Novel Use of Dual Anti-Inflammatory Therapy to Overcome Drug Resistance and Improve Functional Recovery Following Spinal Cord Injury

Over 1.2 million Americans are currently living with a traumatic spinal cord injury (SCI). Despite the need for effective therapies, there are currently no proven effective treatments that can improve recovery of function in SCI patients. Many therapeutic compounds have shown promise in preclinical models of SCI, but all of these have fallen short in clinical trials. P-glycoprotein (Pgp) is an active transporter expressed on capillary endothelial cell membranes at the blood-spinal cord barrier (BSCB). Pgp limits passive diffusion of blood-borne drugs into the CNS, by actively extruding drugs from the endothelial cell membrane. Pgp can become pathologically up-regulated, thus greatly impeding therapeutic drug delivery (‘multidrug resistance’). Importantly, many drugs that have been evaluated for the treatment of SCI are Pgp substrates. We hypothesized that Pgp-mediated drug resistance diminishes the delivery and efficacy of neuroprotective drugs following SCI. We observed a progressive, spatial spread of Pgp overexpression within the injured spinal cord. To assess Pgp function, we examined spinal cord uptake of systemically-delivered riluzole, a drug that is currently being evaluated in clinical trials as an SCI intervention. Blood-to-spinal cord riluzole penetration was reduced following SCI in wild-type but not Pgp-null rats, highlighting a critical role for Pgp in mediating spinal cord drug resistance after injury. Others have shown that pro-inflammatory signaling drives Pgp up-regulation in cancer and epilepsy. We have detected inflammation in both acutely- and chronically-injured spinal cord tissue. We therefore evaluated the ability of the dual COX-/5-LOX inhibitor licofelone to attenuate Pgp-mediated drug resistance following SCI. Licofelone treatment both reduced spinal cord Pgp levels and enhanced spinal cord riluzole bioavailability following SCI. Thus, we propose that licofelone may offer a new combinatorial treatment strategy to enhance spinal cord drug delivery following SCI. Additionally, we assessed the ability of licofelone, riluzole, or both to enhance recovery of locomotor function following SCI. We found that licofelone treatment conferred a significant improvement in hindlimb function that was sustained through the end of the study. In contrast, riluzole did not improve functional outcome. We therefore conclude that licofelone holds promise as a potential neuroprotective intervention for SCI.

Exposure to nonsteroidal anti-inflammatory drugs and weight loss and hospitalization in non-small cell lung cancer patients

Background. Cancer cachexia is a common syndrome complex in cancer, occurring in nearly 80% of patients with advanced cancer and responsible for at least 20% of all cancer deaths. Cachexia is due to increased resting energy expenditure, increased production of inflammatory mediators, and changes in lipid and protein metabolism. Non-steroidal anti-inflammatory drugs (NSAIDs), by virtue of their anti-inflammatory properties, are possibly protective against cancer-related cachexia. Since cachexia is also associated with increased hospitalizations, this outcome may also show improvement with NSAID exposure. ^ Design. In this retrospective study, computerized records from 700 non-small cell lung cancer patients (NSCLC) were reviewed, and 487 (69.57%) were included in the final analyses. Exclusion criteria were severe chronic obstructive pulmonary disease, significant peripheral edema, class III or IV congestive heart failure, liver failure, other reasons for weight loss, or use of research or anabolic medications. Information on medication history, body weight and hospitalizations was collected from one year pre-diagnosis until three years post-diagnosis. Exposure to NSAIDs was defined if a patient had a history of being treated with NSAIDs for at least 50% of any given year in the observation period. We used t-test and chi-square tests for statistical analyses. ^ Results. Neither the proportion of patients with cachexia (p=0.27) nor the number of hospitalizations (p=0.74) differed among those with a history of NSAID use (n=92) and those without (n=395). ^ Conclusions. In this study, NSAID exposure was not significantly associated with weight loss or hospital admissions in patients with NSCLC. Further studies may be needed to confirm these observations.^

Meta-analysis of short term low dose prednisolone versus placebo and non-steroidal anti-inflammatory drugs in rheumatoid arthritis

Objective: To determine whether short term, oral low dose prednisolone (⩽15 mg daily) is superior to placebo and non-steroidal anti-inflammatory drugs in patients with rheumatoid arthritis.

Audit of selective and non-selective non-steroidal anti-inflammatory drug use in rural general practice

Aim: To identify the demographics and risk factors in a selected patient population prescribed non-selective and cyclo-oxygenase-2 (COX- 2) selective non-steroidal anti-inflammatory drugs (NSAIDs). Method: A structured clinical self-audit form was distributed in January to March 2001 to 155 interested general practitioners (GPs) in rural Queensland. Results: Seventy one GPs participated in the audit and contributed 1417 patient records - 790 patients had received nonselective NSAIDs and 627 had received COX-2 inhibitors (celecoxib or rofecoxib). Patients who received COX-2 inhibitors were significantly older, more likely to have clinically important concomitant illness, and more likely to be taking medication known to interact with NSAIDs. They were also twice as likely to have two or more risk factors for adverse effects. The most common reasons for switching from an NSAID to a COX-2 inhibitor were reported to be a previous side effect from an NSAID (primarily related to gastrointestinal effects) or the doctor's perception of the superior efficacy of COX-2 inhibitor therapy. Conclusions: This study has shown that COX-2 inhibitors were used in a distinctly different patient population compared to non-selective NSAIDs. There were significant variations in the demographics and number of risk factors - for example, cardiovascular and renal - between the two identified populations. These differences may be due to doctors selecting COX-2 inhibitors for patients at high risk of gastrointestinal complications. However, the prescribing pattern may also be partly due to misconceptions about the relative safety and efficacy of COX-2 inhibitor drugs.

Motivations and perceived influences on rural and urban general practitioners when prescribing conventional non-steroidal anti-inflammatory drugs or COX-2 inhibitors

Background and objective: Prescribers in rural and remote locations perceive that there are different influences on their prescribing compared with those experienced by urban prescribers. The aim of this study was to compare the motivations and perceived influences on general practitioners (GPs) when prescribing COX-2 inhibitors rather than conventional non-steroidal anti-inflammatory drugs (NSAIDs) between rural and urban-based GPs in Queensland, Australia. Methods: A questionnaire was administered to two geographically distinct groups of GPs, one urban (n = 67) and one rural (n = 67), investigating the reasons that the GP would prescribe a COX-2 inhibitor rather than a conventional NSAID or vice versa and also focusing on patients requesting a prescription for a COX-2 inhibitor. Results and discussion: A 51% response rate (n = 68) was achieved. The difference between the rural and the urban GPs was that the urban GPs were more likely to perceive that they were influenced to prescribe COX-2 inhibitors by their patients' knowledge of these new (at the time) drugs. GPs in both the rural and urban areas perceived the COX-2 selective inhibitors to be safer than conventional NSAIDs, and that there was little difference in terms of efficacy between the two drug classes. However, GPs from both of the study areas stated that conventional NSAIDs were preferred over COX-2 selective inhibitors, primarily due to their expense, if their patients were not at risk for developing a GI bleed. Conclusion: The motivations and perceived influences to prescribe a COX-2 inhibitor in rural and in urban areas of Queensland, Australia were very similar. Almost all surveyed GPs in rural and urban areas had patients request a prescription, or enquire about the COX-2 inhibitors. Urban GPs were more likely to feel pressured to prescribe a COX-2 inhibitor than their rural counterparts, agreeing with other research which found that patient pressure to prescribe appears to be greater in urban general practice.

Penetration of a topically applied nonsteroidal anti-inflammatory drug into local tissues and synovial fluid of dogs

Objective-To investigate penetration of a topically applied nonsteroidal anti-inflammatory drug (NSAID) into tissues and synovial fluid. Animals-5 Greyhounds. Procedure-Dogs were anesthetized and microdialysis probes placed in the dermis and gluteal muscle over each coxofemoral (hip) joint. Methylsalicylate (MeSA) was applied topically over the left hip joint. Dialysate and plasma (blood samples from the cephalic and femoral veins) were obtained during the subsequent 5 hours. Dogs were euthanatized, and tissue samples and synovial fluid were collected and analyzed for salicylic acid (SA) and MeSA by use of high-pressure liquid chromatography. Results-SA and MeSA concentrations increased rapidly (< 30 minutes after application) in dialysate obtained from treated dermis. Salicylic acid also appeared in plasma within 30 minutes and reached a plateau concentration after 2 hours, although combined drug concentrations (SA plus MeSA) in plasma obtained from femoral vein samples were twice those measured in plasma obtained from the cephalic vein (SA only). Treated muscle had a progressive decrease in NSAID concentration with increasing depth (SA and MeSA), but it was significantly higher than the concentration in untreated muscle. Substantial amounts of SA and MeSA were also measured in synovial fluid of treated joints. Conclusions and Clinical Relevance-Topically applied NSAIDs can penetrate deeply into tissues and synovial fluid. Local concentrations higher than circulating systemic concentrations are suggestive that direct diffusion and local blood redistribution are contributing to this effect. Systemic blood concentrations may be inadequate to describe regional kinetics of topically applied drugs.