Effect of l-carnitine and deferoxamine on hepatotoxicity, erythrocyte ergothioneine and testicular testosterone synthesis in sodiumvalproate-treated rats

The aim of the present study was to evaluate the effect of sodium valproate [VPA] as anantiepileptic drug on liver and erythrocyte oxidative state and on testicular testosterone synthesis. The therapeuticefficacy of either L-carnitine or deferoxamine [DFO] was assessed in such situations. This study included 108 albino rats divided into control groups, single dose VPA treated groups withand without L-carnitine or DFO treatment and repeated dose VPA treated groups with and without L-carnitine orDFO treatment. Liver triglycerides and malondialdehyde levels and catalase and glutathione S transferaseactivities as well as erythrocyte ergothioneine were estimated. In testes, P450cl7 and 17/3 hydroxysteroiddehydrogenase activities were measured as testosterone synthesis. Single and repeated VPA administration caused an increase in liver triglycerides, malondialdehyde,catalase and glutathione S transferase and a decrease in erythrocyte ergothioneine. Only repeated VPAadministration could decrease testicular testosterone synthesis. Co-administration of L-carnitine or DFO withVPA resulted in improvement of all the studied parameters. These data support the oxidative stress as a possible mechanism implicated in VPA-induced liver anderythrocyte damage. Moreover, VPA could alter testosterone synthesis giving a possible link between malereproductive function and VPA. The protective influence of L-carnitine and DFO may be partly mediated by theirantioxidant effects and by improving gonadal testosterone synthesi

Effect of selective and non-selective cyclooxygenase inhibitors on survival, platelet function and vein wall inflammation in a rat model of deep vein thrombosis

Worldwide, the withdrawal of rofecoxib and valdecoxib from the United State, Australian and European markets with substantial decline in the number of prescriptions for celecoxib attract attention. Inhibition of vascular synthesis of prostacyclin [PGI[2]] leaving platelet thromboxane A[2][TXA[2] synthesis unopposed is thought to increase risk ofthrombotic events. To decrease this risk, adding low aspirin has been suggested. In the present study, we compared celecoxib alone and with low-dose aspirin to indomethacin and to low-dose aspirin regarding the effects on survival, platelet function and vein wall inflammation in a rat model of deep vein thrombosis [DVT] induced by 3 days inferior vena cava ligation.The results showed significant decline in rate of survival in the celecoxib group and enhanced thrombogenesis compared to aspirin and indomethacin. Co-administration of low dose aspirin significantly reduced wet thrombus weight compared to celecoxib monotherapy. Platelet function was assessed by bleeding time and two platelet proteins released into plasma from a granules during platelet activation namely platelet factor 4 [PF4] and micro 3-thromboglobulin [f]-TG]. In the celecoxib group, bleeding time was not altered while plasma PF4 and /beta-TG were high compared to sham group. The level of these platelet markers in celecoxib group was comparable to the DVT group denoting significant platelet activation. Conversely, indomethacin, aspirin alone or with celecoxib were associated with significant increase in bleeding time and significant low values of plasma PF4 and /3-TG compared to DVT group denoting significant inhibition of platelet activity. All COX inhibitor treatments were associated with significant anti-inflammatory effect demonstrated by the low values of vein wall content of tumor necrosis factor-a [TNF-alpha] and interleukin-1 beta [IL-1beta] compared to DVT group. However, attenuation in the rise of myeloperoxidase activity was significant only with indomethacin possibly due to its greater anti-inflammatory effect.The present study shows that celecoxib shares standard non-steroidal anti-inflammatory [NSAIDs] e.g. indomethacin and aspirin, significant anti-inflammatory effect but seems to lack significant inhibitory effect on platelets. This would raise concerns about increased risk of acute vascular events in patients receiving COX-2 inhibitors. The risk may be increased with underlying inflammatory disorders and platelet activation e.g. venous stasis

Pharmacological, histological and immunohistochemical study of the induced osteoporotic changes in ovariectomized rats and possible protective and therapeutic effects of rofecoxib and indomethacin

The aim of this study was to assess the possible modulatory effects of rofecoxib [selective cyclooxygenase -2 inhibitor], and indomethacin [non-selective cyclooxygenase inhibitor], on the development of osteoporosis in experimentally induced postmenopausal osteoporosis in female rats. This study was carried out on sixty-four adult female albino rats weighing 180-190 grams of nine months of age. Under light ether anesthesia, the rats underwent ovariectomy [OVX] or Sham operation by the dorsal approach and assigned to eight groups of eight rats each. Group 1: Sham operated and treated with vehicle and served as a control for groups 2-4. Groups 2, 3 and 4: OVX treated with; vehicle, rofecoxib [3mg/kg BW/day] and indomethacin [1mg/kg BW/day] respectively. Groups 1-4 were given vehicle or respective drugs daily orally for six weeks through gavage starting immediately after OVX. Group 5: Sham operated and treated with vehicle and served as a control for groups 6-8. Groups 6, 7 and 8: OVX treated with; vehicle, rofecoxib [3mg/kg BW/day] and indomethacin [1mg/kg BW/day] respectively. Groups 5-8 were given vehicle or the respective drugs daily orally through gavage started at the sixth week after OVX and continued for consecutive six weeks. At the end of the experiment period, six weeks of groups 1-4 and twelve weeks for groups 5-8, 24 hours urine was collected after the last treatment for estimation of urinary hydroxyproline and calcium. Under light ether anesthesia blood samples were collected from the retro-orbital venous plexus. Sera were separated for estimation of osteocalcin, bone specific alkaline phosphatase and serum calcium. Then, the animals were sacrificed and the lumbar vertebrae and both femurs were excised for histological and immunohistochemical studies. The present study demonstrated that estrogen deficiency induced by OVX was clearly associated with increased bone turnover. The bone resorption was manifested by a significant increase in the mean value of urinary hydroxyproline, and urinary calcium excretion, thinning of bone trabeculae, widening of bone lamellae, anastmosis of bone marrow cavities and decreased expression of collagen type I staining. The trabecular bone was affected earlier and to a greater extent than long cortical bone. Bone formation was also evident by a significant increase in the mean value of serum osteocalcin, bone specific alkaline phosphatase and a significant decrease in mean value of serum calcium, presence of many osteogenic cells at the periosteal and endosteal surface, multiple cement lines and random orientation of less flattened osteocyte's lacunae. There was no significant difference between the mean values of the studied parameters in the vehicle treated ovariectomized groups at the 6[th] and 12[th] weeks after OVX. Immediate administration of rofecoxib [but not indomethacin] after OVX produced remarkable protective effect on the development of osteoporosis as manifested by decreased bone turnover markers and normal histological and immunohistochemical structure. On the other hand, administration of either rofecoxcib or indomethacin six weeks after OVX for another consecutive six weeks failed to produce significant protective effect but improve the quality of the newly formed bones. Selective cyclooxygenase -2 inhibitors are recommended early during development of osteoporosis as they have a protective effect on bone resorption. Nonsteroidal anti-inflammatory drugs [either selective or non-selective] would be beneficial when given after the development of osteoporosis as they improve the quality of the newly formed bones

Role of rosiglitazone and pravastalin in freund's adjuvant arthritis and mixed-type hypersensitivity in rats

Recent studies have shown that peroxisome proliferator- activated receptor- gamma [PPAR gamma] may participate in control of inflammation, especially in modulating the production of inflammatory mediators. Similarly, the cholesterol lowering drugs, statins, have been found to exhibit anti-inflammatory properties that are beyond their lipid lowering effects. The present study was conducted to investigate the effect of a PPAR gamma agonist [rosiglitazone] and a statin [pravastatin] on immunologically mediated chronic inflammation. Two models were chosen, namely, Freund's adjuvant arthritis [FA] and mixed- type hypersensitivity [MH] in rats. The effect of these drugs was assessed on the basis of biochemical markers in blood and / or inflammatory exudate. The investigated drugs were given orally daily during the course of inflammation development. The results of the present study demonstrated that, in either model, rosiglitazone and pravastatin reduced the elevated serum and exudate [local] leukotriene B[4] [LTB[4]] and interleukine-6 [IL-6] levels. The anti-inflammatory effect of these drugs was also accompanied by reduction or normalization of elevated systemic and or local levels of lipid peroxide [LP], superoxide dismutase [SOD], and reduced glutathione [GSH]. It could be concluded that long-term treatment with rosiglitazone or pravastatin confers a good anti-inflammatory activity against arthritis in rat, leading to improvement of the oxidative stress induced by the arthritic insult. The reparative effect of these drugs could be mediated via reduction of LTB[4] and IL-6