Coadministration Of Indomethacin Research Articles

Impact of Cuminaldehyde and Indomethacin Co-Administration on Inflammatory Responses in MIA-Induced Osteoarthritis in Rats.

Osteoarthritis (OA) remains a chronic incurable condition, presenting substantial challenges in treatment. This study explores a novel strategy by investigating the concurrent use of cuminaldehyde, a natural compound, with indomethacin in animal models of MIA-induced OA. Our results demonstrate that the co-administration of cuminaldehyde and indomethacin does indeed produce a superior effect when compared to these compounds individually, significantly enhancing therapeutic outcomes. This effect is evidenced by a marked reduction in pro-inflammatory cytokines IL-6 and IFN-γ, alongside a significant increase in the anti-inflammatory cytokine IL-10, compared to treatments with each compound alone. Radiographic analyses further confirm the preservation of joint integrity and a reduction in osteoarthritic damage, highlighting the association's efficacy in cartilage-reducing damage. These findings suggests that the association of cuminaldehyde and indomethacin not only slows OA progression but also offers enhanced cartilage-reducing damage and fosters the production of protective cytokines. This study underscores the potential benefits of integrating natural products with pharmaceuticals in OA management and stresses the importance of further research to fully understand the mechanisms underlying the observed potentiated effects.

Manganese abated indomethacin-induced gastrohepatorenal toxicities in Rats via suppression of oxidative stress, polyamine catabolism, inflammation and activation of Caspase-3

Indomethacin (IND) is a non-steroidal anti-inflammatory drug with many therapeutic benefits and multi-organ toxicities. Manganese (Mn) is a trace metal essential in many biological processes. However, there is dearth of information concerning the effect of Mn on IND-induced gastrohepatorenal damage in rats. This study investigated the mitigating effect of manganese on IND-induced gastrohepatorenal damage in rats. Adult male rats were assigned into four groups of eight rats each and were treated once daily for 14 days. Group 1 served as control; group 2 received IND alone (5 mg/kg); group 3 received IND (5 mg/kg) and Mn alone (10 mg/kg) and group 4 received Mn alone Mn alone (10 mg/kg). Administration of IND significantly increased ulcer score, ulcer index, titrable acidity and peptic activity and decreased pH, mucus content, hexosamine and sialic acid levels. IND also increased hepatorenal markers, myeloperoxidase (MPO), nitric oxide (•NO), malondialdehyde (MDA), lipid hydroperoxide (LOOH), protein carbonyl (PCO), spermine oxidase (SpmOX), putrescine Oxidase (PutOX), tumor necrosis factor-α (TNF-α) interleukin-1β (IL-1β), caspase-3 and decreased the activities of superoxide dismutase (SOD), catalase, glutathione S-transferase (GST), glutathione peroxidase (GPx) and glutathione (GSH) level relative to control. Co-administration of IND and Mn significantly decreased ulcerogenic parameters, hepatorenal markers, MPO, •NO, MDA, LOOH, PCO, SpmOX, PutOX, TNF-α, IL-1β, caspase-3 and increased antioxidant status relative to IND alone group.Histological examination showed that injuries induced by IND were ameliorated by Mn rats.Mn suppressed IND-induced oxidative stress, inflammation, polyamine catabolism and caspase-3 activation in the liver and kidney of the rats.

Synergistic Antinociceptive Effects of Indomethacin-Pregabalin and Meloxicam-Pregabalin in Paclitaxel-Induced Neuropathic Pain.

Neuropathic pain is often closely associated with nerve injury or inflammation, and the role of traditional nonsteroidal anti-inflammatory drugs as adjuvants for treating chemotherapy-induced peripheral neuropathic pain remains unclear. In this study, the potential synergistic antinociceptive effects of indomethacin–pregabalin and meloxicam–pregabalin were evaluated in paclitaxel-induced neuropathic pain and carrageenan-induced inflammatory pain in rodents. Although indomethacin and meloxicam alone only slightly relieved mechanical allodynia in the above two models, isobolographic analysis showed that the combination of indomethacin or meloxicam with pregabalin produced significant synergistic antinociceptive effects for paclitaxel-induced neuropathic pain (IN-PGB, experimental ED25 = [4.41 (3.13–5.82)] mg/kg, theoretical ED25 = [8.50 (6.62–10.32)] mg/kg; MEL-PGB, experimental ED25 = [3.96 (2.62–5.46)] mg/kg, theoretical ED25 = [7.52 (5.73–9.39)] mg/kg). In addition, MEL-PGB dosed via intraplantar injection into the left paw, intragastric injection, or intraperitoneal injection reversed paclitaxel-induced allodynia, indicating that they may act at multiple sites in the neuroaxis and periphery. However, indomethacin–pregabalin and meloxicam–pregabalin exerted antagonistic antiallodynic interactions in carrageenan-induced inflammatory pain in rats. Taken together, coadministration of indomethacin or meloxicam with pregabalin may possess potential therapeutic advantages for treating chemotherapy-induced neuropathic pain.

Thymol Reduces Hepatorenal Oxidative Stress, Inflammation and Caspase-3#xd; Activation in Rats Exposed to Indomethacin

ABSTRACT Indomethacin (IND) is a non-steroidal anti-inflammatory drug with many pharmacological benefits and multi-organ toxicities. Thymol (THY) is a natural phenolic monoterpenoid with many biological properties. However, there is scarcity of information on its potential on IND-induced hepatorenal damage in rats. This study investigated the effect of THY on IND-induced hepatorenal damage in rats. The four experimental groups contain control, IND alone (5 mg/kg), THY alone (250 mg/kg) and co-treated group that were treated orally for 21 consecutive days. Twenty four hour after treatments, rats were sacrificed and markers of hepatorenal damage (ALT, ALP, AST, G6PDH, GGT, BIL, CHOL, GLDH, LDH, MDH, SDH, creatinine, urea, uric acid, cystatin-C and electrolytes), antioxidant status markers, myeloperoxidase (MPO) activity, nitric oxide (NO), lipid peroxidation (LPO), tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β) levels and caspase-3 activity were evaluated. IND increased hepatorenal toxicity, inflammatory and apoptotic markers and decreased antioxidant status. Co-administration of IND with THY significantly decreased hepatorenal damage biomarkers improved the antioxidant status and reduced the MPO activity, LPO, NO, TNF-α, IL-1β levels and caspase-3 activity in the liver and kidney of rats. In conclusion, THY mitigates against IND-induced oxidative stress, inflammation and caspase-3 activation in the liver and kidney of the rats.

Gastroprotective Effects of Methanolic Leaves and Stem Extracts of Sphagneticola trilobata on Indomethacin-Induced Gastric Ulcer in Rats

The medicinal plant Sphagneticola trilobata native to South America is used in local folk medicine to treat inflammation and analgesics. In present study, gastroprotective effects of methanolic extracts of S. trilobata leaves and stem were investigated in indomethacin-induced gastric ulcers in rats at doses of 200 mg/kg for leave extract and 350 mg/kg for stem extract. Indomethacin produced stomach ulcers and increased neutrophil percentage and MDA levels compared to the control group (p < 0.001). Co-administration of indomethacin and omeprazole, methanolic extracts of leaves (200 mg/kg) (p < 0.001) and methanolic extracts (350 mg/kg) (p < 0.05) of stem compared to indomethacin group to ulcers was low (p < 0.001). Methanolic extracts (200 mg/kg) of leaves and methanolic extracts (350 mg/kg) of stem reduced MDA levels (p < 0.001). Methanolic extracts (200 mg/kg) of leaves and methanolic extracts (350 mg/kg) of the stem significantly decreased neutrophil percentage compared to indomethacin group (p < 0.001). The results suggest that the methanolic extracts of Sphagneticola trilobata leaves and stem have a protective effect on indomethacin-induced gastric ulcers.

Gastroprotective effects of both aqueous and ethanolic extracts of Lemon verbena leaves against indomethacin-induced gastric ulcer in rats.

Objective(s):Regarding Lemon verbena gastroprotective effects, we investigated the protective effects of Lemon verbena extracts on reducing gastric ulcer induced by indomethacin.Materials and Methods:Rats received aqueous and ethanolic extracts of Lemon verbena (50, 100, and 200 mg/kg), zileuton (100 mg/kg), montelukast (10 mg/kg), or 1% Tween 80 in presence or absence of indomethacin (100 mg/kg).Results:Indomethacin produced stomach ulcer and increased neutrophils percentage and MDA level compared with the control group (P<0.001). Co-administration of indomethacin and zileuton, montelukast and ethanolic (200 mg/kg) (P<0.001), aqueous extract (200 mg/kg) (P<0.05) reduced ulcer compared with the indomethacin group (P<0.001). Ethanolic extracts (100 and 200 mg/kg) and aqueous extract (200 mg/kg) reduced the MDA level (P<0.001). Ethanolic (50, 100, and 200 mg/kg) and aqueous extracts (200 mg/kg) significantly decreased neutrophils percentage compared with the indomethacin group (P<0.001).Conclusion:Aqueous and particularly ethanolic extracts of Lemon verbena have protective effects on indomethacin-induced gastric ulcers.

Manganese Inhibits Indomethacin-Induced Hepatorenal Oxidative Stress in Wistar Rats

Aim: Manganese (Mn) is an essential trace element in many cellular processes. However, there is dearth of literature on its influence on indomethacin-induced hepatorenal damage. Therefore, this study was conducted to investigate the effect of manganese on indomethacin-induced hepatorenal damage in rats.&#x0D; Methods: Rats were divided into four groups of eight rats consisting of control group, indomethacin (IND) alone (20 mg/kg), Mn alone (10 mg/kg) and co-treated group that were treated orally for 14 consecutive days. Twenty four hours after treatment, under pentobarbital anesthesia, blood was collected and liver was excised to prepare homogenate and histology staining. Liver and kidney function tests aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), lactate dehydrogenase (LDH), malate dehydrogenase (MDH), glutamine dehydrogenase (GLDH), sorbitol dehydrogenase (SDH), glucose-6-phosphate dehydrogenase (G6PD), bilirubin (BIL), urea, creatinine, cholesterol (CHOL), triglycerides (TG), low and high density lipoprotein (LDL and HDL), electrolytes and oxidative stress superoxide dismutase (SOD), catalase (CAT), glutathione (GSH) and lipid peroxidation (LPO) biomarkers were assessed.&#x0D; Results: The results showed that indomethacin caused hepatorenal damage in rats manifested with increase in serum hepatic and renal function biomarkers. But co-administration of IND with Mn significantly (p &lt; 0.05) decreased the level of hepatorenal biomarkers. Additionally, co-administration of IND with Mn improved the antioxidant status with concomitant reduction of LPO and restored the integrity of the liver and kidney histologically.&#x0D; Conclusion: The results of this study emphasize that co-administration of IND with Mn to rats alleviated IND-induced hepatorenal toxicities and oxidative stress in rats.

Larger Dose Reductions of Vancomycin Required in Neonates with Patent Ductus Arteriosus Receiving Indomethacin versus Ibuprofen.

Ibuprofen and indomethacin are commonly used to induce ductus arteriosus closure in preterm neonates. Our group previously reported that ibuprofen decreased vancomycin clearance by 16%. In this study, we quantified the impact of indomethacin coadministration on vancomycin clearance by extending our vancomycin population pharmacokinetic model with a data set containing vancomycin concentrations measured in preterm neonates comedicated with indomethacin. The modeling data set includes concentration-time data of vancomycin administered alone or in combination with either ibuprofen or indomethacin collected in the neonatal intensive care units of UZ Leuven (Leuven, Belgium) and São Francisco Xavier Hospital (Lisbon, Portugal). The derived vancomycin pharmacokinetic model was subsequently used to propose dose adjustments that yield effective vancomycin exposure (i.e., area under the concentration-time curve from 0 to 24 h [AUC0-24] between 300 to 550 mg·h/liter, with a probability of <0.1 of subtherapeutic exposure) in preterm neonates with patent ductus arteriosus. We found that indomethacin coadministration reduced vancomycin clearance by 55%. Model simulations showed that the most recent vancomycin dosing regimen, which was based on an externally validated model, requires 20% and 60% decreases of the loading and maintenance doses of vancomycin, respectively, when aiming for optimized exposure in the neonatal population. By analyzing vancomycin data from preterm neonates comedicated with indomethacin, we found a substantial decrease in vancomycin clearance of 55% versus a previously reported 16% for ibuprofen. This decrease in clearance impacts vancomycin dosing, and we anticipate that other drugs eliminated by glomerular filtration are likely to be affected to a similar extent as vancomycin.

Indomethacin plus minocycline coadministration relieves chemotherapy and antiretroviral drug-induced neuropathic pain in a cannabinoid receptors-dependent manner

Neuropathic pain sometimes occurs during chemotherapy with paclitaxel or HIV/AIDS antiretroviral therapy with nucleoside reverse transcriptase inhibitors (NRTIs). We previously reported that coadministration of indomethacin plus minocycline (IPM) was antihyperalgesic in a cannabinoid type 1 (CB1) receptor-dependent manner in a mouse model of paclitaxel-induced neuropathic pain. We evaluated if IPM combination has antihyperalgesic and antiallodynic activities in animal models of paclitaxel or NRTI (ddC, zalcitabine)-induced neuropathic pain, and whether antagonists of CB1, CB2 receptors or G protein-coupled receptor 55 (GPR55) can inhibit these activities of IPM. IPM produced antihyperalgesic and antiallodynic effects against paclitaxel and ddC-induced thermal hyperalgesia and mechanical allodynia. WIN 55,212-2, a cannabinoid receptor agonist, also had antihyperalgesic activity. The antihyperalgesic and antiallodynic activities of IPM were antagonized by a CB1 receptor antagonist AM251 and a CB2 receptor antagonist AM630, but not a GPR55 antagonist ML193. IPM had no effects on the mean time spent on the rotarod, whereas WIN 55,212-2 reduced it in a dose-dependent manner. These results show that IPM at a fixed ratio produces antihyperalgesic and antiallodynic effects in mice models of both paclitaxel and NRTI-induced neuropathic pain which is dependent on both CB1 and CB2 receptors, without causing the typical cannabinoid receptor agonist-induced motor impairment.

546 Co-Administration of Indomethacin and Fk-506 to Prevent Post-Ercp Pancreatitis

546 Co-Administration of Indomethacin and Fk-506 to Prevent Post-Ercp Pancreatitis

Non-Steroidal Anti-Inflammatory Drugs and Vitamin C in the Rotenone Induced Nigrostriatal Damage in Mice

The nigrostriatal pathway is a dopaminergic pathway that connects the substantia nigra with the dorsal striatum. Loss of dopamine neurons in the substantia nigra is one of the main pathological features of Parkinson's disease, leading to a marked reduction in dopamine function in this pathway. This study aimed at evaluating the protective role of two anti-inflammatory drugs, indomethacin and nimesulide separately or in combination with vitamin C against biochemical disturbances, brain damage and motor impairment in rotenone-induced mice model of Parkinson's disease. Animals were divided into 7 groups. 1 st received the vehicle (DEMSO); 2nd received rotenone (1.5 mg/kg); 3rd received rotenone then were left for two weeks recovery; 4th rotenone + indomethacin (10 mg/kg); 5th received rotenone + indomethacin in combination with vitamin C (25 mg/kg). 6th received rotenone + nimesulide (10 mg/kg); group 7 received rotenone + nimesulide in combination with vitamin C. All treatments were given subcutaneously three times per week for one month. Rotenone treatment caused significant Increases in brain malondialdehyde (MDA), nitric oxide (NO), but induced significant decreases in brain reduced glutathione (GSH) level, acetylcholinesterase (AChE) activity, dopamine (DA), norepinephrine (NE) and serotonin (5-HT) levels. These changes lasted for two weeks after the termination of rotenone treatment. Histologically, Rotenone caused degeneration of neurons in striatum, cellular infiltration, atrophy, pyknosis, necrosis, as well as focal gliosis in cerebral cortex and pyknosis of pyramidal cells in the hippocampus. Furthermore, rotenone treatment caused a significant impairment in the motor function of the mice (stair test). Co-administration of indomethacin or nimesulide separately or in combination with vitamin C to rotenone treated mice resulted in alleviation of biochemical and motor activity but not the histological disturbances caused by rotenone treatment alone.

Co-administration of Magnesium Ion Prevents Indomethacin-Induced Intestinal Ulcerogenic Lesions in Adjuvant-Induced Arthritis Rats.

In a study to find ways to prevent the side effects of indomethacin (IMC), we previously reported that magnesium ion (Mg2+) can prevent the onset of IMC-induced gastric mucosa in adjuvant-induced arthritis (AA) rats, a model for rheumatoid arthritis (RA). In this study we investigated whether the co-administration of IMC and Mg2+ prevents the formation and aggravation of intestinal ulcerogenic lesions in AA rats. The single oral administration of an excessive dose of IMC (40 mg/kg) induces hemorrhagic lesions and nitric oxide (NO) production via inducible nitric oxide synthase (iNOS) in the jejunal and ileal mucosa of AA rats, and the extent of the lesions, as well as iNOS and NO levels in AA rats are higher than in normal rats. On the other hand, the co-administration of 200 mg/kg Mg2+ attenuates intestinal ulceration and the elevation in the iNOS and NO levels in AA rats. Further, hemorrhagic lesioning and enhanced iNOS and NO levels in AA rats also result from the repetitive oral administration of 3 mg/kg IMC (therapeutic dose) for 42 d (once a day), and these changes are also prevented by the co-administration of 200 mg/kg Mg2+. In conclusion, the co-administration of Mg2+ suppresses the ulcerogenic response to IMC in the jejunal and ileal mucosa of AA rats, probably by preventing the elevation of iNOS and NO levels in the region.

The Effect of Tramadol and Indomethacin Coadministration on Gastric Barrier Function in Dogs

BackgroundTramadol is a centrally acting analgesic that is often used in conjunction with nonsteroidal anti‐inflammatory drugs (NSAIDs). The effect of coadministration of tramadol and indomethacin on gastric barrier function in dogs is unknown.Hypothesis/ObjectivesThat coadministration of a nonselective NSAID (indomethacin) and tramadol would decrease recovery of barrier function as compared with acid‐injured, indomethacin‐treated, and tramadol‐treated mucosa.AnimalsGastric mucosa of 10 humanely euthanized shelter dogs.MethodsEx vivo study. Mounted gastric mucosa was treated with indomethacin, tramadol, or both. Gastric barrier function, prostanoid production, and cyclooxygenase expression were quantified.ResultsIndomethacin decreased recovery of transepithelial electrical resistance after injury, although neither tramadol nor the coadministration of the two had an additional effect. Indomethacin inhibited production of gastroprotective prostanoids prostaglandin E2 (acid‐injured PGE 2: 509.3 ± 158.3 pg/mL, indomethacin + acid injury PGE 2: 182.9 ± 93.8 pg/mL, P < .001) and thromboxane B2 (acid‐injured TXB 2: 233.2 ± 90.7 pg/mL, indomethacin + acid injury TXB 2: 37.9 ± 16.8 pg/mL, P < .001), whereas tramadol had no significant effect (PGE 2 P = .713, TXB 2 P = .194). Neither drug had an effect on cyclooxygenase expression (COX‐1 P = .743, COX‐2 P = .705). Acid injury induced moderate to marked epithelial cell sloughing, which was unchanged by drug administration.Conclusions and Clinical ImportanceThere was no apparent interaction of tramadol and a nonselective cyclooxygenase in this ex vivo model. These results suggest that if there is an adverse interaction of the 2 drugs in vivo, it is unlikely to be via prostanoid inhibition.

Effects of Histamine H4 Receptor Ligands in a Mouse Model of Gastric Ulceration

Aim: In the present study we examined whether histamine H₄ receptors (H₄Rs) have a role in gastric ulcerogenesis using a mouse model of gastric damage. Methods: The H₄R antagonist JNJ7777120 and the H₄R agonists VUF8430 and VUF10460 were investigated in fasted CD-1 mice against the ulcerogenic effect induced by co-administration of indomethacin (IND, 30 mg/kg s.c.) and bethanechol (BET, 5 mg/kg i.p.). Both macroscopic and histologic lesions were examined. Strain-related differences were investigated by testing JNJ7777120 also in NMRI, BALB/c and C57BL/6J mice. Results: Neither JNJ7777120 nor the H₄R agonists displayed effects in the normal stomach at any dose tested (10 and 30 mg/kg s.c.). As expected, IND+BET provoked several lesions in the fundic mucosa, which were significantly reduced by JNJ7777120 (10 and 30 mg/kg s.c.). The gastroprotective effect of JNJ7777120 (10 and 30 mg/kg s.c.) was observed in CD-1, NMRI and BALB/c, but not in C57BL/6J, mice. In CD-1 mice, the H₄R agonists VUF8430 and VUF10460 (both at 10 and 30 mg/kg s.c.) did not modify the damage induced by IND+BET, however VUF8430 (10 mg/kg s.c.) prevented the gastroprotection induced by JNJ7777120 (10 mg/kg s.c.). Conclusions: Data obtained with selective ligands suggest that the H₄R may have a role in mouse gastric ulcerogenesis. If confirmed in humans, these data would emphasize the potential advantage of H₄R blockers as gastrosparing anti-inflammatory drugs. The lack of effects of JNJ7777120 in C57BL/6J mice has to be carefully considered in the pharmacological characterization of H₄R functions and/or new selective ligands.

Chemopreventive effects of NSAIDs as inhibitors of cyclooxygenase-2 and inducers of apoptosis in experimental lung carcinogenesis

Roles of cyclooxygenase (COX) enzyme and intrinsic pathway of apoptosis have been explored for the chemopreventive effects of non-steroidal anti-inflammatory drugs (NSAIDs) on 9,10-dimethyl benz(a)anthracene (DMBA)-induced lung cancer in rat model. 16 weeks after the administration of DMBA, morphological analysis revealed the occurrences of tumours and lesions, which were regressed considerably with the co-administration of indomethacin and etoricoxib, the two NSAIDs under investigation. DMBA group was marked by hyperplasia and dysplasia as observed by histological examination, and these features were corrected to a large extent by the two NSAIDs. Elevated levels of COX-2 were seen in the DMBA group, the enzyme responsible for prostaglandin synthesis during inflammation and cancer, whilst the expression of the constitutive isoform, COX-1, was equally expressed in all the groups. Apoptosis was quantified by studying the activities of apaf-1, caspase-9, and 3 by immunofluorescence and western blots. Their activities were found to diminish in the DMBA-treated animals as compared to the other groups. Fluorescent co-staining of the isolated broncho-alveolar lavage cells showed reduced number of apoptotic cells in the DMBA group, indicating decrease in apoptosis after carcinogen administration. The present results thus suggest that the mechanism of cancer chemoprevention of NSAIDs may include the suppression of COX-2 and the induction of apoptosis.

Histopathologic study on the effects of methionine in reduction of nephrotoxicity due to co-administration of gentamicin and indomethacin in rats

Gentamicin is a wide spectrum aminoglycoside used against gram negative bacterial infections, but its clinical utility is restricted due to nephrotoxicity.Indomethacin is one of the NSAIDs with side effects on Kidney. Co-administration of indomethacin and gentamicin is necessary in some cases and may exaggerate gentamicin nephrotoxic effects. L-methionine can reduce gentamicin nephrotoxicity, so it may protect kidney from gentamicin and indomethacin co-administrative side effects.In this research, 42 male Sprague dawley rats were divided randomly into 6 equal groups. In the period of 14 days group 1-6 received normal saline (I.P),gentamicin (80 mg/kg BW, intramuscularly (I.M)), indomethacin ( I.M), gentamicin (I.M) plus indomethacin (I.M), L-methionine ( I.P),and gentamicin (I.M) plus indomethacin (I.M)and L-methionine(I.P) respectively once a day. In day 15, rats were euthanized and histopathologic slides of the kidneys were prepared.Histopatho logic examination revealed renal congestion, severe acute tubular necrosis, interstitial nephritis, glomerular atrophy and tubular dilatation in cortex in group 2. Glomerular hypercellularity was seen in group 3. In group 4, renal congestion, severe acute tubular necrosis,interstitial nephritis, glomerular hypercellularity and hyaline casts were seen. In group 5, medullary congestion and in group 6, renal congestion, tubular epithelial regeneration and normal tubules were seen. There was no microscopic lesion in group 1. The results of the present study showed that co-administration of gentamicin and indomethacin caused severe nephrotoxicity and L-methionine could ameliorate this effect.

Histopathologic study on the effects of methionine in reduction of hepatotoxicity and gastritis due to co-administration of gentamicin and indomethacin in rats

Gentamicin is a wide spectrum aminoglycoside used against gram negative bacterial infections, therapeutic does of this drug resulted in nephrotoxicity and hepatotoxicity. Indomethacin is one of the NSAIDs with side effects on stomach, liver and Kidney. Co-administration of indomethacin and gentamicin may resulted in exaggeration of their side efects .In this research, 42 male Sprague dawley rats were divided randomly into 6 equal groups. In the period of 14 days group 1-6 received normal saline (I.P), gentamicin (I.M), indomethaci (I.M), gentamicin (I.M) plus indomethacin (I.M), L-methionine (I.P), and gentamicin (I.M) plus indomethacin (I.M) and L-methionine(I.P) respectively once a day. In day 15, rats were euthanized and histopathologic slides of the liver and stomach were prepared. Histopathologic examination revealed and edema in tunica mucosa and submucosa of stomach in group 3 and 4, and mild hemorrahage in tunica mucosa of stomach of group 3 .In group 2 and 4 capillarization , deformed hepatocytes , apoptosis and mononuclear cell infiltration in portal area were seen in liver . Fibrosis of portal area was obvious in group 4. For the first time the results of the peresent study showed that methionine can prevent form side effects of Co-administration of indomethacin and gentamicin in liver and stomach.

Coadministration of Estradiol/Drospirenone and Indomethacin Does Not Cause Hyperkalemia in Healthy Postmenopausal Women: A Randomized Open‐Label Crossover Study

The effect of drospirenone on plasma potassium when coadministered with nonsteroidal anti-inflammatory drugs, such as indomethacin, is unknown. An open-label crossover study investigated the effects of estradiol/drospirenone and indomethacin coadministration on plasma potassium levels in 32 postmenopausal women. Each participant received 2 treatments in random order: indomethacin alone for 5 days and estradiol/drospirenone alone for 12 days, then estradiol/drospirenone plus indomethacin for 5 days. Plasma potassium profiles (24 hours) were measured on the first and last days of indomethacin administration. No difference was seen between treatments in the area under the curve or maximum concentration of plasma potassium. No participant experienced hyperkalemia (potassium >5.5 mmol/L). Twenty-seven participants had at least 1 potassium value above the upper limit of normal (4.4 mmol/L), but these occurred during both treatments. Coadministration of estradiol/drospirenone and a nonsteroidal anti-inflammatory drug such as indomethacin is not expected to result in increased plasma potassium or hyperkalemia in healthy postmenopausal women.

The influence of indomethacin co-administration on ofloxacin levels in plasma and cerebrospinal fluid in rats

The possible increase of ofloxacin levels in serum and cerebrospinal fluid (CSF) by concomitant indomethacin administration was investigated in 120 healthy adult rats. The animals were administered intramuscular doses of ofloxacin 30 mg/kg alone (Group A, n=60) or with indomethacin 2 mg/kg (Group B, n=60). Blood and CSF samples were obtained from both groups at 30, 45, 60 and 90 min post-administration. Concentrations of ofloxacin were estimated using a microbiological assay. Co-administration of indomethacin did not affect plasma levels of ofloxacin significantly; however, higher levels were found in all CSF samples after co-administration with indomethacin, particularly after 90 min with 0.59 μg/ml versus zero median values when only ofloxacin was administered ( P=0.05). No central nervous system adverse effects were observed clinically. No correlation between levels of ofloxacin in plasma and CSF could be established either in rats administered only ofloxacin or in rats administered both drugs. The presented pharmacokinetic findings revealed that co-administration of ofloxacin and indomethacin may result in protracted quinolone levels in the CSF. However, the absence of significant correlation between concentrations of ofloxacin in plasma and CSF upon co-administration of indomethacin, as well as of central nervous system adverse effects, make the probability of an epileptogenic interaction between them unlikely. These results merit further clinical evaluation.

Evidence for the involvement of cyclooxygenase activity in the development of cocaine sensitization

Phospholipase A2 (PLA 2) activation generates the release of arachidonic acid (AA) and platelet-activating factor (PAF), two compounds which may be involved in neuroplasticity. In previous studies, we found that PLA 2 activation is involved in the development of stimulant sensitization. In the present study, we have examined the roles of AA and PAF in the development of stimulant sensitization using agonists and antagonists selective for PAF receptors or the induction of various AA cascade-mediated eicosanoids. Sprague–Dawley rats were treated for 5 days with cocaine (30 mg/kg) or d-amphetamine (1 mg/kg) preceded 15 min earlier by various antagonists, and then tested following a 10-day withdrawal period for cocaine (15 mg/kg) or d-amphetamine (0.5 mg/kg)-induced locomotion. Consistent with our earlier work, pretreatment with the PLA 2 inhibitor quinacrine (25 mg/kg) blocked the development of cocaine and amphetamine sensitization. The lipoxygenase (LOX) inhibitors nordihydroguaiaretic acid (NDGA) (5–10 mg/kg) and MK-886 (1 mg/kg) had no effect on cocaine sensitization. The PAF receptor antagonist WEB 2086 (5–10 mg/kg) reduced the development of cocaine sensitization. The cyclooxygenase (COX) inhibitors indomethacin (1–2 mg/kg), piroxicam (0.5–1 mg/kg), 6-methoxy-2-napthylacetic acid (6-MNA; 0.5–1 mg/kg), and NS-398 (0.5–1 mg/kg) blocked the development of cocaine sensitization. The COX inhibitors indomethacin (2 mg/kg) and 6-MNA (1 mg/kg) also reduced the development of amphetamine sensitization. Rats were administered bilateral intraventral tegmental area (VTA) injections of d-amphetamine (5 μg/side) or saline coadministered with indomethacin (0.5 μg/side) or vehicle three times over 5 days and were then tested after a 10-day withdrawal for d-amphetamine (0.5 mg/kg ip)-induced locomotion. Intra-VTA amphetamine induced a robust form of amphetamine sensitization, which was blocked by coadministration of indomethacin. Unilateral intra-VTA injections of PAF (1 μg) did not significantly alter cocaine (15 mg/kg ip)-induced locomotion when tested after a 3-day withdrawal. These findings suggest that COX, and possibly PAF, activity is involved in the development of stimulant sensitization. Neuroanatomical studies demonstrate that this may occur at the level of the VTA.