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Long-term Administration (long-term + administration)
Selected AbstractsLong-term Administration of Rapamycin Reduces Adiposity, but Impairs Glucose Tolerance in High-Fat Diet-fed KK/HlJ MiceBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 3 2009Geng-Ruei Chang In this study, we investigated the metabolic effects of rapamycin in an obese animal model, KK/HlJ mice. Mice were treated with a daily intraperitoneal injection of rapamycin at 2 mg/kg or vehicle for 42 days on a high-fat diet. Treated mice lost body weight and adiposity, reduced weight gain and retroperitoneal and epididymal fat pads/body weight, decreased serum leptin and plasma triglyceride levels and had lower liver fat concentration. However, treated mice had higher serum insulin levels and food intake. Dissection of rapamycin-treated mice revealed a marked reduction in fatty liver scores and fat cell size in retroperitoneal and epididymal adipocytes. Moreover, Western blot analysis revealed that rapamycin treatment resulted in decreasing adipophilin expression, as a marker of lipid accumulation, and reducing phosphorylation of mTOR downstream targets S6K1 compared to control group. Unfortunately, rapamycin-treated animals showed a marked decline in glucose tolerance as judged by the 180-min. area under the curve for plasma glucose levels, paralleled by increased generation of plasma reactive oxygen species. These results suggest that continual rapamycin administration may help to prevent diet-induced obesity, while prolonged use of rapamycin may exacerbate glucose intolerance. [source] Long-term clopidogrel administration following severe coronary injury reduces proliferation and inflammation via inhibition of nuclear factor-kappaB and activator protein 1 activation in pigsEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 3 2009K. Pels ABSTRACT Background, The optimal duration of clopidogrel treatment following percutaneous coronary intervention (PCI) and the patient population that would benefit most are still unknown. In a porcine coronary injury model, we tested two different durations of clopidogrel treatment on severely or moderately injured arteries and examined the arterial response to injury. To understand the molecular mechanism, we also investigated the effects on transcription factors nuclear factor-kappaB (NF-,B) and activator protein 1 (AP-1). Materials and methods, In 24 cross-bred pigs, one coronary artery was only moderately injured by percutaneous transluminal coronary angioplasty (PTCA) and one coronary artery was severely injured by PTCA and subsequent beta-irradiation (Brachy group). Animals received 325 mg aspirin daily for 3 months and 75 mg clopidogrel daily for either 28 days [short-term (ST) clopidogrel group] or 3 months [long-term (LT) clopidogrel group]. Results, After 3 months, the number of proliferating cells per cross-section differed significantly between ST and LT in both injury groups (PTCAST 90·2 ± 10·3 vs. PTCALT 19·2 ± 4·7, P < 0·05; BrachyST 35·8 ± 8·4 vs. BrachyLT 7·5 ± 2·0, P < 0·05). Similar results were seen for inflammatory cells (CD3+ cells): PTCAST 23·5 ± 3·55 vs. PTCALT 4·67 ± 0·92, P < 0·05; BrachyST 83·17 ± 11·17 vs. BrachyLT 20 ± 4·82, P < 0·05). Long-term administration also reduced the activity of NF-,B and AP-1 by 62,64% and 42,58%, respectively. However, the effects of different durations of clopidogrel administration on artery dimensions were not statistically significant. Conclusions, Regarding inflammation and transcription factor activity at the PCI site, long-term clopidogrel administration is superior to short-term administration, especially in severely injured arteries. Transferring our results to the human situation, patients with more severely diseased arteries may benefit from a prolonged clopidogrel medication after PCI. [source] Aminoguanidine prevents arterial stiffening in a new rat model of type 2 diabetesEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 8 2006K.-C. Chang Abstract Background, Formation of advanced glycation end-products (AGEs) on collagen within the arterial wall may be responsible for the development of diabetic vascular injury. This study focused on investigating the role of aminoguanidine (AG), an inhibitor of AGE formation, in the prevention of noninsulin-dependent diabetes mellitus (NIDDM)-derived arterial stiffening and cardiac hypertrophy in rats. Materials and methods, The NIDDM was induced in male Wistar rats, which were administered intraperitoneally with 180 mg kg,1 nicotinamide (NA) 30 min before an intravenous injection of 50 mg kg,1 streptozotocin (STZ). After induction of diabetes mellitus type 2, animals receiving daily peritoneal injections with 50 mg kg,1 AG for 8 weeks were compared with the age-matched, untreated, diabetic controls. Results, After exposure to AG, the STZ-NA diabetic rats had improved aortic distensibility, as evidenced by 18·8% reduction of aortic characteristic impedance (P < 0·05). Treatment of the experimental syndrome with AG also resulted in a significant increase in wave transit time (+23·7%, P < 0·05) and a decrease in wave reflection factor (,26·6%, P < 0·05), suggesting that AG may prevent the NIDDM-induced augmentation in systolic load of the left ventricle. Also, the glycation-derived modification on aortic collagen was found to be retarded by AG. The diminished ratio of left ventricular weight to body weight suggested that prevention of the diabetes-related cardiac hypertrophy by AG may correspond to the drug-induced decline in aortic stiffening. Conclusions, Long-term administration of AG to the STZ-NA diabetic rats imparts significant protection against the NIDDM-derived impairment in vascular dynamics, at least partly through inhibition of the AGE accumulation on collagen in the arterial wall. [source] Long-term administration of IgG2a anti-NK1.1 monoclonal antibody ameliorates lupus-like disease in NZB/W mice in spite of an early worsening induced by an IgG2a-dependent BAFF/BLyS productionIMMUNOLOGY, Issue 2 2008Edilberto Postól Summary The role of natural killer (NK) T cells in the development of lupus-like disease in mice is still controversial. We treated NZB/W mice with anti-NK1.1 monoclonal antibodies (mAbs) and our results revealed that administration of either an irrelevant immunoglobulin G2a (IgG2a) mAb or an IgG2a anti-NK1.1 mAb increased the production of anti-dsDNA antibodies in young NZB/W mice. However, the continuous administration of an anti-NK1.1 mAb protected aged NZB/W mice from glomerular injury, leading to prolonged survival and stabilization of the proteinuria. Conversely, the administration of the control IgG2a mAb led to an aggravation of the lupus-like disease. Augmented titres of anti-dsDNA in NZB/W mice, upon IgG2a administration, correlated with the production of BAFF/BLyS by dendritic, B and T cells. Treatment with an anti-NK1.1 mAb reduced the levels of interleukin-16, produced by T cells, in spleen cell culture supernatants from aged NZB/W. Adoptive transfer of NK T cells from aged to young NZB/W accelerated the production of anti-dsDNA in recipient NZB/W mice, suggesting that NK T cells from aged NZB/W are endowed with a B-cell helper activity. In vitro studies, using purified NK T cells from aged NZB/W, showed that these cells provided helper B-cell activity for the production of anti-dsDNA. We concluded that NK T cells are involved in the progression of lupus-like disease in mature NZB/W mice and that immunoglobulin of the IgG2a isotype has an enhancing effect on antibody synthesis due to the induction of BAFF/BLyS, and therefore have a deleterious effect in the NZB/W mouse physiology. [source] Long-term administration of Salvia miltiorrhiza ameliorates carbon tetrachloride-induced hepatic fibrosis in ratsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 11 2003Tzung-Yan Lee ABSTRACT Carbon tetrachloride (CCl4) is metabolized by cytochrome P450 to form a reactive trichloromethyl radical that triggers a chain of lipid peroxidation. These changes lead to cell injury, and chronic liver injury leads to excessive deposition of collagen in liver, resulting in liver fibrosis. The aim of this study was to evaluate the effects of long-term Salvia miltiorrhiza administration in CCl4 -induced hepatic injury in rats. Salvia miltiorrhiza (10, 25 or 50 mg kg,1 twice a day) was given for 9 weeks, beginning at the same time as the injections of CCl4. Rats receiving CCl4 alone showed a decreased hepatic glutathione level and an increased glutathione-S-transferase content. The hepatic thiobarbituratic acid-reactive substance levels were increased. CCl4 also caused a prominent collagen deposition in liver histology that was further supported by the increased hepatic mRNA expression of transforming growth factor-,1, tissue inhibitor of metallproteinase-1 and procollagen I. Salvia miltiorrhiza administration led to a dose-dependent increase in hepatic glutathione levels and a decrease in peroxidation products. Additionally, it reduced the mRNA expression of markers for hepatic fibrogenesis. In conclusion, long-term administration of Salvia miltiorrhiza in rats ameliorated the CCl4 -induced hepatic injury that probably related to a reduced oxidant stress and degree of hepatic fibrosis. [source] Long-term effect of tacrolimus therapy in patients with refractory ulcerative colitisALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 5 2008S. YAMAMOTO Summary Background, Little is known about long-term outcome of tacrolimus therapy for ulcerative colitis. Aim, To evaluate long-term efficacy and safety of tacrolimus in Japanese patients with refractory ulcerative colitis. Methods, Twenty-seven patients with UC refractory to conventional therapy were administered tacrolimus with trough whole-blood levels of 10,15 ng/mL to induce remission and 5,10 ng/mL to maintain remission. Median treatment duration was 11 months (1,39 months) and median follow-up duration was 17 months (2,65 months). Evaluation of the clinical response was based on a modified Truelove,Witts severity index (MTWSI). Results, Tacrolimus produced a clinical response in 21 patients (77.8%), and remission was achieved in 19 of these 21 (70.4%) within 30 days. Overall cumulative colectomy-free survival was estimated as 62.3% at 65 months. In 18 of 19 patients treated with corticosteroids at the initiation of tacrolimus therapy, corticosteroids were discontinued or tapered. Adverse events were tremor (25.9%), renal function impairment (18.5%), infectious disease (14.8%), hot flashes (11.1%), hyperkalaemia (7.4%), headache (7.4%), epigastralgia (7.4%) and nausea (3.7%). No mortality occurred. Conclusion, Long-term administration of tacrolimus appears to be an effective and well-tolerated treatment for Japanese patients with refractory ulcerative colitis. [source] Norfloxacin decreases bacterial adherence of quinolone-resistant strains of Escherichia coli isolated from patients with cirrhosisALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 6 2005I. Gascón Summary Background:, Long-term administration of norfloxacin is recommended for secondary prophylaxis of spontaneous bacterial peritonitis in cirrhosis, but it may be associated with the development of quinolone-resistant bacteria in stools. However, these bacteria rarely cause infections. Aim:, To assess bacterial adherence of either quinolone-sensitive or -resistant Escherichia coli obtained from stools of cirrhotic patients, as one of the main virulence factors, and its variations when sub-minimum inhibitory concentration of norfloxacin were added to the medium. Methods:,E. coli strains were co-cultured with oral epithelial cells obtained from patients in presence/absence of norfloxacin. Bacterial adherence was measured as percentage of cells exhibiting positive adherence and the number of bacteria attached to epithelial cells. Results:, 37 sensitive and 22 resistant E. coli strains were studied. Bacterial adherence was similar in both series (78% vs. 81%, P = N.S.), and these percentages were similarly and significantly reduced when subminimum inhibitory concentration of norfloxacin was added to the culture medium (P < 0.001). Conclusions:, Bacterial adherence of E. coli obtained from patients with cirrhosis is unrelated to the sensitivity/resistance to quinolones, and is similarly reduced in both cases when subminimum inhibitory concentration of norfloxacin is added to the medium. [source] Disparate osteogenic response of mandible and iliac crest bone marrow stromal cells to pamidronateORAL DISEASES, Issue 5 2008D Stefanik Objective:, Long-term administration of intravenous bisphosphonates like pamidronate is associated with jaw osteonecrosis but axial and appendicular bones remain unaffected. Pathogenesis of bisphosphonate-associated jaw osteonecrosis may relate to skeletal site-specific effects of bisphosphonates on osteogenic differentiation of bone marrow stromal cells (BMSCs) of orofacial and axial,/,appendicular bones. This study evaluated and compared skeletal site-specific osteogenic response of mandible (orofacial bone) and iliac crest (axial bone) human BMSCs to pamidronate. Materials and methods:, Mandible and iliac crest BMSCs from six normal healthy volunteers were established in culture and tested with pamidronate to evaluate and compare cell survival, osteogenic marker alkaline phosphatase, osteoclast differentiation in co-cultures with CD34+ hematopoietic stem cells, gene expression of receptor activator of NF,B ligand (RANKL) and osteoprotegerin, and in vivo bone regeneration. Results:, Mandible BMSCs were more susceptible to pamidronate than iliac crest BMSCs based on decreased cell survival, lower alkaline phosphatase production, and structurally less organized in vivo bone regeneration. Pamidronate promoted higher RANKL gene expression and osteoclast recruitment by mandible BMSCs. Conclusion:, Mandible and iliac crest BMSC survival and osteogenic differentiation are disparately affected by pamidronate to favor dysregulated mandible bone homeostasis. [source] Caspase-1/interleukin-1beta signaling in diabetic retinopathyACTA OPHTHALMOLOGICA, Issue 2008S MOHR Purpose The pro-inflammatory cytokine, interleukin-1, (IL-1,), is known to induce vascular dysfunction and cell death. Previously, we have shown that caspase-1 activity is increased in retinas of diabetic and galactosemic mice, and diabetic patients. Therefore, we investigated the role of IL-1, and caspase-1 (the enzyme that produces it) in diabetes-induced degeneration of retinal capillaries. Methods First, we determined the effect of agents known to inhibit caspase-1 (minocycline and tetracycline) on IL-1, production and retinal capillary degeneration in diabetic and galactose-fed mice. Diabetic and galactose-fed mice were injected intraperitoneally with minocycline or tetracycline (5mg/kg). Second, we examined the effect of genetic deletion of the IL-1, receptor on diabetes-induced caspase activities and retinal capillary degeneration using IL-1 receptor knock-out mice. Results At 2 months of diabetes, minocycline inhibited hyperglycemia-induced caspase-1 activity and IL-1, production in the retina. Long-term administration of minocycline prevented retinal capillary degeneration in diabetic (6 months) and galactose-fed (13 months) mice. Tetracycline inhibited hyperglycemia-induced caspase-1 activity in vitro, but not in vivo. Mice deficient in the IL-1, receptor were protected from diabetes-induced caspase activation and retinal pathology at 7 months of diabetes. Conclusion These results indicate that the caspase-1/IL-1, signaling pathway plays an important role in diabetes-induced retinal pathology and its inhibition might represent a new strategy to inhibit capillary degeneration in diabetic retinopathy. [source] PRECLINICAL STUDY: Long-term haloperidol treatment (but not risperidone) enhances addiction-related behaviors in mice: role of dopamine D2 receptorsADDICTION BIOLOGY, Issue 3 2009Rita C. Carvalho ABSTRACT The high prevalence of psychostimulant abuse observed in schizophrenic patients may be related to the development of mesolimbic dopaminergic supersensitivity (MDS) or nigrostriatal dopaminergic supersensitivity (NDS) in response to the chronic blockade of dopamine receptors produced by typical neuroleptic treatment. We compared the effects of withdrawal from long-term administration of the typical neuroleptic haloperidol (Hal) and/or the atypical agent risperidone (Ris) on MDS and NDS, behaviorally evaluated by amphetamine-induced locomotor stimulation (AILS) and apomorphine-induced stereotypy (AIS) in mice, respectively. We further evaluated the duration of MDS and investigated the specific role of dopamine D2 receptors in this phenomenon by administering the D2 agonist quinpirole (Quin) to mice withdrawn from long-term treatment with these neuroleptics. Withdrawal (48 hours) from long-term (20 days) Hal (0.5 mg/kg i.p.) (but not 0.5 mg/kg Ris i.p.) treatment potentiated both AILS and AIS. Ris co-administration abolished the potentiation of AILS and AIS observed in Hal-withdrawn mice. Ten days after withdrawal from long-term treatment with Hal (but not with Ris or Ris + Hal), a potentiation in AILS was still observed. Only Hal-withdrawn mice presented an attenuation of locomotor inhibition produced by Quin. Our data suggest that the atypical neuroleptic Ris has a pharmacological property that counteracts the compensatory MDS and NDS developed in response to the chronic blockade of dopamine receptors imposed by Ris itself or by typical neuroleptics such as Hal. They also indicate that MDS may be long lasting and suggest that an upregulation of dopamine D2 receptors in response to long-term treatment with the typical neuroleptic is involved in this phenomenon. [source] Practical guidelines for treating inflammatory bowel disease safely with anti-tumour necrosis factor therapy in AustraliaINTERNAL MEDICINE JOURNAL, Issue 2 2010W. Connell Abstract Anti-tumour necrosis factor (TNF) therapy is an effective but expensive option for treating inflammatory bowel disease (IBD). Its use is generally reserved for patients with severe refractory disease, often involving long-term administration. Anti-TNF therapy has the potential to be associated with various adverse effects, such as infection, malignancy and immunogenicity. Clinicians and patients should be familiar with these possibilities and adopt appropriate precautions prior to and during treatment to minimize risk. Guidelines have been developed for Australian prescribers intending to use anti-TNF therapy in IBD by a Working Party commissioned by IBD-Australia, a Special Interest Group affiliated with the Gastroenterology Society of Australia. [source] Therapeutic effects of long-term administration of an oral adsorbent in patients with chronic renal failure: two-year studyINTERNATIONAL JOURNAL OF UROLOGY, Issue 1 2005NOBUYOSHI TAKAHASHI Abstract Background:, Kremezin is an oral adsorbent that attenuates the progression of chronic renal failure by removing uremic toxins and their precursors from the gastrointestinal tract. Previously two clinical studies based on reciprocal serum creatinine levels (1/Scr) have confirmed the efficacy of Kremezin (Kureha Chemical, Tokyo, Japan) in undialyzed patients who had been followed up for 6 months or 1 year. This is the first report to evaluate the therapeutic effects of long-term administration (2 years.) of Kremezin in undialyzed patients. Methods:, Kremezin was given to 48 enrolled undialyzed patients with a median Scr level of 4.3 mg/dL. Rates of decline of 1/Scr, as well as the time for Scr level to reach 10 mg/dL, the critical value requiring dialysis, were compared before and after administration of Kremezin. Results:, During the 2-year therapeutic period, 1/Scr gradients were significantly attenuated (P = 0.0083), and the estimated time to dialysis was prolonged from 16.3 ± 16.3 months to 29.8 ± 24.1 months (P = 0.002). When the patients were divided into two groups, based on of systolic blood pressure (SBP), defined by the World Health Organization (WHO) classification, a significantly smaller number of patients in the low blood pressure group (SBP < 160 mmHg) were introduced to dialysis (P = 0.0005), and the estimated time to dialysis was significantly extended in the low blood pressure group (P = 0.0125). Conclusion:, In addition to the control of blood pressure in undialyzed patients, Kremezin has additive salutary effects to halt the progressive loss of renal function, resulting in the delay of dialysis. [source] One-year dog toxicity study of D-002, a mixture of aliphatic alcoholsJOURNAL OF APPLIED TOXICOLOGY, Issue 3 2001Celia Alemán Abstract D-002 is a mixture of high-molecular-weight aliphatic alcohols, obtained from bees wax (Apis mellifera), with mild anti-inflammatory properties and effective anti-ulcer activities demonstrated in experimental models. This study investigated the oral toxicity of D-002 administered for 1 year to beagle dogs. Twenty-four beagle dogs (12 males and 12 females) were distributed randomly in three experimental groups (four animals per group): a control and two treated groups received D-002 at 50 and 250 mg kg,1 (7 days/week) by gastric gavage. Overall, D-002 was well tolerated throughout the study. No signs or symptoms of toxicity were observed, and no mortality occurred during the study. All groups showed similar weight gain and food consumption. No hematological, blood biochemical or histopathological disturbances attributable to treatment were observed. This study shows no drug-related toxicity induced by long-term administration of up to 250 mg kg,1 D-002 to beagle dogs. Copyright © 2001 John Wiley & Sons, Ltd. [source] FGF-23 Is a Potent Regulator of Vitamin D Metabolism and Phosphate Homeostasis,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 3 2004Takashi Shimada Abstract We analyzed the effects of an FGF-23 injection in vivo. FGF-23 caused a reduction in serum 1,25-dihydroxyvitamin D by altering the expressions of key enzymes for the vitamin D metabolism followed by hypophosphatemia. This study indicates that FGF-23 is a potent regulator of the vitamin D and phosphate metabolism. Introduction: The pathophysiological contribution of FGF-23 in hypophosphatemic diseases was supported by animal studies in which the long-term administration of recombinant fibroblast growth factor-23 reproduced hypophosphatemic rickets with a low serum 1,25-dihydroxyvitamin D [1,25(OH)2D] level. However, there is no clear understanding of how FGF-23 causes these changes. Materials and Methods: To elucidate the molecular mechanisms of the FGF-23 function, we investigated the short-term effects of a single administration of recombinant FGF-23 in normal and parathyroidectmized animals. Results: An injection of recombinant FGF-23 caused a reduction in serum phosphate and 1,25(OH)2D levels. A decrease in serum phosphate was first observed 9 h after the injection and was accompanied with a reduction in renal mRNA and protein levels for the type IIa sodium-phosphate cotransporter (NaPi-2a). There was no increase in the parathyroid hormone (PTH) level throughout the experiment, and hypophosphatemia was reproduced by FGF-23 in parathyroidectomized rats. Before this hypophosphatemic effect, the serum 1,25(OH)2D level had already descended at 3 h and reached the nadir 9 h after the administration. FGF-23 reduced renal mRNA for 25-hydroxyvitamin D-1,-hydroxylase and increased that for 25-hydroxyvitamin D-24-hydroxylase starting at 1 h. In addition, an injection of calcitriol into normal mice increased the serum FGF-23 level within 4 h. Conclusions: FGF-23 regulates NaPi-2a independently of PTH and the serum 1,25(OH)2D level by controlling renal expressions of key enzymes of the vitamin D metabolism. In conclusion, FGF-23 is a potent regulator of phosphate and vitamin D homeostasis. [source] Effects of long-term administration of N-3 polyunsaturated fatty acids (PUFA) and selective estrogen receptor modulator (SERM) derivatives in ovariectomized (OVX) miceJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 2 2003L. Zeitlin Abstract We studied the beneficial effects of dietary consumption of n-3 polyunsaturated fatty acids (PUFA) and two selective estrogen receptor modulator (SERM) derivatives (SERM-I and SERM-II) and their combined effect on serum lipids, skin dermis and adipose layers, bone marrow adipogenesis, and cytokine secretion in mice. Two different ovariectomized (OVX) models were studied: treatment began immediately post-OVX in one and 3 months post-OVX in the other. Our results showed that n-3 PUFA and both SERMs decreased triglyceride levels in the serum, and that SERMs also decreased serum cholesterol levels while n-3 PUFA had no similar effect. SERMs had no effect on IL-6, IL-1 beta, or IL-10 levels, but they decreased ex vivo tumor necrosis factor (TNF-,). N-3 PUFA decreased secretion of non-induced IL-6 and TNF-, from cultured BMC and IL-1 beta levels in vivo (i.e., in bone marrow plasma), but its main effect was a significant elevation in the secretion of IL-10, a known anti-inflammatory cytokine. OVX-induced B-lymphopoiesis was not affected by LY-139481 (SERM-I) while LY-353381 (SERM-II) exhibited an estrogen-antagonistic effect in sham and OVX mice and elevated the amount of B-cells in bone marrow. Fish oil consumption prevented the elevation in B-lymphopoiesis caused by OVX, but had no curative effect on established augmented B-lymphopoiesis. This activity could be mediated via the elevation of IL-10 which was shown to suppress B-lymphopoiesis. Both SERMs and n-3 PUFA inhibited the increase in adipose tissue thickness caused by OVX in mice. Our results showed that n-3 PUFA, could prevent some of the deleterious outcomes of estrogen deficiency that were not affected by SERMs. We observed no significant beneficial effects of the combined administration of SERM-I, SERM-II, and PUFA on the studied parameters. The exact mechanism by which polyunsaturated fatty acids exert their activities is still not clear, but peroxisome proliferator-activated receptors (PPARs) might be involved in processes which are modulated by n-3 PUFA. J. Cell. Biochem. 90: 347,360, 2003. © 2003 Wiley-Liss, Inc. [source] Troglitazone prevents fatty changes of the liver in obese diabetic ratsJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 10 2000Dong Mei Jia Abstract Background and Aims: Troglitazone is a newly developed antidiabetic drug and is indicated to be useful for the treatment of patients with type II diabetes mellitus. Recently, however, it became clear that troglitazone could cause liver dysfunction in some patients. In addition, a relationship between the activation of the peroxisome proliferator-activated receptor gamma receptor by troglitazone and colon tumorigenesis has been suggested. The present study was undertaken to examine the effects of long-term administration of troglitazone on the liver and intestine in genetically obese and diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) and control Long-Evans Tokushima Otsuka (LETO) rats. Methods: A troglitazone-rich diet (200 mg/100 g normal chow) or a standard rat chow, free of troglitazone (control), was given to OLETF and LETO rats from 12 or 28 weeks of age until 72 weeks of age. Serum levels of glucose, insulin, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were determined at several time points. In addition, histology of the liver and intestine and serum levels of cholesterol and triglycerides were examined at 72 weeks of age. Results: Troglitazone prevented age-related increases in fasting glucose and insulin concentrations in OLETF rats, but had no significant influences on serum levels of AST and ALT in both strains of rats. The liver weights in the control OLETF rats were significantly heavier than in the LETO rats. Troglitazone significantly reduced serum cholesterol and triglyceride levels and the liver weight. However, it had no influence on the large intestine weight and the number of colonic polyps in both OLETF and LETO rats. Sections of the liver from the untreated OLETF rats showed mild fatty changes in the central zone of the hepatic lobule, whereas those from the troglitazone-treated OLETF rats appeared normal with no fat deposition in the hepatocytes. Troglitazone in LETO rats also caused no significant histopathologic changes of the liver tissue. Conclusion: Our present study demonstrated that long-term administration of troglitazone prevents the progress of the metabolic derangement and fatty changes of the liver in genetically determined obese diabetes. [source] Activity of the Chinese prescription Hachimi-jio-gan against renal damage in the Otsuka Long-Evans Tokushima Fatty rat: a model of human type 2 diabetes mellitusJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 4 2006Noriko Yamabe Currently, in Japan, approximately 95% of patients with diabetes mellitus have non-insulin-dependent (type 2) diabetes mellitus (NIDDM), and diabetic nephropathy is a major cause of patients requiring chronic haemodialysis. A previous study showed that Hachimi-jio-gan has a protective effect in rats subjected to subtotal nephrectomy plus streptozotocin injection, a model of insulin-dependent (type 1) diabetic nephropathy. In this study, we used the Otsuka Long-Evans Tokushima Fatty (OLETF) rat, a model of human NIDDM, to investigate whether long-term administration of Hachimi-jio-gan affects glycaemic control and renal function in NIDDM. Male OLETF rats, aged 22 weeks, were divided into 4 groups of 10 and given Hachimi-jio-gan (50, 100 or 200 mg kg,1 daily) orally or no treatment for 32 weeks. Male Long-Evans Tokushima Otsuka (LETO) rats (n = 6) were used as non-diabetic normal controls. Hachimi-jio-gan reduced hyperglycaemia dose-dependently from 16 weeks of the administration period. Urinary protein excretion decreased significantly from an early stage, and creatinine clearance levels improved at 32 weeks. In addition, the levels of serum glycosylated protein and renal advanced glycation end-products were effectively reduced. Hachimi-jio-gan also significantly reduced the levels of thiobarbituric acid-reactive substances in renal mitochondria, although it showed only a tendency to reduce these in serum. Furthermore, long-term administration of Hachimi-jio-gan reduced renal cortical expression of proteins, such as transforming growth factor-,1 (TGF-,1), fibronectin, inducible nitric oxide synthase and cyclooxygenase-2. The 100- and 200-mg kg,1 daily doses of Hachimi-jio-gan significantly reduced TGF-,1 and fibronectin protein expression to levels below those of LETO rats. These data suggest that Hachimi-jio-gan may have a beneficial effect on the progression of diabetic nephropathy in OLETF rats by attenuating glucose toxicity and renal damage. [source] Long-term administration of Salvia miltiorrhiza ameliorates carbon tetrachloride-induced hepatic fibrosis in ratsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 11 2003Tzung-Yan Lee ABSTRACT Carbon tetrachloride (CCl4) is metabolized by cytochrome P450 to form a reactive trichloromethyl radical that triggers a chain of lipid peroxidation. These changes lead to cell injury, and chronic liver injury leads to excessive deposition of collagen in liver, resulting in liver fibrosis. The aim of this study was to evaluate the effects of long-term Salvia miltiorrhiza administration in CCl4 -induced hepatic injury in rats. Salvia miltiorrhiza (10, 25 or 50 mg kg,1 twice a day) was given for 9 weeks, beginning at the same time as the injections of CCl4. Rats receiving CCl4 alone showed a decreased hepatic glutathione level and an increased glutathione-S-transferase content. The hepatic thiobarbituratic acid-reactive substance levels were increased. CCl4 also caused a prominent collagen deposition in liver histology that was further supported by the increased hepatic mRNA expression of transforming growth factor-,1, tissue inhibitor of metallproteinase-1 and procollagen I. Salvia miltiorrhiza administration led to a dose-dependent increase in hepatic glutathione levels and a decrease in peroxidation products. Additionally, it reduced the mRNA expression of markers for hepatic fibrogenesis. In conclusion, long-term administration of Salvia miltiorrhiza in rats ameliorated the CCl4 -induced hepatic injury that probably related to a reduced oxidant stress and degree of hepatic fibrosis. [source] Consistent control of psoriasis by continuous long-term therapy: the promise of biological treatmentsJOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY & VENEREOLOGY, Issue 6 2006PCM Van De Kerkhof Abstract Psoriasis is a chronic, incurable disease that frequently requires long-term treatment. Although many patients benefit from effective traditional systemic therapies, namely methotrexate, cyclosporin, retinoids and fumaric acid esters, and some patients achieve long-term disease control, unrestricted long-term administration is not recommended due to the potential for cumulative toxicity. In order to diminish the risk of toxicity, physicians have adopted various treatment approaches (e.g. rotational, sequential, intermittent, and combination). However, these approaches may not provide continuous disease control or a stable treatment regimen. The recent advent of targeted biological therapeutics such as etanercept, infliximab, adalimumab, alefacept and efalizumab may offer physicians and their patients treatment options with improved safety profiles that may permit continuous disease control. [source] Treatment of hepatitis DJOURNAL OF VIRAL HEPATITIS, Issue 1 2005G. A. Niro Summary., Delta virus related chronic hepatitis is difficult to treat. The response to , -interferon (IFN), which still represents the only therapy for chronic hepatitis D, varies widely and occurs at different times from the beginning of treatment. The rate of response is proportional to the dose of IFN, with 9 million units (MU) three times a week being more effective than 3 MU thrice weekly. Sustained responses are unusual and are accompanied by the clearance of serum hepatitis B virus surface antigen (HBsAg), seroconversion to anti-HBs and improvement of liver histology. Although disease of a short-standing may respond better to therapy, clear predictors of response are still unidentified. Besides IFN, other therapeutic approaches such as immunosuppressive drugs, acyclovir, ribavirin and thymosin, have been unhelpful. Available evidence does not support the use of deoxynucleotide analogues. Famciclovir has no effect on disease activity and hepatitis D virus (HDV)-RNA levels. Twelve- or 24-month lamivudine treatment does not significantly affect biochemical, virological or histological parameters. Pegylated-IFN could represent a reasonable therapeutic option in the long-term treatment required for chronic hepatitis D. Antisense oligonucleotides and prenylation inhibitors hold promise as therapeutic agents of the future. Liver transplantation provides a valid option for end-stage HDV liver disease; the risk of re-infection is lower for HDV than for HBV under long-term administration of hyperimmune serum against HBsAg. Molecularly tailored drugs capable of interfering with crucial viral replicative processes of HDV appear to be the best prospect in the treatment of hepatitis D. [source] Long-term oral branched chain amino acids in patients undergoing chemoembolization for hepatocellular carcinoma: a randomized trialALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 7 2004R. T.-P. Summary Background :,Patients undergoing transarterial chemoembolization for hepatocellular carcinoma have advanced tumour or severe cirrhosis and frequently have associated protein-calorie malnutrition. The role of nutritional supplements for such patients is unclear. Aim :,To investigate, in a randomized controlled trial, any benefit of the long-term administration of branched chain amino acids in patients undergoing chemoembolization for hepatocellular carcinoma. Methods :,Forty-one patients received oral branched chain amino acids for up to four courses of chemoembolization and 43 patients did not receive any nutritional supplement. Morbidity, liver function, nutritional status, quality of life and long-term survival were compared between the two groups. Results :,The administration of branched chain amino acids resulted in a lower morbidity rate compared with the control group (17.1% vs. 37.2%, P = 0.039). In particular, the group given branched chain amino acids showed a significantly lower rate of ascites (7.3% vs. 23.2%, P = 0.043) and peripheral oedema (9.8% vs. 27.9%, P = 0.034). Significantly higher serum albumin, lower bilirubin and a better quality of life were observed after chemoembolization in the group given branched chain amino acids. However, there was no significant difference in survival between the two groups. Conclusions :,Nutritional supplementation with oral branched chain amino acids is beneficial in increasing the serum albumin level, reducing the morbidity and improving the quality of life in patients undergoing chemoembolization for inoperable hepatocellular carcinoma. [source] Updates on bisphosphonates and potential pathobiology of bisphosphonate-induced jaw osteonecrosisORAL DISEASES, Issue 3 2008J Sarin Osteonecrosis of the jaws is a major complication associated with long-term use of bisphosphonates. While osteonecrosis can arise from other precipitating conditions, bisphosphonate-induced jaw osteonecrosis (BJON) is highly associated with long-term administration of pamidronate (Aredia®) and zoledronic acid (Zometa®), which are two intravenous bisphosphonate formulations. The underlying pathogenesis of BJON and its site-specific presentation still remain to be fully elucidated. This review will discuss clinically available bisphosphonates, current opinions, pathogenesis, and management guidelines for bisphosphonate-induced jaw osteonecrosis. [source] Anti-inflammatory treatment for recurrent wheezing in the first five years of lifePEDIATRIC PULMONOLOGY, Issue 4 2003Athanasios G. Kaditis MD Abstract Medications identified for the treatment of recurrent wheezing in preschool children by the Expert Panel Report of the NHLBI Guidelines for the Diagnosis and Management of Asthma include inhaled corticosteroids, chromones, theophylline, and leukotriene pathway modifiers. However, these various agents differ in their mechanism, extent of action on the airway inflammatory process, and degree of clinical efficacy. Inhaled corticosteroids can control symptoms in many young children with even severe persistent wheezing, but data on their long-term safety when administered in preschool-age children are scarce. There is some information on the uninterrupted use of inhaled corticosteroids in school-age children and the absence of an adverse effect on ultimate adult height. Despite laboratory evidence of adrenal suppression in some studies, few pediatric cases of clinical adrenal insufficiency have been reported. Low-dose inhaled corticosteroid (<400 mcg/day for beclomethasone), which is adequate for controlling mild persistent symptoms, is generally safe. Chromones have a remarkable safety profile, but they are most effective for symptoms of mild severity. Promising data have been published on the efficacy and safety of leukotriene pathway modifiers when used in young children with persistent symptoms. It is uncertain whether early introduction and long-term administration of inhaled corticosteroids prevent development of irreversible airway obstruction. Nevertheless, they may be especially useful for patients with moderate to severe disease in whom other agents (chromones or leukotriene pathway modifiers) will most likely fail to control symptoms. Pediatr Pulmonol. 2003; 35:241,252. © 2003 Wiley-Liss, Inc. [source] Immune response, growth and survival of Labeo rohita fingerlings fed with levamisole supplemented diets for longer durationAQUACULTURE NUTRITION, Issue 4 2009C.K. MISRA Abstract The study was to determine the effect of long-term administration of different dosages of levamisole on growth, immune response and disease resistance against Aeromonas hydrophila & Edwardsiella tarda in Labeo rohita fingerlings. Fish were fed with four different dosages of levamisole (0, 125, 250 and 500 mg kg,1 diet) for 56 days. Different serum biochemical and haematological parameters such as serum total protein content, albumin content, globulin content, albumin/globulin ratio, glucose content, leucocytes count; cellular immune parameters including superoxide anion production, phagocytic activities, lymphokine production index; humoural immune parameters including lysozyme, complement and serum bactericidal activities were evaluated after 14 days interval. After 56 days, fish were divided into two subgroups under each treatment group for challenge with pathogens A. hydrophila and E. tarda. The cumulative mortality (%) and agglutinating antibody titre was recorded on 28th day postchallenge. WBC count, phagocytic ratio, lymphokine production index, lysozyme activity and serum bactericidal activity were increased upon administration of levamisole dosages for long term. However, the growth performance and survival against pathogens was not significantly changed over 56 days administration of levamisole. But incorporation of moderate dosage of levamisole for 42 days results better immune response without effect on growth and survival of L. rohita fingerlings. [source] Pharmacokinetic interaction of ketoconazole and itraconazole with ciprofloxacinBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 1 2008Hisham S. Abou-Auda Abstract The effect of the concomitant administration of the antifungal drugs ketoconazole (KTC) and itraconazole (ITC) on the pharmacokinetics of ciprofloxacin (CIP) following short- and long-term administration in mice was investigated. Animals received either a dose of CIP (20,mg/kg, i.p.), CIP (20,mg/kg, i.p.) together with KTC (50,mg/kg, p.o.) or CIP (20,mg/kg, i.p.) and ITC (30,mg/kg, p.o.). The same treatments were repeated for 7 days. Blood samples were collected up to 4,h following drug administration and two urine samples were collected at 2,h and 4,h after drug administration. CIP plasma concentrations were significantly higher in KTC- and ITC-treated groups compared with the corresponding control groups. The concomitant administration of KTC or ITC with CIP also significantly (p<0.05) increased Cmax, t1/2, MRT and AUC0,, with no change in Tmax. CIP clearance was significantly reduced by both agents. KTC and ITC reduced CIP urinary excretion. This study suggests that an important pharmacokinetic interaction between CIP and KTC or ITC is likely to occur when either of the two antifungal drugs is administered concomitantly with CIP. The results may suggest possible reductions in total clearance of CIP, owing to inhibition of its renal tubular excretion by KTC and ITC. Copyright © 2007 John Wiley & Sons, Ltd. [source] Nonstationary disposition of valproic acid during prolonged intravenous infusion: contributions of unbound clearance and protein bindingBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 6 2001Tori L. Arens Abstract Circadian variations in disposition have been observed for a variety of agents, including anticonvulsants. Valproic acid (VPA), an anticonvulsant used to control generalized and partial seizures, has exhibited diurnal oscillations in steady-state concentrations during long-term administration to humans and non-human primates. The present study was conducted to assess potential diurnal changes in the disposition of VPA during prolonged i.v. infusion in rats. Animals, maintained on a strict 12-h per day light cycle, were equipped with venous cannulae and an arterial microdialysis probe. VPA was administered as a 50-mg/kg loading dose followed by a 42 mg/kg/h infusion for 70 h. Blood and microdialysate samples were obtained at timed intervals after establishment of steady-state throughout two complete light/dark cycles; and total (serum) and unbound (microdialysate) VPA was determined by gas chromatography. Modest oscillations (6,7 h period) in total and unbound VPA were observed; clearance and binding parameters were not different between light and dark periods. However, unbound clearance increased, and unbound fraction decreased, with time over the course of the infusion. These results suggest that time-dependent changes in VPA disposition occur in rats, although oscillations in steady-state concentrations do not appear to be diurnal in nature. Copyright © 2001 John Wiley & Sons, Ltd. [source] Low incidence of hypertensive disorders of pregnancy in women treated with spiramycin for toxoplasma infectionBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 3 2006T. Todros Aims Toxoplasma infection in pregnancy is usually treated with long-term administration of the macrolide spiramycin to prevent fetal malformations. We had empirically observed that treated patients seldom developed pregnancy-induced hypertension (PIH), a common and severe disorder of pregnancy whose aetiology and pathogenesis are still debated. Some clinical and experimental data suggest that infection could play a role in its development. Methods To test this hypothesis, we studied a cohort of 417 pregnant women treated with spiramycin because of seroconversion for Toxoplasma gondii and 353 low-risk women who did not take any antibiotic during pregnancy. PIH was defined as blood pressure >140/90 mmHg on two or more occasions, occurring after 20 weeks of gestational age. Results Seventeen (5.2%) women in the control group developed PIH compared with two (0.5%) in the case group. The odds of developing the disease were significantly lower in the treated subjects (odds ratio =,0.092, 95% confidence interval 0.021, 0.399; P < 0.001). Conclusions Our results suggest that antibiotic treatment during pregnancy can reduce the incidence of PIH, thus opening new perspectives in its prevention and therapy. [source] | |||||||||||||||||||||||||||||||