Aspirin Synergistically Potentiates Isoflurane Minimum Alveolar Concentration Reduction Produced by Morphine in the Rat 

1998 ◽  
Vol 89 (6) ◽  
pp. 1489-1494 ◽  
Author(s):  
Ignacio A. Gomez de Segura ◽  
Ana B. Criado ◽  
Martin Santos ◽  
Francisco J. Tendillo
Keyword(s):  
Side Effects ◽  
Minimum Alveolar Concentration ◽  
Synergistic Effects ◽  
Objective Measure ◽  
Nonsteroidal Antiinflammatory Drugs ◽  
Antiinflammatory Drugs ◽  
Before And After ◽  
Male Wistar Rats ◽  
Clinically Significant ◽  
Analgesic Potency

Background The combination of opioids and nonsteroidal antiinflammatory drugs is more analgesic than the summed effect of each drug administered separately. This synergism has been used to obtain analgesia in the postoperative period at doses at which side effects are minimal. The aim of this study is to evaluate the analgesic interaction between aspirin and morphine in the rat during isoflurane anesthesia. The reduction in minimum alveolar concentration of isoflurane (MAC(ISO)) was used as an objective measure of the analgesic potency of individual drugs and their use in combination. Methods Thirty-seven male Wistar rats were anesthetized with isoflurane in oxygen, and the MAC(ISO) was determined before and after the intravenous administration of aspirin and morphine. Rats were administered morphine alone (1, 3, and 10 mg/kg) or morphine (1 and 3 mg/kg) and aspirin (30 mg/kg). The MAC(ISO) was determined from alveolar gas samples at the time of tail clamp. The duration of MAC(ISO) reduction was recorded. Results Aspirin did not have an effect on MAC(ISO), (average, 1.35+/-0.1%), whereas the combination of morphine (1 and 3 mg/kg) and aspirin (30 mg/kg) produced a reduction in the dose of morphine needed to produce the same degree of MAC(ISO) reduction. Actual MAC(ISO+drug) data were as follows: 1 mg/kg morphine, 1.17+/-0.14%; 3 mg/kg morphine, 0.98+/-0.15%; 1 mg/kg morphine plus aspirin, 0.90+/-0.04%; 10 mg/kg morphine, 0.63+/-0.13%; and 3 mg/kg morphine plus aspirin, 0.64+/-0.06%. Conclusions The synergistic effects of aspirin and morphine allow a clinically significant reduction in the requirements of isoflurane and isoflurane plus morphine, and these drug combinations may decrease the side effects associated with the use of single higher, equianalgesic doses of these drugs.

Dexamethasone and indomethacin modify endotoxin-induced respiratory failure in pigs

1985 ◽  
Vol 58 (1) ◽  
pp. 274-284 ◽  
Author(s):  
N. C. Olson ◽  
T. T. Brown ◽  
D. L. Anderson
Keyword(s):  
Respiratory Failure ◽  
Phase 1 ◽  
Dynamic Compliance ◽  
Nonsteroidal Antiinflammatory Drugs ◽  
Arachidonic Acid Metabolism ◽  
Antiinflammatory Drugs ◽  
Lung Water ◽  
Pulmonary Response ◽  
Flunixin Meglumine ◽  
Before And After

We studied the porcine pulmonary response to endotoxemia before and after administration of nonsteroidal antiinflammatory drugs (NSAID, i.e., indomethacin or flunixin meglumine) or dexamethasone (DEX). Escherichia coli endotoxin was infused intravenously into anesthetized 10- to 12-wk old pigs for 4.5 h. In endotoxemic pigs, the phase 1 (i.e., 0–2 h) increases in pulmonary arterial pressure, pulmonary vascular resistance (PVR), and alveolar-arterial O2 gradient and the decreases in cardiac index (CI) and lung dynamic compliance (Cdyn) were blocked by NSAID. Thus phase 1 changes were cyclooxygenase dependent. Furthermore, these effects were blocked or greatly attenuated by DEX. During phase 2 of endotoxemia (i.e., 2–4.5 h), the increased PVR and decreased CI and Cdyn were not blocked by NSAID but were attenuated by DEX, suggesting the presence of cyclooxygenase-independent metabolites. Both NSAID and DEX blocked the endotoxin-induced increases in lung water, bronchoalveolar lavage (BAL) neutrophil, and BAL albumin content. The fall in plasma proteins persisted in NSAID but not DEX-treated pigs. We conclude that endotoxemia in the pig causes severe acute respiratory failure largely mediated by cyclooxygenase and possibly lipoxygenase products of arachidonic acid metabolism.

scholarly journals Computer search for molecular mechanisms of ulcerogenic action of nonsteroidal antiinflammatory drugs

2014 ◽  
Vol 60 (1) ◽  
pp. 7-16 ◽  
Author(s):  
S.M. Ivanov ◽  
A.A. Lagunin ◽  
A.V. Zakharov ◽  
D.A. Filimonov ◽  
V.V. Poroikov
Keyword(s):  
Side Effects ◽  
Molecular Mechanisms ◽  
Structural Formula ◽  
Nonsteroidal Antiinflammatory Drugs ◽  
Mechanisms Of Action ◽  
Computer Search ◽  
Peptic Ulcers ◽  
Antiinflammatory Drugs ◽  
Material Resources ◽  
Data Signal

“Peptic ulcers” is the most frequent side effect of non-steroidal anti-inflammatory drugs (NSAIDs). Experimental data indicate that pathogenesis of peptic ulcers cannot be explained only by the inhibition of cyclooxygenases. The knowledge about other molecular mechanisms of action of drugs related with development of peptic ulcers could be useful for design of new safe NSAIDs. However, considerable time and material resources are needed for corresponding experimental research. For simplification of experimental search, we have developed an approach for in silico identification of probable molecular mechanisms of action of drugs related with its side effects. We have created the set of NSAIDs containing 85 substances with data about structures and side effects. The computer program PASS (Prediction of Activity Spectra for Substances) predicting more than 3000 molecular mechanisms of action based on structural formula of substances was used to estimate unknown molecular mechanisms of action for these set of NSAIDs. Statistically significant relationships between predicted molecular mechanisms of action and development of peptic ulcers have been established. We have discovered twenty-six molecular mechanisms of action (two known previously and twenty-four new) which probably related with development of peptic ulcers. By analyzing of Gene Ontology data, signal and metabolic pathways, publications in Medline, we formulated hypotheses about the role of ten molecular mechanisms of action in pathogenesis of peptic ulcer.

Methotrexate and Nonsteroidal Antiinflammatory Drug Interactions

1992 ◽  
Vol 26 (2) ◽  
pp. 234-237 ◽  
Author(s):  
Maureen L. Frenia ◽  
Kimberly S. Long ◽  
Edward A. Hartshorn
Keyword(s):  
Case Reports ◽  
Clinical Manifestations ◽  
Hepatic Metabolism ◽  
Antiinflammatory Drug ◽  
Nonsteroidal Antiinflammatory Drugs ◽  
Nonsteroidal Antiinflammatory Drug ◽  
Pharmacokinetic Studies ◽  
Hematologic Toxicity ◽  
Antiinflammatory Drugs ◽  
Clinically Significant

OBJECTIVE: To determine if the coadministration of methotrexate (MTX) and nonsteroidal antiinflammatory drugs (NSAIDs) results in a clinically significant drug interaction. DATA SOURCES: A case report of hematologic toxicity following the administration of MTX and flurbiprofen at our institution is presented. Six previously published case reports and five pharmacokinetic studies regarding MTX and NSAID interactions are available to assist in the evaluation of this potential interaction. DATA SYNTHESIS: Cases of various clinical manifestations during concomitant MTX and NSAID administration, including acute renal failure and pancytopenia, have been reported. The exact mechanism of the interaction has not been fully elucidated. Suggested theories to explain the mechanism of MTX toxicity include reduction in MTX clearance secondary to renal capillary constriction induced by NSAIDs, displacement of MTX or its metabolite from plasma proteins, competition between MTX and NSAIDs for renal tubular excretion, or impairment of hepatic metabolism of MTX by NSAIDs. Studies comparing MTX pharmacokinetics with or without concurrent NSAID therapy have not shown statistical differences in the parameters evaluated. However, one study did demonstrate differences in the pharmacokinetics of 7-hydroxymethotrexate, the active metabolite of MTX, when MTX was administered with aspirin. CONCLUSIONS: Although a clinically significant interaction does not occur in all patients, numerous case reports are available that demonstrate possible problems following the coadministration of MTX and NSAIDs. To date, the specific circumstances during which the reaction may occur have not been well defined.

Adrenal and vagus modulation of cisplatin-induced gastric emptying and ulceration

1993 ◽  
Vol 51 ◽  
pp. 406-407
Author(s):  
Surinder K. Aggarwal
Keyword(s):  
Smooth Muscle ◽  
Gastric Emptying ◽  
Side Effects ◽  
Broad Spectrum ◽  
Wistar Rats ◽  
Adrenal Glands ◽  
Secretory Activity ◽  
Ovarian Cancers ◽  
Before And After ◽  
Male Wistar Rats

Cisplatin is a most valuable broad spectrum antineoplastic drug available for the treatment of testicular and ovarian cancers. It has several severe toxic side effects of which gastrointestinal and nephrotoxicity are the major dose limiting. It also induces hypocalcemia and Hypomagnesemia that have been demonstrated to effect the secretory activity of the neurohypophysis and the parathyroid glands. In rats cisplatin treatment causes stomach bloating and ulceration that can be ablated by daily injections of calcium just before the treatment and during the treatment or using vagotomy. Adrenalectomy has also been shown to prevent ulceration. Present study is an effort to determine the effect of cisplatin on morphological and cytochemical changes in the neuromuscular interactions of the stomach smooth muscle and the adrenal glands before and after vagotomy.Male Wistar rats [Crl:(WI)BR] weighing 200-300 g were given intraperitoneal injection of 9 mg/kg in 0.85% saline. Alternate group of animals received in addition daily injections of calcium (1 ml of 1.3% calcium chloride).

scholarly journals Colonic Side Effects of Nonsteroidal Antiinflammatory Drugs

1999 ◽  
Vol 38 (3) ◽  
pp. 219-220 ◽  
Author(s):  
Norihiro KAMINAGA ◽  
Adolfo PARRA-BLANCO ◽  
Rikiya FUJITA
Keyword(s):  
Side Effects ◽  
Nonsteroidal Antiinflammatory Drugs ◽  
Antiinflammatory Drugs

scholarly journals Systematic study of constitutive cyclooxygenase-2 expression: Role of NF-κB and NFAT transcriptional pathways

2015 ◽  
Vol 113 (2) ◽  
pp. 434-439 ◽  
Author(s):  
Nicholas S. Kirkby ◽  
Melissa V. Chan ◽  
Anne K. Zaiss ◽  
Eliana Garcia-Vaz ◽  
Jing Jiao ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Side Effects ◽  
Constitutive Expression ◽  
Nonsteroidal Antiinflammatory Drugs ◽  
Cyclooxygenase 2 ◽  
Antiinflammatory Drugs ◽  
Activated T Cells ◽  
Nfat Activation ◽  
Cox 2 ◽  
Specific Tissue

Cyclooxygenase-2 (COX-2) is an inducible enzyme that drives inflammation and is the therapeutic target for widely used nonsteroidal antiinflammatory drugs (NSAIDs). However, COX-2 is also constitutively expressed, in the absence of overt inflammation, with a specific tissue distribution that includes the kidney, gastrointestinal tract, brain, and thymus. Constitutive COX-2 expression is therapeutically important because NSAIDs cause cardiovascular and renal side effects in otherwise healthy individuals. These side effects are now of major concern globally. However, the pathways driving constitutive COX-2 expression remain poorly understood. Here we show that in the kidney and other sites, constitutive COX-2 expression is a sterile response, independent of commensal microorganisms and not associated with activity of the inflammatory transcription factor NF-κB. Instead, COX-2 expression in the kidney but not other regions colocalized with nuclear factor of activated T cells (NFAT) transcription factor activity and was sensitive to inhibition of calcineurin-dependent NFAT activation. However, calcineurin/NFAT regulation did not contribute to constitutive expression elsewhere or to inflammatory COX-2 induction at any site. These data address the mechanisms driving constitutive COX-2 and suggest that by targeting transcription it may be possible to develop antiinflammatory therapies that spare the constitutive expression necessary for normal homeostatic functions, including those important to the cardiovascular-renal system.

Efficacy and safety of nonsteroidal antiinflammatory drugs for cancer pain: a meta-analysis.

1994 ◽  
Vol 12 (12) ◽  
pp. 2756-2765 ◽  
Author(s):  
E Eisenberg ◽  
C S Berkey ◽  
D B Carr ◽  
F Mosteller ◽  
T C Chalmers
Keyword(s):  
Single Dose ◽  
Side Effects ◽  
Cancer Pain ◽  
Multiple Dose ◽  
Nonsteroidal Antiinflammatory Drugs ◽  
Efficacy And Safety ◽  
Antiinflammatory Drugs ◽  
Pain Scores ◽  
Multiple Doses ◽  
Dose Effects

PURPOSE To assess the efficacy and safety of nonsteroidal antiinflammatory drugs (NSAIDs) in the treatment of cancer pain by meta-analyses of the published randomized control trials (RCTs). PATIENTS AND METHODS Twenty-five studies met inclusion criteria for analysis. Of these, 13 tested a single-dose effect, nine multiple-dose effects, and three both single- and multiple-dose effects of 16 different NSAIDs in a total of 1,545 patients. Baseline pain intensity (when provided) of moderate or higher was indicated in 81% of patients. RESULTS Single-dose NSAID studies found greater analgesic efficacy than placebo, with rough equivalence to 5 to 10 mg of intramuscular morphine. Pain scores differed insignificantly for aspirin versus three other NSAIDs. Analgesic responses to low- and high-dose NSAIDs suggested a dose-response relationship, but this was not statistically significant. Recommended and supramaximal single doses of three NSAIDs produced comparable changes in pain scores, which indicates a ceiling analgesic effect. Common side effects included upper gastrointestinal symptoms, dizziness, and drowsiness. The incidence of side effects showed a trend to increase with dose, without a ceiling effect, and to increase with multiple doses. Single or multiple doses of weak opioids (WO) alone or in combination (WO/C) with nonopioid analgesics did not produce greater analgesia than NSAIDs alone. Single doses of WO/C analgesics produced more side effects than NSAIDs alone, although both side effect incidence and patient dropout rates were equal when multiple doses were administered. CONCLUSION These findings question whether the traditional World Health Organization (WHO) second analgesic step (addition of a weak opioid when pain is inadequately treated by a nonopioid analgesic alone) is warranted. A lack of comparable studies precluded testing the hypothesis that NSAIDs are particularly effective for malignant bone pain.

A Novel Composite Endpoint to Evaluate the Gastrointestinal (GI) Effects of Nonsteroidal Antiinflammatory Drugs Through the Entire GI Tract

2009 ◽  
Vol 37 (1) ◽  
pp. 167-174 ◽  
Author(s):  
FRANCIS K. L. CHAN ◽  
BYRON CRYER ◽  
JAY L. GOLDSTEIN ◽  
ANGEL LANAS ◽  
DAVID A. PEURA ◽  
...  
Keyword(s):  
Randomized Clinical Trials ◽  
Composite Endpoint ◽  
Nonsteroidal Antiinflammatory Drugs ◽  
Gi Tract ◽  
Antiinflammatory Drugs ◽  
Open Label ◽  
Upper Gi ◽  
Standard Tool ◽  
Gi Toxicity ◽  
Clinically Significant

Objective.Nonsteroidal antiinflammatory drugs (NSAID) not only cause damage to the upper gastrointestinal (GI) tract but also affect the lower GI tract. To date, there is no endpoint that evaluates serious GI events in the entire GI tract. The objective of this report is to introduce a novel composite endpoint that measures damage to the entire GI tract — clinically significant upper and lower GI events (CSULGIE) — in patients with NSAID-induced GI damage.Methods.We reviewed the data from largescale, multicenter, randomized, clinical trials on lower GI toxicity associated with NSAID use. The rationale for using CSULGIE as a primary endpoint in 2 ongoing trials — the Celecoxib vs Omeprazole and Diclofenac for At-risk Osteoarthritis (OA) and Rheumatoid Arthritis (RA) Patients (CONDOR) trial and the Gastrointestinal Randomized Events and Safety Open-Label NSAID Study (GI-REASONS) — is also discussed.Results.Previous randomized trials focused primarily on damage to the upper GI tract and often neglected the lower GI tract. The CSULGIE endpoint extends the traditional “perforation, obstruction, and bleeding” assessment of upper GI complications by including events in the lower GI tract (small/large bowel) such as perforation, bleeding, and clinically significant anemia.Conclusion.By providing clinicians with a new, descriptive language for adverse events through the entire GI tract, the CSULGIE endpoint has the potential to become a standard tool for evaluating the GI effects of a range of therapies.

scholarly journals Adverse Effects of Nonsteroidal Antiinflammatory Drugs: An Update of Gastrointestinal, Cardiovascular and Renal Complications

2014 ◽  
Vol 16 (5) ◽  
pp. 821 ◽  
Author(s):  
Sam Harirforoosh ◽  
Waheed Asghar ◽  
Fakhreddin Jamali
Keyword(s):  
Side Effects ◽  
Adverse Effects ◽  
Nonsteroidal Antiinflammatory Drugs ◽  
Gi Tract ◽  
Antiinflammatory Drugs ◽  
Controlled Release Formulations ◽  
Gi Toxicity ◽  
Inflammatory Drugs ◽  
Cox 2

Non-steroidal anti-inflammatory drugs (NSAIDs) are used chronically to reduce pain and inflammation in patients with arthritic conditions, and also acutely as analgesics by many patients. Both therapeutic and adverse effects of NSAIDs are due to inhibition of cyclooxygenase (COX) enzyme. NSAIDs are classified as non-selective and COX-2-selective inhibitors (COXIBS) based on their extent of selectivity for COX inhibition. However, regardless of their COX selectivity, reports are still appearing on the GI side effect of NSAIDs particularly on the lower gastrointestinal (GI) tract and the harmful role of their controlled release formulations. In addition, previously unpublished data stored in the sponsor’s files, question the GI sparing properties of rofecoxib, a COXIB that has been withdrawn due to cardiovascular (CV) side effects. Presently, the major side effects of NSAIDs are the GI complications, renal disturbances and CV events. There is a tendency to believe that all NSAIDs are associated with renal and CV side effects, a belief that is not supported by solid evidence. Indeed, lower but still therapeutics doses of some NSAIDs may be cardioprotective. In this review, we briefly discuss the GI toxicity of the NSAIDs and assess their renal and CV adverse effects in more detail. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

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