Nitric oxide mediates interleukin-1 induced inhibition of glycosaminoglycan synthesis in rat articular cartilage

Interleek-1β (IL-1) is a key mediator of cartilage matrix degradation in osteoarthritis and rheumatoid arthritis. It was found that the IL-1-induced suppression of glycosaminoglycan (GAG) synthesis in rat articular cartilage occurred simultaneously with the accumulation of nitrite (a metabolite of nitric oxide (NO) in aqueous milieu) in the culture medium. NO-synthase inhibitors, L-NMMA and L-NIO, inhibited both these IL-1 effects. Dexamethasone suppressed GAG synthesis additively to IL-1, but did not alter nitrite accumulation. Three NO-donors (GEA 3175, SNAP and SIN-1) also had an inhibitory effect on cartilage GAG synthesis. Therefore, it is concluded that IL-1 induced suppression of GAG synthesis in rat articular cartilage is mediated by the production of NO

Dexamethasone uses in humans and animals: public health and socio-economic implications

The importance of dexamethasone is demonstrated by its wide uses in human and veterinary medical practice. Unfortunately, dexamethasone use is prone to abuse. Health authorities have emphasized the importance of increasing knowledge of benefits and potential harmful effects of synthetic glucocorticoids use as a guide to responsible and judicious use of the pharmaceutical. This review provides an overview of the uses of dexamethasone and its consequences on public health visa vie socio–economy. Methodology: Source of Data: The review is based on literature searches using PubMed and MeSH and authors' personal manuscript/abstract files and citations of known references. Study selection: The selection of articles reflects the authors' opinion as to originality and importance in the context of the review. The review included human and some aspects of animal study. Data extraction: The electronic searches were scrutinized and full manuscripts of all quotes considered relevant to the study were obtained. All the articles whose abstracts were not available were excluded. Results: Dexamethasone is still one of the most prescribed medicines in human and veterinary medical practice despite over 4-decades of use and its attendant negative consequences. Recently non-medical uses of the drug are also on the increase which greatly contributed to the problems. Conclusion: Dexamethasone use has consequences on public health visa vie socio-economy. Its indispensability is not unconnected with its broad spectrum pharmacological actions and cost effectiveness. Due to rampant abuses and the attendant adverse effects of dexamethasone, it is recommended that the drug be enlisted as controlled drug

Postoperative Pain After The Use Of A Dexamethasone Rinse As An Irrigant Prior To Obturation

Purpose: The purpose of this randomized, double-blind pilot study was to determine the effect of dexamethasone on post-operative pain when used as an intracanal rinse prior to obturation. Materials and Methods: Nine adult volunteers consented to enroll. They presented to the Marquette University School of Dentistry Endodontic Department with a diagnosis of irreversible pulpitis. Patients recorded their baseline pain levels on the numering rating scale (NRS). Patients were randomly assigned to either experimental or control group. Patients in the experimental group received 4 mg/mL dexamethasone solution as a final rinse prior to obturation were as patients in the control group received saline as a final rinse. Patients recorded their pain levels at 3, 6, 12, 24, and 48 hours post-operatively. Means and standard deviations were calculated. Treatment effects were analyzed using repeated measures ANOVA. Statistical significance was set at p\u3c.05. Results: Eight patients returned the participation forms. Pain reduction after endodontic treatment was statistically significant (p=0.039). There was no significant difference in post-operative pain between the control and experimental groups (p-0.789). Conclusion: The patient sample size was not large enough to state any conclusions with confidence. However, endodontic treatment remains an effective means of reducing post-operative pain

Non infectious intermediate and posterior uveitis: Treatment and place of local steroids

n/

Analiza DNK oštećenja izazvanog tiazofurinom u humanim ćelijama pune krvi primenom in vitro komet testa

Objective. Inosine 5’-monophosphate dehydrogenase (IMPDH) activity in cancer cells is increased. Tiazofurin selectively inhibits the activity of IMPDH, and it has been granted for the treatment of different cancers and new viral diseases. Its widespread use was limited because exposure to tiazofurin under certain circumstances was found to have a higher frequency of severe non-hematologic toxicity. Therefore, the objective of this study was to examine genotoxic action and inducement of DNA damage of tiazofurin using the comet assay. Methods. The ability of tiazofurin to induce DNA damage was evaluated using single-cell gel electrophoresis (SCGE) technique/comet assay. Human whole blood cells were exposed to three final concentrations of tiazofurin (1 µM/mL, 2 µM/mL, and 5 µM/mL) for 30 min in vitro. Results. Our results indicate that tiazofurin produced a significant level of DNA damage on whole blood cells after 30 min of exposure vs. control. All tested concentrations were significantly comet-forming, in a concentration-dependent manner. Conclusion. Our investigation on the tiazofurin-treated cells and their relationship to the formation of DNA damage demonstrated that the genotoxic effect was induced after exposure to tiazofurin under described conditions.Cilj. Aktivnost inozin 5'-monofosfat dehidrogenaze (IMPDH) povec'ana je u c'elijama karcinoma. Tiazofurin selektivno inhibira aktivnost IMPDH i odobren je za lečenje različitih karcinoma i novih virusnih bolesti. Njegova široko rasprostranjena upotreba bila je ograničena jer je utvrđeno da je izloženost tiazofurinu pod određenim okolnostima imala vec'u incidencu ozbiljne nehematološke toksičnosti. Stoga je cilj ove studije bio da se pomoc'u komet testa ispita genotoksično delovanje i izazivanje DNK oštec'enja tiazofurinom. Metode. Sposobnost tiazofurina da izazove DNK oštec'enje procenjena je primenom elektroforeze DNK pojedinačnih ćelija (SCGE) / komet testa. Ćelije pune krvi su bile izložene trima konačnim koncentracijama tiazofurina (1 µM/mL, 2 µM/mL, and 5 µM/mL) tokom 30 minuta in vitro. Rezultati. Naši rezultati ukazuju na to da je tiazofurin proizveo značajan nivo DNK oštec'enja na c'elijama pune krvi nakon 30 minuta izlaganja u odnosu na kontrolu. Sve ispitivane koncentracije su dovele do značajnog nastanka kometa, pri čemu je nivo oštećenja rastao s koncentracijom. Zaključak. Naše istraživanje c'elija tretiranih tiazofurinom i njihova reakcija na izazivanje DNK oštec'enja pokazalo je da je tiazofurin ispoljio genotoksični efekat pod opisanim uslovima

The use of dexamethasone in animals: implication for fertility, pregnancy and extrapolation of the animal data to humans

Exposure to dexamethasone causes numerous changes in various biological systems including the reproductive system and this has huge implication on fertility and pregnancy. Maternal dexamethasone administration promotes foetal lung maturation and thermoregulation in premature foetuses. This indication makes dexamethasone a drug of choice in maternal and neonatal human and veterinary health care. In addition, dexamethasone is widely used in human and veterinary medicine as potent anti-inflammatory, immunosuppressive and analgesic drug in all age categories. Although the safety profile of short term dexamethasone treatment has been established, there has been growing concern about the long term effects of dexamethasone therapy and its implication on fertility and pregnancy in animals and humans. Most of the indications or uses in humans are extrapolated from animal data. This necessitates the need to provide review updates of current literature on dexamethasone use in humans and animals as there are many intrinsic differences between humans and animals. The review provides an overview of dexamethasone uses, its merits and demerits on animal pregnancy and fertility and implication on extrapolation of the animal data to humans. The review is based on a comprehensive literature search of relevant materials between 1969 and 2016 as well as authors’ personal manuscript/abstract files and citations of known references and discussed according to the multidisciplinary clinical experience of the authors. Although low-dose dexamethasone treatment has been used in veterinary and human clinics for many years and produced no severe effect on vital functions, repetitive high dose or long-term therapy may be associated with more serious sequelae on fertility and pregnancy. While no animal truly recapitulates human pregnancy and fertility, it is recommended that results from animal data be subjected to rigorous preclinical pharmacokinetic scaling processes to justify possible extrapolation to humans.Keywords: Animals, Dexamethasone, Fertility, Humans, Pregnanc

Efficacy of Pre-Operative Submucosal Injection of Dexamethasone in Mandibular Third Molar Surgery: A Randomized Control Trial

INTRODUCTION: Surgical extraction of third molar irrespective of any technique results in postoperative pain, swelling of face and limited mouth opening. The aim of the present study was to assess and compare the effects of Dexamethasone (4mg) administered prior to surgery.MATERIALS AND METHOD: A randomized control trial was conducted which included a total of fifty patients. All the patients were randomly put in two groups of twenty five each. Group I patients underwent transalveolar extraction of third molar under local anesthesia and standard oral drug regime. Group II patients received an additional submucosal injection of dexamethasone 4 mg, thirty minutes prior administration of local anaesthesia. Pain, swelling and mouth opening was recorded on second, seventh and tenth post-operative days after surgery.RESULTS: The difference in pain scores on second post-operative day between two groups were found statistically non-significant. However, there was significant reduction in pain scores on seventh and tenth day in both groups. Mouth opening showed statistically significant difference between the two groups.CONCLUSION: The observations of the present study provide a fundamental basis for the use of corticosteroids such as dexamethasone sodium phosphate in the form of submucosal administration in lower than usual doses to decrease postoperative inflammation when compare to other routes of drug administration

The Tumor Coagulome as a Transcriptional Target and a Potential Effector of Glucocorticoids in Human Cancers

Background: The coagulome, defined as the repertoire of genes that locally regulate coagulation and fibrinolysis, is a key determinant of vascular thromboembolic complications of cancer. In addition to vascular complications, the coagulome may also regulate the tumor microenvironment (TME). Glucocorticoids are key hormones that mediate cellular responses to various stresses and exert anti-inflammatory effects. We addressed the effects of glucocorticoids on the coagulome of human tumors by investigating interactions with Oral Squamous Cell Carcinoma, Lung Adenocarcinoma, and Pancreatic Adenocarcinoma tumor types. Methods: We analyzed the regulation of three essential coagulome components, i.e., the tissue factor (TF), urokinase-type plasminogen activator (uPA), and plasminogen activator inhibitor-1 (PAI-1) in cancer cell lines exposed to specific agonists of the glucocorticoid receptor (GR) (dexamethasone and hydrocortisone). We used QPCR, immunoblots, small-interfering RNA, Chromatin immunoprecipitation sequencing (ChIPseq) and genomic data from whole tumor and single-cell analyses. Results: Glucocorticoids modulate the coagulome of cancer cells through a combination of indirect and direct transcriptional effects. Dexamethasone directly increased PAI-1 expression in a GR-dependent manner. We confirmed the relevance of these findings in human tumors, where high GR activity/high SERPINE1 expression corresponded to a TME enriched in active fibroblasts and with a high TGF-β response. Conclusion: The transcriptional regulation of the coagulome by glucocorticoids that we report may have vascular consequences and account for some of the effects of glucocorticoids on the TME.</p

Acquired activated protein C resistance and thrombosis in multiple myeloma patients

BACKGROUND: An increased incidence of deep venous thrombosis (DVT) has been described in multiple myeloma (MM). A recently described mechanism of hypercoagulability in cancer patients including MM patients is acquired activated protein C resistance (APC-R). The purpose of the present study was to examine the association between the combination of thalidomide plus chemotherapy and DVT development in a cohort of patients with newly diagnosed multiple myeloma. We also evaluated the association between acquired activated protein C resistance and DVT. METHODS: Patients with newly diagnosed and symptomatic MM (untreated or with one cycle of preceding chemotherapy) were evaluated. The present study is a prospective, descriptive, longitudinal and observational one. The coagulations tests were performed including: prothrombin time, activated partial thromboplastic time (aPTT), fibrinogen, anticardiolipin antibodies, lupus anticoagulant, antithrombin, protein C and protein S activities, factor VIII, activated protein C (APC) resistance, factor V Leiden, and quantitative D-dimers. Factor V Leiden mutation was detected by analysis of the polymerase chain reaction amplification of genomic DNA. RESULTS: Fifty newly diagnosed multiple myeloma patients were included in the study. DVT was developed in 8 patients (16%). Six patients were confirmed to have acquired activated C protein resistance. All of them were tested twice. Four out of 6 patients developed DVT (66%), all of them received thalidomide at a median dose of 200 mg qd. CONCLUSION: APC-R appears to be a transitional condition that may be related to myeloma status. Thrombotic complications can affect morbidity and even mortality in these patients. To fully evaluate the potential synergistic anticancer activity of combinations of chemotherapy and thalidomide, effective prophylactic anticoagulation should be implemented in all controlled trials, at least during the first few cycles of treatment