Severe complications of tramadol overdose in Iran / 한국역학회지

OBJECTIVES: Severe complications of tramadol overdose have been reported; however, few large-scale studies have investigated this issue. Therefore, this study aimed to explore the presentation and complications of tramadol overdose in patients admitted to an intoxication referral center in northwestern Iran. METHODS: Patients with tramadol overdose admitted to Sina Teaching Hospital in Tabriz, Iran during 2013-2017 were included. For each patient, the following data were collected: demographics, previous drug or medication overdose, whether the patient was in the process of quitting drug use, ingested dose of tramadol and co-ingestants, Glasgow Coma Scale (GCS) score, clinical symptoms at the time of admission, and admission characteristics. Serotonin toxicity was diagnosed in patients who fit the Hunter criteria. Multiple logistic regression was performed to identify variables associated with the incidence of severe complications of tramadol overdose. RESULTS: In total, 512 cases of tramadol overdose were evaluated, of which 359 patients were included, with a median age of 41 years (range, 16-69) and a median tramadol dose of 1,500 mg (range, 500-4,000). The most frequent complications associated with tramadol overdose were hypertension (38.4%), tachycardia (24.8%), and seizure (14.5%). No serotonin toxicity was detected in patients. Having a GCS score 1,000 mg, being in the process of quitting drug use, being 30-49 years old, and male sex were significantly related to the incidence of severe complications of tramadol overdose. CONCLUSIONS: Although seizure was prevalent among Iranian patients with tramadol poisoning, serotonin toxicity and cardiogenic shock were rare findings.

Severe complications of tramadol overdose in Iran / 한국역학회지

OBJECTIVES: Severe complications of tramadol overdose have been reported; however, few large-scale studies have investigated this issue. Therefore, this study aimed to explore the presentation and complications of tramadol overdose in patients admitted to an intoxication referral center in northwestern Iran.METHODS: Patients with tramadol overdose admitted to Sina Teaching Hospital in Tabriz, Iran during 2013-2017 were included. For each patient, the following data were collected: demographics, previous drug or medication overdose, whether the patient was in the process of quitting drug use, ingested dose of tramadol and co-ingestants, Glasgow Coma Scale (GCS) score, clinical symptoms at the time of admission, and admission characteristics. Serotonin toxicity was diagnosed in patients who fit the Hunter criteria. Multiple logistic regression was performed to identify variables associated with the incidence of severe complications of tramadol overdose.RESULTS: In total, 512 cases of tramadol overdose were evaluated, of which 359 patients were included, with a median age of 41 years (range, 16-69) and a median tramadol dose of 1,500 mg (range, 500-4,000). The most frequent complications associated with tramadol overdose were hypertension (38.4%), tachycardia (24.8%), and seizure (14.5%). No serotonin toxicity was detected in patients. Having a GCS score <15, having taken a tramadol dose of >1,000 mg, being in the process of quitting drug use, being 30-49 years old, and male sex were significantly related to the incidence of severe complications of tramadol overdose.CONCLUSIONS: Although seizure was prevalent among Iranian patients with tramadol poisoning, serotonin toxicity and cardiogenic shock were rare findings.

Severe complications of tramadol overdose in Iran / 한국역학회지

OBJECTIVES@#Severe complications of tramadol overdose have been reported; however, few large-scale studies have investigated this issue. Therefore, this study aimed to explore the presentation and complications of tramadol overdose in patients admitted to an intoxication referral center in northwestern Iran.@*METHODS@#Patients with tramadol overdose admitted to Sina Teaching Hospital in Tabriz, Iran during 2013-2017 were included. For each patient, the following data were collected: demographics, previous drug or medication overdose, whether the patient was in the process of quitting drug use, ingested dose of tramadol and co-ingestants, Glasgow Coma Scale (GCS) score, clinical symptoms at the time of admission, and admission characteristics. Serotonin toxicity was diagnosed in patients who fit the Hunter criteria. Multiple logistic regression was performed to identify variables associated with the incidence of severe complications of tramadol overdose.@*RESULTS@#In total, 512 cases of tramadol overdose were evaluated, of which 359 patients were included, with a median age of 41 years (range, 16-69) and a median tramadol dose of 1,500 mg (range, 500-4,000). The most frequent complications associated with tramadol overdose were hypertension (38.4%), tachycardia (24.8%), and seizure (14.5%). No serotonin toxicity was detected in patients. Having a GCS score 1,000 mg, being in the process of quitting drug use, being 30-49 years old, and male sex were significantly related to the incidence of severe complications of tramadol overdose.@*CONCLUSIONS@#Although seizure was prevalent among Iranian patients with tramadol poisoning, serotonin toxicity and cardiogenic shock were rare findings.

Cardioprotective effects of essential oil of Lavandula angustifolia on isoproterenol-induced acute myocardial infarction in rat

Myocardial infarction [MI] is a common presentation of the ischemic heart disease. Lavandula angustifolia is an herbaceous plant with antioxidative effects. This study was designed to investigate the cardioprotective effects of lavandula angustifolia essential oil against isoproterenol-induced MI in rats. The dried sample was subjected to hydrodistillation by using a Clevenger and the oils were dried over anhydrous Na[2]SO[4]. Male Wistar rats were assigned to 6 groups of control, sham, isoproterenol and treatment with 5, 10, 20 mg/Kg of the essential oil. MI was induced by subcutaneous injection of Isoproterenol [100 mg/Kg] for 3 consecutive days at an interval of 24 h. The essential oil was given intraperitoneally every 24 h started at MI induction. Following anesthesia, hemodynamic parameters were measured. After sacrificing the animals, the hearts were removed to measure the heart to body weight ratio and histopathological examination. Myeloperoxidase [MPO] and Malondialdehyde [MDA] were measured in heart tissues for evaluating the activity of neutrophils and lipid peroxidation, respectively. The essential oil amended ECG pattern by suppressing ST-segment elevation and increasing R-amplitude. 10 mg/Kg of the essential oil significantly decreased heart to body weight ratio [P<0.001] and the elevation of MDA and MPO in myocardium, it also increased dp/dtmax from 2793 +/- 210 to 4488 +/- 253 mmHg/sec [P<0.001], and 20 mg/Kg of it significantly lowered LVEDP from 14 +/- 3.43 to 4.3 +/- 0.83 mmHg [P<0.001].The results demonstrated that L. angustifolia protects myocardium against isoproterenol-induced MI that it could be related to its antioxidant properties

Hydrocortisone reduces toll-like receptor 4 expression on peripheral CD14[+] monocytes in patients undergoing percutanoues coronary intervention

Evidence from several lines of investigations suggests that Toll-like receptor 4 [TLR4] is involved in atherosclerosis as a bridge between innate and acquired immunity. Percutaneous coronary intervention [PCI] can trigger inflammation through activation of human TLR4 [hTLR4] on monocytes. Hydrocortisone as an anti-inflammatory and immuno-suppressant agent has multiple mechanisms of action. In this study, we aimed at assessing the effects of hydrocortisone on monocyte expression and activity of hTLR4 in patients underwent PCI. Blood samples were taken from a total of 71 patients with chronic stable angina who were scheduled for a PCI, before the intervention. Thirty patients received 100 mg hydrocortisone prior to the procedure. Control group was composed of 41 patients underwent PCI without receiving hydrocortisone. Blood collection was repeated 2 and 4 h after PCI. The expression of hTLR4 on the surface of CD14[+] monocytes and the serum levels of TNF- alpha and IL-1 beta were measured using flowcytometry and Sandwich ELISA. Compared with controls, hydrocortisone significantly reduced monocyte expression of hTLR4 in test group [P<0.01]. In addition, it had a significant effect on reduction of serum concentrations of TNF- alpha and IL-1 beta in test group in a time-dependent manner [P<0.01]. In this study, hydrocortisone was able to reduce the hTLR4/CD14 positive monocytes and its related pro-inflammatory cytokines, thus it can decrease inflammatory responses following PCI

Biological evaluation of a siliconized analog of clofibrate [silafibrate] in rodents

Silicon is the element very similar to carbon, and bioactive siliconized compounds have therefore received much attention. Siliconization of a compound enhances its biological activities. In the present study the hypolipidemic effect and toxicity of clofibrate and its siliconized analog, silafibrate, were compared. The experiments were performed in hypercholesterolemic Wistar rats. Animals received high fat diet with 62.75% normal chow, 2% cholesterol, 0.25% cholic acid, 15% lard oil, 10% wheat flour and 10% sucrose. Silafibrate[40 mg/kg/day] produced a predominant reduction in the serum levels of total cholesterol [28.4%, p < 0.001], triglycerides [62%, p < 0.0001] and low-density lipoproteins [27%, p < 0.001] being more effective than the reference drug clofibrate [20%, 40%, 14.5%; p < 0.05]. Similarly, it increased the total antioxidant levels in serum by 40% [p < 0.05]. Simultaneously, treatment with silafibrate also reduced the malondialdehyde [MDA] concentration by 41% [p < 0.05]. LD[50] of silafibrate, given orally, was greater than 2000 mg/kg body weight in albino mice while LD[50] for clofibrate was calculated to be 1220 mg/kg. Thirty-day subacute toxicity was also evaluated with oral daily dose at 25, 50 and 100 mg/kg body weight in Wistar rats. No significant changes in body weight, food intake, behavior, mortality, hematology, blood biochemistry, vital organ weight were detected. The results of this study indicate that the effectiveness and safety of the hypolipidemic drug, clofibrate, were enhanced remarkably by replacing chlorine atom in its phenoxy ring with trimethylsilyl

Monocyte expression of toll-like receptor-4 in patients with stable angina undergoing percutanoeus coronary intervention

Toll like receptors [TLRs] are well recognized players in inflammatory conditions. Among them TLR-4 is involved in chronic inflammatory processes such as formation of atherosclerotic plaques. The present study was aimed to examine the effects of percutanoeus coronary intervention [PCI] as a revascularization method on monocyte expression of hTLR-4 and on the serum levels of two proinflammatory cytokines [TNF-alpha and IL-1beta]. Blood samples were obtained from 41 patients with stable angina who were candidates for PCI. The samples were collected immediately before and 2h and 4h after PCI. The expression of hTLR-4 on CD14[+] monocytes and the serum levels of TNF-alpha and IL-1beta were measured using flowcytometry and ELISA techniques, respectively. By comparing the frequency of circulating hTLR-4[+]/CD14[+] monocytes at different time points, it was observed that PCI procedure up regulates the monocyte expression of hTLR-4 [p<0.05]. The increase in expression was associated with the elevation of the serum levels of proinflammatory cytokines [p<0.05]. There was a significant correlation between monocyte expression of hTLR-4 and serum levels of TNF-alpha and IL-1beta only before PCI. In spite of parallel increase in the serum levels of proinflammatory cytokines and the monocyte expression of hTLR-4, the correlation did not attain a significant level after PCI intervals. PCI is positively associated with an increase in the monocyte expression of hTLR-4. It is also associated with the elevation in the serum levels of proinflmmatory cytokines. These findings suggest that hTLR-4 monocyte expression may be used as a potential prognostic tool in patients with stable angina undergoing PCI.

Ambivalent effects of atorvastatin on angiogenesis, epidermal cell proliferation and tumorgenesis in animal models

A growing body of preclinical data indicates that statins may possess antineoplastic properties; however, some studies have raised the possibility that statins may also have carcinogenic potential. An air pouch model was used for angiogenesis. Single or multiple applications of croton oil on the back of Swiss albino mice with or without initiation by dimethylbenz[a]antheracene [DMBA] were used to evaluate the skin tumorgenesis, ultrastructural and histological alterations. Atorvastatin [orally, 10 mg/kg/day] produced a significant [P<0.05] reduction in angiogenesis. Concurrent administration of mevalonate reversed the antiangiogenic effect of atorvastatin. However, local injection of atorvastatin [200 micro g] into the pouches induced a significant [P<0.5] increase in angiogenesis that was not reversed by co-administration of mevalonate. The disturbance of cell polarity, inflammatory response, thickness of epidermal layer, and mitotic index induced by croton oil were inhibited markedly and dose-dependently [P<0.001] by pre-treatment with atorvastatin. In spite of the strong anti-inflammatory and anti-proliferative effects of atorvastatin on epidermal cell proliferation, it was identified that the same doses of atorvastatin in DMBA-initiated and croton oil-promoted skin tumorgenesis in mice increased the incidence of tumors and their conversion into malignant carcinoma. The reasons for these discrepancies remain unclear, and could be related to ambivalent effects of atorvastatin on angiogenesis or to specific differences in the experimental conditions. It is suggested that the pro-angiogenic effect of the drug, which could be responsible for promotion of skin tumors, is independent of the 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibition that can be mediated directly by atorvastatin

Synthesis of a novel siliconized analog of clofibrate [silafibrate] and comparison of their anti-inflammatory activities

Fibrates, as hypolipidemic drugs known as agonists of peroxisome proliferator-activated receptors, diminish inflammatory responses. Studies have shown that incorporation of a silicon atom into a drug structure improves its pharmacological potency, modifies its selectivity toward a given target, or changes its metabolic rate, in addition to increasing the lipophilicity of the compounds. A siliconized analog of clofibrate, ethyl-2-methyl-2-[4-[trimethylsilyl]phenoxy]propionate was synthesized, whereby the chlorine atom in the phenoxy ring was replaced by a trimethylsilyl group. The anti-inflammatory effects of the siliconized analog [silafibrate] were evaluated in an air-pouch model of inflammation and compared with those of clofibrate. Oral administration of both drugs produced a significant anti-inflammatory action by reducing carrageenan induced pouch leukocyte recruitment, exudates production, and granulated tissue weight. The silicon isostere of clofibrate has improved anti-inflammatory properties

Vascular dysfunction in short-term hypercholesterolemia despite the absence of atherosclerotic lesions

The atherosclerotic effect of hypercholesterolemia on the vascular function is well-known. However, limited studies were done on the effect of hypercholesterolemia without atherosclerotic lesion on thq vascular compliance. The aim of this study was to investigate the effects of hyperlipidemia induced by cholesterol rich diet on vessel function in isolated rat aorta in the absence of atherosclerotic lesion. Male wistar rats were randomly divided into 3 groups of 6 animals in each. The rats in normal control group were fed a standard laboratory diet and two other groups were fed a high fat diet for 36 days. A group of high fat fed rats was treated orally with Lovastatin started at day of 16 and continued for last 20 days of the experimental period. At the end of the experiment, inferior vena cava blood was collected to measure the lipid levels and the thoracic aorta was excised and used for isolated vessel preparation and histological study. Results: The results of this study indicated that high-cholesterol diet significantly increased total cholesterol and LDL levels in serum [p<0.001]. The increase in the serum levels of cholesterol was associated with a profound reduction of endothelium dependent vasodilatation of the thoracic aorta. However, in histopathological study no atherosclerotic lesion was observed. Short-term treatment by Lovastatin [10 mg/kg/day] produced a significant reduction[p<0.05] in the level of total cholesterol and LDL. The endothelium-dependent vasodilatation was improved significantly [P<0.01] by Lovastatin as an anti-hyperlipidemic drug. Hypercholesterolemia is associated with endothelial dysfunction in aorta, despite the absence of atherosclerotic lesions

Erythropoietin prevention effect on induced apoptosis by ischemia- reperfusion in myocytes of rat

Ischemia- reperfusion is the common cause of apoptosis in most of cells specially myocytes. Prevention and reduction of apoptosis in myocardium can be one of the main medical goal before surgical operation, angioplasty and after infarction. Erythropoietin receiving effect 24 hours before hypoxia beginning on myocytes apoptosis rate and inflammatory process following half an hour hypoxia and 1.5 hour reperfusion are aim of this study. 40 Rats were divided randomly into two groups. 24 hours before surgical operation, 5000 Iu/Kg erythropoietin was injected to experimental group. During operation 12 rats from experimental group and 11 rats from control group were lost. After anesthesia, using ligation in left coronary artery for 30 minutes hypoxia and 1.5 hours reperfusion were applied. Then Thorax was opened and after bleeding, the animal's heart was isolated and two tissue samples of infarct and non-infarct area were separated and fixed. Then blood serum samples separated and incubated in -76[degree] C. Apoptosis intensity in heart tissue was measured by tunel method CK-MB level by method and DGKC, hsCRP by Elisa using Immunodiagnostic kit. The results were calculated Mean +/- SD. Then using paired student's t- test their deference were shown. Level of statistical significant was considered P< 0.05. Activity level of CK-MB [1550U/L to 340] in experimental group was less than control group [P

Pharmacological preconditioning with l-carnitine: relevance to myocardial hemodynamic function and glycogen and lactate content

Carnitine is a vital biologic substance facilitating fatty acids transport into mitochondria for ATP production. This study was to investigate the effects of pre-ischemic pharmacological preconditioning [PC] with L-carnitine [L-Car] on myocardial infarct size and cardiac functions in ischemic and reperfused isolated rat heart and meanwhile on left ventricular glycogen and lactate content. Isolated rat hearts were subjected to 30 min coronary artery occlusion followed by 120 min reperfusion. The hearts [n=8-12] were perfused with L-Car [0.5-5 mM] only for 15 min before to 10 min after induction of ischemia. Preconditioning of the hearts with L-Car provided concentration-dependent cardioprotection as evidenced by improved postischemic ventricular functional recovery [developed pressure, left ventricular end diastolic pressure and coronary flow rate] and reduced myocardial infarct size [p<0.001]. L-Car [2.5 mM] decreased both glycogen [p<0.001] and lactate [p<0.05] content in left ventricle during ischemia compared with the control. The results of this study demonstrate that L-Car pharmacologically precondition the hearts against ischemic and reperfusion injury in part by recovery of postischemic ventricular hemodynamic functions, depletion of glycogen and therefore reduction of lactate accumulation

Effects of total extract of Dracocephalum moldavica on ischemia/reperfusion induced arrhythmias and infarct size in the isolated rat heart

Dracocephalum moldavica [D. moldavica] have been traditionally used as a cardiotonic agent in the folk medicine of some regions of Iran. In the present study, effects of total extract of D. moldavica on ischemia/reperfusion induced arrhythmias and infarct size investigated in isolated rat heart. The isolated hearts were mounted on a Langendorff apparatus then perfused during 30 min regional ischemia and 120 min reperfusion, either by a modified Krebs-Henseleit solution as the control group or by enriched Krebs solution with total extract of D. moldavica [25-200 micro g/ml] as the treatment groups. The ECGs recorded and analyzed to determine cardiac arrhythmias. At the end of the reperfusion, the hearts stained by Evans blue solution then incubated by triphenyltetrazolium chloride. The volume of infarcted tissue and percentage of infarct size determined by computerized planimetry. The results demonstrated that total extract of D. moldavica caused a significant reduction in the number of ventricular tachycardia [VT], total ventricular ectopic beats [VEBs] and VT duration in ischemic and reperfusion periods. The incidence of ischemic VT reduced from 93% in the control group to 0, 50 and 50% in the treatment groups. The infarct size was 37 +/- 1% in the control group, however, perfusion of the extract [25, 50, 200 micro g/ml] reduced it to 13 +/- 2, 8 +/- 1 and 18 +/- 2%, respectively [P < 0.001]. In addition, the extract remarkably lowered volume of infarcted tissue compared to the control group [P < 0.05]. Our findings showed cardioprotective effects of total extract of D. moldavica against ischemia/reperfusion injuries in the isolated rat heart

Screening of extracts and fractions from aerial parts of stachys schtschegleevii sosn. for anti-inflammatory activities

Stachys schtschegleevii Sosn. is a native plant widely distributed in Iran and belongs to family of Lamiaceae and genus of Stachys. The plant is used in Iranian folk medicine in infective, rheumatic and other inflammatory disorders. In the present study the anti-inflammatory properties of different extracts and components isolated from aerial parts of Stachys schtschegleevii Sosn. were investigated. Intraperitoneal injection of hydroalcoholic extract 60 min before the induction of carrageenan-induced rat paw oedema significantly reduced the maximal oedema response attained during 4 hr and the total oedema response. A low dose of chloroform extract [100 mg/kg] caused significant inhibition of the carrageenan-induced inflammation, whereas a high dose of 400 mg/kg produced a pro-inflammatory response. One of the ethyl acetate extract caused a potent and dose-related inhibition of inflammation. This extract was fractionated into 11 major fractions according to increasing polarity of solvent mixtures. These results suggest that the hydroalcoholic extract of aerial parts of Stachys schtschegleevii attenuate the inflammatory response. The compounds in different fractions have also been identified to exhibit anti-inflammatory activity through thin layer chromagoraphy

Biphasic effects of atorvastatin on inflammation

Statins have been shown to exert "pleiotropic effects" independent of their cholesterol lowering actions that include anti-inflammatory properties. We show in this study that atorvastatin dependent on the way of administration may exert anti- or pro- inflammation effects. Carrageenan-induced rat paw edema and mouse air-pouch as inflammatory models were used in this study. Animals were received statins orally prior to induction of inflammation by injection of carrageenan into rat paw or the pouch. The local effect of atorvastatin was determined by injection of the drug into the pouch. Oral administration of statins reduced both the maximal edema response and neutrophils infiltration in the inflammation zone. Lovastatin had the lowest and atorvastatin had the greatest effects. Also, in the mouse air-pouch model oral treatment by atorvastatin produced a very significant [p < 0.0001] reduction in carrageenan-induced pouch leukocyte recruitment and exudates production. Concurrent administration of mevalonate revers ed the anti-inflammatory effect of atorvastatin. However, local injection of atorvastatin into the pouch induced a dose depend and significant increase in leukocyte recruitment into the pouch that was not reversed by co-administration of mevalonate. This study shows that atorvastatin dependent on the way of administration has both pro- and anti- inflammatory properties. Contrary to anti-inflammatory effects, the pro-inflammatory responses are independent of HMG CoA reductase inhibition and can be mediated directly by atorvastatin

Effects of hydroalcoholic extract from aerial parts of the sterile stems of Stachys inflata on myocardial infarct size in rats

Recently a potent anti-inflammatory effect of hydroalcoholic extract of the aerial parts of the sterile stems of Stachys inflata has been reported. This study examined whether hydroalcoholic extract isolated from aerial parts of non-flowering stems of Stachys inflata [standardized to contain 4.5% caffeic acid derivatives] reduce myocardial infarct size arising from coronary artery occlusion [30min] and reperfusion [2 h] in anaesthetized rats. In addition, the extract was also tested on the incidence and severity of ischaemic arrhythmias. Infusion of the extract [1.35 micro g/kg/min] 5 min before coronary artery ligation and for the duration of the ischaemic [30 min] and reperfusion [2 h] periods resulted in a marked [p<0.001] decrease in infarct size [from 48.2 1% in control to 29.3 2.7% in treated rats]. However, an infarct size of 46.7 3.4% was seen with the higher dose of the extract [2.70 micro g/kg/min]. The extract had no effect either on the severity and incidence of ischaemic arrhythmias or on the blood pressure. These results suggest that the hydroalcoholic extract of aerial parts of Stachys inflata attenuates the infarct size following ischaemia and reperfusion without any effect on the cardiovascular system. Anti-inflammatory actions of the extract may play a major role in reducing the infarct size

Protective effects of some azo derivatives of 5-aminosalicylic acid and their pegylated prodrugs on acetic acid-induced rat colitis

The protective and anti-inflammatory effects of azo and azo-linked polymeric prodrugs of 5-aminosalicylic acid [5-ASA] on acetic acid induced colitis in rats were investigated. Three azo prodrugs; 4,4 -dihydroxy-azobenzene-3-carboxilic acid [azo compound I], 4-hydroxy-azobenzene-3,4-dicarboxilic acid [azo compound II], 4,4-dihydroxy-3-formyl-azobenzene-3-carboxylic acid [azo compound III] and their polyethylene glycol [PEG 6000] derivatives were synthesized. Rats were pretreated orally [1 hour prior to induction of colitis] with sulfasalazin [300 mg/kg], azo compounds I, II, III and polyethylene glycol conjugates of azo compounds II and III in doses which had the same amount of 5-ASA as sulfasalazin contains. The colonic damage was examined 24 hours later and characterized by gross microscopic injury and colonic edema. Among prodrugs only azo compound III [215 mg/kg] produced a significant [p<0.01] protective effect against colonic injury comparable with sulfasalazin. Doubling the dose [430 mg/kg] showed more anti-colitis effects. Polyethylene glycol conjugate of azo compounds II and III also showed reduction in the extent of the cell death and tissue disorganization similar to sulfasalazin. While neither sulfasalazin, nor azo compound II and its PEG polymer produced anti-edema effects, both azo compound III and its PEG polymer decreased colon edema significantly [p<0.05]. Histological examinations also indicated a marked reduction in tissue injury and inhibition in neutrophil infiltration in rats treated with azo compound III and PEG conjugates of azo compounds II and III. Results of this investigation provide experimental evidence supporting new cytoprotective, anti-inflammatory and anti-edema properties of the azo derivatives of 5-ASA and their PEGylated prodrugs