sulindac and Pain

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Asthma; Chemical and Drug Induced Liver Injury; Diagnosis, Differential; Eosinophilia; Fatigue; Female; Fever; Headache; Hepatomegaly; Humans; Nausea; Pain; Sulindac

Prodrugs are pharmacologically inactive chemical derivatives of a drug molecule that require a transformation within the body in order to release the active drug. They are designed to overcome pharmaceutical and/or pharmacokinetically based problems associated with the parent drug molecule that would otherwise limit the clinical usefulness of the drug. The scientific rationale, based on clinical, pharmaceutical and chemical experience, for the design of various currently used prodrugs is presented in this review. The examples presented are by no means comprehensive, but are representative of the different ways in which the prodrug approach has been used to enhance the clinical efficacy of various drug molecules.

Topics: Absorption; Adrenal Cortex Hormones; Blood-Brain Barrier; Chloramphenicol; Drug Stability; Drug Therapy; Drug-Related Side Effects and Adverse Reactions; Humans; Pain; Pharmaceutical Preparations; Phenytoin; Solubility; Sulindac; Taste

The efficacy and safety of the nonsteroidal anti-inflammatory drugs imidazole.2-hydroxybenzoate and sulindac were compared in 30 patients with classical or definite rheumatoid arthritis. The trial was designed as a randomized parallel-group study comprising 15 patients given imidazole.2-hydroxybenzoate and 15 given sulindac orally for 28 days. Patients in both groups improved significantly in almost all of the variables evaluated. Imidazole.2-hydroxybenzoate was more effective than sulindac on Ritchie's articular index, left hand proximal interphalangeal joint circumference, erythrocyte sedimentation rate, and C-reactive protein. The incidence of side effects was significantly higher in patients treated with sulindac.

Topics: Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Rheumatoid; Blood Sedimentation; C-Reactive Protein; Clinical Trials as Topic; Female; Humans; Imidazoles; Indenes; Male; Middle Aged; Pain; Random Allocation; Salicylates; Sulindac

In a double-blind parallel group randomised study 191 patients with acute sprains and strains of ankle, hip, shoulder or knees were treated with either 400 mg sulindac or 1200 mg ibuprofen per day for 4 days; of these, 176 completed the trial. Spontaneous pain (day and night), pain on active movement, swelling and tenderness were assessed before and after the treatment period along with a physician's and patient's assessment of therapy at the end of the study. The vast majority of patients had a successful outcome whichever treatment they were taking. No patients reported any adverse effect during the study.

Topics: Adolescent; Adult; Clinical Trials as Topic; Double-Blind Method; Humans; Ibuprofen; Indenes; Male; Pain; Random Allocation; Sprains and Strains; Sulindac; Time Factors

Twenty-eight patients presenting with sports injuries were randomly allocated to receive either 200 mg sulindac twice daily or 400 mg ibuprofen 3-times daily. Pain symptoms (day and night ratings) and observer assessment of pain on movement, swelling and tenderness were recorded pre-treatment and after 3 and 7 days of therapy. One patient in the sulindac group was excluded from the study because initial symptoms were mild. Response, in terms of decrease in scores, was better in those receiving sulindac than in those given ibuprofen at both 3 and 7 days for the parameters of pain during the day (p less than 0.05 at 7 days) and pain on movement (p less than 0.05 at 3 days). Patient assessment of treatment at 3 and 7 days was significantly better in the sulindac group than in the ibuprofen group (p less than 0.025). The only reported side-effect was gastro-intestinal upset in a patient in the ibuprofen group. The results suggest that sulindac is an effective and well-tolerated treatment for the symptoms associated with sprain and strain injuries.

Topics: Adult; Anti-Inflammatory Agents; Athletic Injuries; Female; Humans; Ibuprofen; Indenes; Male; Pain; Sulindac; Time Factors

To examine benefit of sulindac for relief of musculoskeletal symptoms (MSS) in patients stable on aromatase inhibitors (AIs).. Sulindac was evaluated at 150 mg twice daily for effects on MSS at 3, 6, 9, and 12 months in 50 postmenopausal women stable on AI therapy for a median of 12.5 months for hormone receptor-positive breast cancer. A separate, non-randomized group of 50 similar patients was observed for change in MSS over 12 months. MSS severity was assessed using the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Index and Brief Pain Inventory Short Form (BPI-SF). The Functional Assessment of Cancer Therapy-General form (FACT-G) measured quality of life (QOL). Change in MSS and QOL across time was assessed in each group using linear mixed effects models.. Stiffness, not pain, was the main complaint at baseline. At 12 months, sulindac patients reported decreases (improvements) in mean (95% CI) Total WOMAC score [- 5.85 (- 9.73, - 1.96)] and WOMAC pain [- 5.40 (- 10.64, - 0 .18)], Stiffness [- 9.53 (- 14.98, - 4.08)] and Physical Function [- 5.61 (- 9.62, - 1.60)] subscales, but not BPI-SF worst pain. Among sulindac patients with higher baseline MSS severity, 35% experienced ≥ 50% improvement in Total WOMAC and Total FACT-G scores [6.18 (2.08, 10.27); P = 0.003]. For the observation group, MSS and QOL did not improve over 12 months, even among those with higher baseline MSS severity.. Sulindac may relieve MSS in AI patients, especially physical function and stiffness. Randomized controlled trials should further evaluate NSAIDs on AI-MSS and AI adherence.. NCT01761877, December, 2012.

Topics: Aromatase Inhibitors; Breast Neoplasms; Female; Humans; Pain; Quality of Life; Sulindac; Treatment Outcome

Osteoarthritis (OA), a most common and highly prevalent joint disease, is closely associated with dysregulated expression and modification of RXRα. However, the role of RXRα in the pathophysiology of OA remains unknown. The present study aimed to investigate whether RXRα modulator, such as K-80003 can treat OA. Experimental OA was induced by intra-articular injection of monosodium iodoacetate (MIA) in the knee joint of rats. Articular cartilage degeneration was assessed using Safranin-O and fast green staining. Synovial inflammation was measured using hematoxylin and eosin (H&E) staining and enzyme-linked immunosorbent assay (ELISA). Expressions of MMP-13, ADAMTS-4 and ERα in joints were analyzed by immunofluorescence staining. Western blot, RT-PCR and co-Immunoprecipitation (co-IP) were used to assess the effects of K-80003 on RXRα-ERα interaction. Retinoid X receptor α (RXRα) modulator K-80003 prevented the degeneration of articular cartilage, reduced synovial inflammation, and alleviated osteoarthritic pain in rats. Furthermore, K-80003 markedly inhibited IL-1β-induced p65 nuclear translocation and IκBα degradation, and down-regulate the expression of HIF-2α, proteinases (MMP9, MMP13, ADAMTS-4) and pro-inflammatory factors (IL-6 and TNFα) in primary chondrocytes. Additionally, knockdown of ERα with siRNA blocked these effects of K-80003 in chondrocytes. In conclusion, RXRα modulators K-80003 suppresses inflammatory and catabolic responses in OA, suggesting that targeting RXRα-ERα interaction by RXRα modulators might be a novel therapeutic approach for OA treatment.

Topics: Animals; Cartilage; Cells, Cultured; Chondrocytes; Disease Models, Animal; Estrogen Receptor alpha; HEK293 Cells; Humans; Inflammation; Joints; Male; NF-kappa B; Osteoarthritis; Pain; Protective Agents; Protein Binding; Rats, Sprague-Dawley; Retinoid X Receptor alpha; Signal Transduction; Sulindac; Synovial Membrane; Synovitis; Up-Regulation

The human glycine receptors (hGlyRs) are chloride-selective ion channels that mediate inhibitory neurotransmission in the brain stem and spinal cord. They are also targets for compounds of potential use in analgesic therapies. Here, we develop a strategy to discover analgesic drugs via structure-based virtual screening based on the recently published NMR structure of the hGlyR-α1 transmembrane domain (PDB ID: 2M6I ) and the critical role of residue S296 in hGlyR-α1 potentiation by Δ(9)-tetrahydrocannabinol (THC). We screened 1549 FDA-approved drugs in the DrugBank database on an ensemble of 180 hGlyR-α1 structures generated from molecular dynamics simulations of the NMR structure of the hGlyR-α1 transmembrane domain in different lipid environments. Thirteen hit compounds from the screening were selected for functional validation in Xenopus laevis oocytes expressing hGlyR-α1. Only one compound showed no potentiation effects; seven potentiated hGlyR-α1 at a level greater than THC at 1 μM. Our virtual screening protocol is generally applicable to drug targets with lipid-facing binding sites.

Topics: Analgesics, Non-Narcotic; Animals; Binding Sites; Cannabinoids; Drug Evaluation, Preclinical; Female; Lipids; Molecular Dynamics Simulation; Molecular Targeted Therapy; Nuclear Magnetic Resonance, Biomolecular; Oocytes; Pain; Protein Conformation; Protein Structure, Tertiary; Receptors, Glycine; Reproducibility of Results; Xenopus laevis

Topics: Anti-Inflammatory Agents, Non-Steroidal; Bipolar Disorder; Comorbidity; Drug Therapy, Combination; Lithium; Pain; Sulindac

Forty of 416 patients with familial adenomatous polyposis were noted to have intra-abdominal desmoid tumors, and a subgroup of 16 were treated with noncytotoxic drug therapy. Drugs used were sulindac (14 patients), sulindac plus tamoxifen (3 patients), indomethacin (4 patients), tamoxifen (4 patients), progesterone (DEPO-PROVERA; Upjohn Co., Kalamazoo, MI) (2 patients), and testolactone (1 patient). Therapy with these drugs for continuous periods of six months or more resulted in three complete and seven partial remissions. When treated patients were compared with untreated patients (n = 12), there were significant benefits for the treated group, both in reduction of desmoid size and in improvement of symptoms, despite the inherent selection bias against this. Sulindac was the only drug used in enough patients to permit independent evaluation of its effect, with one complete and seven partial reductions of tumor size. Some patients had a delayed response to sulindac, with tumor shrinkage occurring after an initial period of tumor enlargement. When using sulindac for the treatment of desmoid tumors, this phenomenon should be considered.

Topics: Abdominal Neoplasms; Adenomatous Polyposis Coli; Adult; Antineoplastic Combined Chemotherapy Protocols; Female; Fibroma; Humans; Male; Neoplasms, Multiple Primary; Pain; Remission Induction; Retrospective Studies; Sulindac

Sulindac (Clinoril), a nonsteroidal anti-inflammatory agent, has few reported neurologic toxic effects, all of which have been associated with systemic disease. To our knowledge, we describe the first reported case of isolated paresthesia and peripheral neuropathy, without systemic involvement, secondary to sulindac administration. A healthy, 30-year-old man, exposed to sulindac on two separate occasions, had an incapacitating isolated idential sensory neuropathy. The onset and duration of symptoms correlated directly to drug ingestion. This hypersensitivity response cannot be explained pathophysiologically by any mechanism. Repeated exposure and rechallenge of the subject to sulindac was deemed too dangerous, and precludes exact method to establish mechanisms to explain this transient, reproducible, idiosyncratic, adverse drug reaction.

Topics: Adult; Drug Hypersensitivity; Humans; Indenes; Male; Pain; Paresthesia; Peripheral Nervous System Diseases; Sulindac

Topics: Humans; Indenes; Knee; Male; Middle Aged; Pain; Psychoses, Substance-Induced; Sulindac

Topics: Adolescent; Arthritis, Rheumatoid; Drug Hypersensitivity; Humans; Indenes; Leukopenia; Liver; Male; Pain; Pharyngitis; Pneumonia; Pruritus; Sulindac