erythrocytes (PCEs) to normochromatic erythrocytes (NCEs). The present results indicate that chronic treatment with Immu-21 prevented CP-induced genotoxicity in mice. Copyright © 2003 John Wiley & Sons, Ltd. [source] High-dose cyclophosphamide versus monthly intravenous cyclophosphamide for systemic lupus erythematosus: A prospective randomized trial,ARTHRITIS & RHEUMATISM, Issue 5 2010Michelle Petri Objective Monthly intravenous (IV) cyclophosphamide for 6 months has been the standard induction regimen for lupus nephritis, followed by a maintenance regimen of quarterly infusions for 2 years. We undertook this study to compare the efficacy and safety of the standard regimen versus a high-dose IV cyclophosphamide regimen. Methods We performed a prospective randomized trial comparing monthly IV cyclophosphamide at 750 mg/m2 body surface area for 6 months followed by quarterly IV cyclophosphamide for 2 years (traditional treatment) against high-dose IV cyclophosphamide (50 mg/kg daily for 4 days) (high-dose treatment). Entry criteria included renal lupus, neurologic lupus, or other organ system involvement with moderate-to-severe activity. Results Fifty-one patients were randomized; 3 withdrew before treatment and 1 committed suicide after 2 months of high-dose treatment. Twenty-two had renal lupus, 14 had neurologic lupus, and 11 had other organ involvement. The outcome measure was the Responder Index for Lupus Erythematosus (complete response, partial response, no change, or worsening). At 6 months (the end of induction), 11 of 21 patients (52%) in the high-dose treatment group had a complete response compared with 9 of 26 patients (35%) in the traditional treatment group (P = 0.13). At the final visit (30 months), 10 of 21 patients (48%) in the high-dose treatment group had a complete response compared with 13 of 20 patients (65%) who continued with traditional treatment (P = 0.13). Six patients crossed over from traditional treatment to high-dose treatment because of lack of response, and 3 of those patients became complete responders. Conclusion There was not strong evidence that monthly IV cyclophosphamide and high-dose IV cyclophosphamide differed in complete or in any (complete or partial) response to induction or maintenance therapy. However, nonresponders to monthly IV cyclophosphamide can sometimes be rescued with high-dose IV cyclophosphamide. [source] Procyanidins Produce Significant Attenuation of Doxorubicin-Induced Cardiotoxicity via Suppression of Oxidative StressBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 3 2009Wei Li The major side effect of doxorubicin is oxidative injury-related cardiotoxicity, which has dramatically hindered its usage. Procyanidins from grape seeds are potent free radical scavengers that have been shown to protect against anthracycline-induced cardiotoxicity. In the present study, we tested whether procyanidins would prevent the doxorubicin-induced cardiotoxicity in rats. Rats were intraperitoneally treated with doxorubicin at a cumulative dose of 15 mg/kg with and without pre-administration of procyanidins. Our data showed that doxorubicin led to cardiac function deterioration, myocardial injury and increased oxidative stress in cardiac tissues. The cardiac function deterioration by doxorubicin included increased QT-interval and ST-interval in electrocardiograph (ECG) and decreased left ventricular developed pressure. Doxorubicin-induced myocardial injury was shown by the increased creatine kinase, alanine aminotransferase and aspartate aminotransferase in serum as well as in myocardial lesions. Pretreatment with procyanidin (150 mg/kg daily) effectively hindered the adverse effects of doxorubicin, such as myocardial injury and impaired heart function. Procyanidin pretreatment attenuated cytoplasmic vacuolization, increased left ventricular developed pressure and improved the ECG. The cardioprotective effect of procyanidin corresponded to the decrease of lipid peroxidation and the increase of cardiac antioxidant potency in doxorubicin-treated rats that were also given procyanidin. An in vitro cytotoxic study showed that procyanidins did not attenuate the antineoplastic activity of doxorubicin to A549 adenocarcinoma cells. All the above lines of evidence suggest that procyanidins protect cardiomyocytes from doxorubicin-induced cardiotoxicity via suppression of oxidative stress. [source] Effects of the combination of rapamycin with tacrolimus or cyclosporin on experimental intimal hyperplasiaBRITISH JOURNAL OF SURGERY (NOW INCLUDES EUROPEAN JOURNAL OF SURGERY), Issue 11 2002Dr J. R. Waller Background: Allograft vasculopathy remains the leading cause of late allograft failure following transplantation and can be inhibited by the antiproliferative drug rapamycin. This study assessed the efficacy of combining rapamycin therapy with calcineurin inhibition. Methods: Male Sprague,Dawley rats received rapamycin 0·05 mg/kg daily and either tacrolimus 0·1 mg/kg or cyclosporin 5 mg/kg daily, and findings were compared with those in an untreated control group. Animals underwent left common carotid artery balloon angioplasty; the artery was explanted after 2 weeks. Morphometric analysis was performed on transverse sections and the intima: media ratio was calculated. Profibrotic gene expression was measured with competitive reverse transcriptase,polymerase chain reaction at 14 and 28 days. Proliferation was determined with proliferating cell nuclear antigen at 14 and 28 days. Extracellular matrix deposition was quantified with Sirius red. Results: The combination of rapamycin and tacrolimus was associated with the greatest reduction in intimal thickening. Furthermore, treatment with rapamycin and tacrolimus significantly attenuated extracellular matrix deposition compared with rapamycin and cyclosporin (P < 0·02). Conclusion: The effects of rapamycin in combination with tacrolimus were better than those observed with rapamycin and cyclosporin. © 2002 British Journal of Surgery Society Ltd [source] An animal model for chemotherapy-associated steatohepatitis and its prevention by the oral administration of fatty acid bile acid conjugateCANCER, Issue 1 2010Daniel Keizman MD Abstract BACKGROUND: Preoperative chemotherapy for hepatic resection of colorectal liver metastases is associated with the development of chemotherapy-associated steatohepatitis (CASH). This increases the risk of perioperative morbidity and mortality. To the authors' knowledge, an animal model for CASH has not been described previously. It has been established that fatty acid bile acid conjugates (FABACs) prevent the formation of diet-induced fatty liver. The current study was designed to establish an animal model of CASH and to use that model to study the effect of FABACs on its occurrence. METHODS: C57BL/6 mice were given different doses of oxaliplatin and irinotecan. Oxaliplatin administered once weekly at a dose of 6 mg/kg for a total dose of 24 mg/kg was tolerated best and was associated most consistently with CASH. Thus, that dose was chosen as the induction model for CASH. Subsequently, mice were divided into a control group (no treatment), an oxaliplatin group, and a CASH-prevention group, which received oxaliplatin and C20-FABAC at a dose of 150 mg/kg daily. The animals were killed after 28 days. RESULTS: Liver fat content was significantly lower (P < .0001) in the control group (51.63 mg/g) and the prevention group (62.13 mg/g) compared with the oxaliplatin group (95.35 mg/g). This difference was mainly because of the accumulation of liver triglycerides in the oxaliplatin group. CONCLUSIONS: The current results indicated that C57BL/6 mice receiving weekly oxaliplatin can be used as a model for CASH. Oral FABAC therapy reduced the development of CASH in animals that received oxaliplatin. To the authors' knowledge, this report is the first description of a model and a potential preventive treatment for CASH. Cancer 2010. © 2010 American Cancer Society. [source] Activity of interferon-, and isotretinoin in patients with advanced, refractory lymphoid malignanciesCANCER, Issue 3 2004Apostolia-Maria Tsimberidou M.D., Ph.D. Abstract BACKGROUND Interferon-, (IFN-,) and retinoids have shown nonoverlapping toxicity and each has shown antitumor activity in patients with lymphoma. The aim of the current study was to assess the toxicity, safety, and efficacy of IFN-, combined with isotretinoin in patients with advanced, refractory lymphoid malignancies. METHODS Adults with biopsy-proven advanced lymphoid malignancy were treated. Patients with compromised bone marrow function (platelet counts as low as 30 × 109/L) were eligible. Treatment was comprised of IFN-, at a starting daily dose of 3 mega units subcutaneously and isotretinoin orally starting at a dose of 1 mg/kg daily in 2 divided doses. RESULTS Forty-four patients were evaluable. Their median age was 57 years (range, 18,82 years). Eighteen patients had advanced cutaneous T-cell lymphoma, 6 patients had peripheral T-cell lymphoma, 14 patients had Hodgkin disease, and 6 patients had a variety of other lymphoid malignancies. Patients with Hodgkin disease had received a median of 6 previous therapies (range, 3,12 therapies) and patients with other lymphoid malignancies had received a median of 4 previous therapies (range, 1,9 therapies). The median duration of treatment was 4 months (range, 0.25,38 months). The overall response rate was 38.6% (complete response in 5 patients [11.3%] and partial response in 12 patients [27.3%]). The median response duration was 3 months (range, 1,95+ months). The most common toxicities were low-grade fever, flu-like symptoms, and fatigue (IFN-, effects); dry mouth and skin and hypertriglyceridemia (cis-retinoic acid effects); and thrombocytopenia (which generally occurred in patients with low baseline platelet counts). CONCLUSIONS IFN-, and isotretinoin combination therapy had antitumor activity and was well tolerated in heavily pretreated patients with lymphoid malignancies. Cancer 2004. © 2003 American Cancer Society. [source] Cost of prophylaxis in the management of cytomegalovirus infection in solid organ transplant recipientsCLINICAL TRANSPLANTATION, Issue 4 2007Federico Oppenheimer Abstract:, Background:, Limited economic data exist on the use of valganciclovir for the prevention of cytomegalovirus (CMV) infection and disease in solid organ transplant (SOT) recipients. We compared the economics of sequential i.v. and oral ganciclovir prophylaxis vs. oral valganciclovir prophylaxis alone in high-risk (D+/R,) SOT patients. Methods:, A cost-minimization analysis was performed from the perspective of the Spanish National Health System comparing the cost of sequential ganciclovir prophylaxis (induction with i.v. ganciclovir 10 mg/kg daily for 14 d followed by oral ganciclovir 1 g t.i.d. for 3 months) vs. oral valganciclovir prophylaxis (900 mg once daily for 100 d). Resource utilization data for both regimens were obtained from the literature and from clinical records of 83 patients in nine Spanish hospitals. Results were expressed as average cost per patient treated. Results:, The average cost per patient treated with sequential ganciclovir or valganciclovir prophylaxis was ,3715.51 and ,3295.90, respectively. The higher cost of ganciclovir therapy was due to concomitant administration of anti-CMV immunoglobulin (,313.73), drug administration costs (,401.45), catheter culture tests (,13.64) and adverse events associated with catheter use (,3.30). Following a sensitivity analysis, taking into account dose and duration of drug, concomitant medications and adverse events, costs for valganciclovir and sequential therapy were similar. Conclusions:, Valganciclovir prophylaxis is as economical as sequential ganciclovir prophylaxis in high-risk D+/R, SOT patients. In addition, the once-daily dosing regimen of valganciclovir is more convenient, and avoids the complications associated with catheter use. [source] | ||||||||||