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Pharmaceutical Research Feb 2004The purpose of this study was to assess if the definition of high solubility as proposed in the FDA Guidance on Biopharmaceutical Classification System (BCS) is too... (Comparative Study)
Comparative Study
PURPOSE
The purpose of this study was to assess if the definition of high solubility as proposed in the FDA Guidance on Biopharmaceutical Classification System (BCS) is too strict for highly permeable acidic drugs.
METHODS
The solubility and permeability values of 20 (18 acidic and 2 non-acidic) nonsteroidal anti-inflammatory drugs (NSAID) were determined. The NSAIDs were grouped into three different sets having acetic acid, propionic acid, or other acidic moieties such as fenamate, oxicam, and salicylate. Two nonacidic NSAIDs (celecoxib and rofecoxib) were also included for comparison purposes. Equilibrium solubility values were determined at pH 1.2, 5.0, 7.4, and in biorelevant media simulating fed intestinal fluid at pH 5.0. For a select number of acids, we also measured solubility values in media simulating gastric and fasted intestinal fluids. Permeability classification was established relative to that of reference drugs in the Caco-2 cell permeability model. Permeability coefficients for all drugs were measured at concentrations corresponding to the lowest and highest marketed dose strengths dissolved in 250 ml volume, and their potential interaction with cellular efflux pumps was investigated.
RESULTS
All NSAIDs with different acidic functional groups were classified as highly permeable based on their Caco-2 cell permeability. Only ketorolac appeared to have a potential for interaction with cellular efflux pumps. Solubility classification was based on comparison of equilibrium solubility at pH 1.2, 5.0. and 7.4 relative to marketed dose strengths in 250 ml. The pKa values for the acidic NSAIDs studied were between 3.5 and 5.1. and, as expected, their solubility increased dramatically at pH 7.4 compared to pH 1.2. Only three NSAIDs, ketorolac, ketoprofen. and acetyl salicylic acid, meet the current criteria for high solubility over the entire pH range. However, with the exception of ibuprofen, oxaprozin, and mefenamic acid, the remaining compounds can be classified as Class I drugs (high solubility-high permeability) relative to solubility at pH 7.4. The use of bio-relevant media simulating gastric and intestinal milieu for solubility measurements or increasing the dose volume to 500 ml did not provide for a better boundary for solubility classification.
CONCLUSIONS
Based on the current definition of solubility, 15 of the 18 acidic NSAIDs in this study will be classified as Class II compounds as the solubility criteria applies to the entire pH range of 1.2 to 7.4, although the low solubility criteria does not hold true over the entire pH range. Whence, of the 18 acidic drugs, 15 can be classified as Class I based on the pH 7.4 solubility alone. This finding is intriguing because these drugs exhibit Class I behavior as their absorption does not seem to be dissolution or solubility limited. It could then be argued that for acidic drugs, the boundaries for solubility are too restrictive. Solubility at pH > 5 (pH in duodenum) may be more appropriate because most compounds are mainly absorbed in the intestinal region. Consideration for an intermediate solubility classification for highly permeable ionizable compounds that reflects physiological conditions seems warranted.
Topics: Acids; Anti-Inflammatory Agents, Non-Steroidal; Caco-2 Cells; Humans; Permeability; Solubility; Terminology as Topic; United States; United States Food and Drug Administration
PubMed: 15032311
DOI: 10.1023/b:pham.0000016242.48642.71 -
Zhonghua Liu Xing Bing Xue Za Zhi =... Nov 2003To observe the rate of efficacy and adverse drug reaction of non-steroidal anti-inflammatory drugs (NSAIDs) in the population with osteoarthritis and rheumatoid... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To observe the rate of efficacy and adverse drug reaction of non-steroidal anti-inflammatory drugs (NSAIDs) in the population with osteoarthritis and rheumatoid arthritis, based on available clinical data.
METHODS
Using Meta analysis to evaluate the data of effect and safety profile of NSAIDs from 19 articles on randomized clinical trials published from 1990 to 2001 in Chinese journals. The total number of patients enrolled for evaluation on rates of effectiveness and adverse drug reaction were 1 732 and 2 925, respectively.
RESULTS
Data on the effect and safety were comparatively heterogeneous among different kinds of NSAIDs. The effective rates (95% CI) were as follows: nabunetone, 66.7% (61.9% - 71.4%); meloxicam, 68.4% (59.2% - 77.6%); naproxen, 64.5% (59.8% - 69.1%); nimesulide, 79.8% (75.7% - 84.0%); ibuprofen, 77.2% (70.7% - 83.8%); diclofenac, 77.1% (69.2% - 85.0%); oxaprozin, 65.8% (59.5% - 72.0%). Rates of adverse drug reaction (95% CI) were as follows: nabunetone, 16.3% (12.5% - 20.0%); meloxicam, 10.2% (4.2% - 16.2%); naproxen, 29.2% (24.8% - 33.6%); nimesulide, 20.2% (16.0% - 24.3%); ibuprofen, 16.7% (14.7% - 18.8%); diclofenac, 19.3% (11.9% - 26.7%); oxaprozin, 12.7% (8.9% - 16.7%) respectively.
CONCLUSION
The rates of effect and adverse reaction on patients having osteoarthritis and rheumatoid arthritis with NSAIDs treatment would largely depend on the drugs being used. Within 2 - 8 weeks of treatment, the effective rate and rate of adverse drug reaction with commonly used NSAIDs as nabumeton, meloxicam, etc., were 59.2% - 85.0% and 4.2% - 33.6%, respectively.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Rheumatoid; Butanones; China; Diclofenac; Humans; Ibuprofen; Meloxicam; Nabumetone; Naproxen; Osteoarthritis; Oxaprozin; Propionates; Randomized Controlled Trials as Topic; Sulfonamides; Thiazines; Thiazoles
PubMed: 14687510
DOI: No ID Found -
The Journal of Rheumatology Oct 2003To quantify the risk of the severe cutaneous adverse reactions Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) associated with use of nonsteroidal...
OBJECTIVE
To quantify the risk of the severe cutaneous adverse reactions Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) associated with use of nonsteroidal antiinflammatory drugs (NSAID).
METHODS
Three large data sources were analyzed: an international case-control study on severe cutaneous reactions (SCAR Study), a population based registry in Germany, and the US Food and Drug Administration (FDA) spontaneous reporting system.
RESULTS
In the international case-control study, the oxicams were associated with the greatest increase in risk of SJS and TEN (relative risk 34, 95% confidence interval 11-105). When the risk for only recently initiated use was compared to that for longterm use of these agents (> 8 weeks), the relative risk of SJS and TEN associated with oxicams was significantly increased (p < 0.05). German data registry confirm these findings. The incidence of spontaneous US reports of SJS and TEN (per 1,000,000 visits with a prescription) for diflusinal, sulindac, oxaprozin, and etodolac were not significantly lower than that of piroxicam (p > 0.05, all comparisons).
CONCLUSION
Although the absolute risks of SJS and TEN associated with NSAID use are low, these risks should be considered in monitoring patients who recently began therapy. In 3 independent databases, oxicams have higher risk of SJS and TEN than other NSAID widely used on the 2 continents. The FDA spontaneous reporting systems suggest some NSAID not widely used in Europe may have risks comparable to the oxicams.
Topics: Adverse Drug Reaction Reporting Systems; Anti-Inflammatory Agents, Non-Steroidal; Case-Control Studies; Female; Germany; Humans; International Cooperation; Male; Multivariate Analysis; Risk Factors; Stevens-Johnson Syndrome; United States
PubMed: 14528522
DOI: No ID Found -
Journal of Cutaneous Medicine and... 2002Pseudoporphyria is a diagnosis that is used when porphyria-like clinical lesions arise in the setting of normal porphyrin levels. This condition was first described in...
BACKGROUND
Pseudoporphyria is a diagnosis that is used when porphyria-like clinical lesions arise in the setting of normal porphyrin levels. This condition was first described in the 1960s and was initially related to the use of certain antibiotic drugs. In 1985, pseudoporphyria was first attributed to the use of nonsteroidal antiinflammatory drugs (NSAIDs). Subsequently, a host of NSAIDs and other drugs have been found to elicit the same clinical entity. The exact mechanism by which certain drugs create clinical lesions resembling porphyria cutanea tarda or erythropoietic protoporphyria is still unknown. A phototoxic mechanism is hypothesized.
OBJECTIVE
We describe six patients diagnosed with pseudoporphyria and detail the diagnostic tests leading to the eventual diagnosis.
RESULTS
The patients ranged in age from 27 to 59 years and had a female:male predominance of 2:1. The offending NSAID was DayPro (oxaprozin) for three of the patients, Relafen (nabumetone) for two of the patients, and Aleve (naproxen) for one patient. For each patient, histology and immunofluorescence was either consistent with the diagnosis of porphyria cutanea tarda or nonspecific, while serum, stool, and urine porphyrins did not support that diagnosis. Withdrawal of the offending agent provided relief from the clinical symptoms for each patient. None of our patients were rechallenged with the putative offending drug. However, prolonged avoidance has provided a sustained remission from symptoms in all six patients.
CONCLUSIONS
Pseudoporphyria is a relatively rarely reported condition. Clinical suspicion with appropriate laboratory and histopathologic findings help to make this diagnosis, and exclude true porphyrias. Rechallenge with the offending drug to produce symptom relapse has been proposed to be helpful in confirming this diagnosis of exclusion. Since all 6 patients with drug-induced pseudoporphyria experienced resolution of their symptoms after discontinuing the offending agent, we propose that this clinical correlation alone is sufficient to confirm this diagnosis. Our observation of six new cases of NSAID-induced pseudoporphyria over a two-year interval suggests that this is not a rare entity.
Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Case-Control Studies; Female; Humans; Male; Middle Aged; Porphyrias; Porphyrins; Skin
PubMed: 12118363
DOI: 10.1007/s10227-001-0051-8 -
The Journal of Pharmacology and... Jul 2002Nonsteroidal anti-inflammatory drugs (NSAIDs) have been reported to induce apoptosis in a variety of cell lines. In this study, we examined the effect of NSAIDs on the...
Nonsteroidal anti-inflammatory drugs (NSAIDs) have been reported to induce apoptosis in a variety of cell lines. In this study, we examined the effect of NSAIDs on the growth and apoptosis of synovial cells from patients with rheumatoid arthritis and analyzed the activation of peroxisome proliferator-activated receptor gamma (PPARgamma) as a possible mechanism of action of NSAIDs. Cell proliferation and viability were assessed from 5-bromo-2'-deoxyuridine incorporation and by 4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzene disulfonate (WST-1) assay, respectively. The apoptosis of synovial cells was identified by DNA fragmentation assay and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay. Indometacin, diclofenac, oxaprozin, and zaltoprofen reduced cell proliferation and induced apoptotic cell death in synovial cells, whereas ketoprofen and acetaminophen did not. N-[2-(cyclohexyloxyl)-4-nitrophenyl]-methanesulfonamide (NS-398), a selective cyclooxygenase-2 inhibitor, also inhibited cell proliferation, whereas it did not cause apoptosis. Rheumatoid synovial cells expressed PPARgamma mRNA, and the PPARgamma ligands 15-deoxy-Delta(12,14)-prostaglandin J(2) and troglitazone reduced the proliferation and induced apoptosis in synovial cells. Luciferase reporter assay demonstrated that not only PPARgamma ligands but also NSAIDs, which could induce apoptosis, increased the activation of PPARgamma in synovial cells. Furthermore, the ability of NSAIDs and PPARgamma ligands to stimulate the activation of PPARgamma correlated with their ability to decrease cell viability(r = 0.92, p < 0.01) and ability to induce DNA fragmentation (r = 0.97, p < 0.001) in synovial cells. These results suggest that PPARgamma is an attractive target for induction of apoptosis in rheumatoid synovial cells and that the activation of the PPARgamma pathway is associated with the apoptotic action of NSAIDs.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Arthritis, Rheumatoid; Biotransformation; Cell Division; Cell Survival; Cells, Cultured; Cyclooxygenase 1; Cyclooxygenase 2; DNA Fragmentation; Humans; In Situ Nick-End Labeling; Isoenzymes; Membrane Proteins; Prostaglandin-Endoperoxide Synthases; Receptors, Cytoplasmic and Nuclear; Reverse Transcriptase Polymerase Chain Reaction; Synovial Membrane; Transcription Factors
PubMed: 12065695
DOI: 10.1124/jpet.302.1.18 -
Journal of Ocular Pharmacology and... Feb 2002The effects of eye drops containing a propionic acid derivative (oxaprozin) at 0.1% concentration on ocular inflammation produced by sodium arachidonate in the rabbit's...
The effects of eye drops containing a propionic acid derivative (oxaprozin) at 0.1% concentration on ocular inflammation produced by sodium arachidonate in the rabbit's eye were evaluated. Furthermore, the aqueous bioavailability of the drug formulation in the uninflamed and inflamed eyes was evaluated. Oxaprozin eye drops significantly reduced the signs of ocular inflammation elicited by sodium arachidonate on conjunctiva and iris. Oxaprozin treatment significantly reduced the levels of polymorphonuclear leukocytes and protein concentration in aqueous samples obtained from the eyes treated with arachidonate. Present data suggest, for the first time, that oxaprozin may be employed topically to prevent ocular reactions where the arachidonic acid cascade is activated.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Aqueous Humor; Area Under Curve; Biological Availability; Conjunctivitis; Male; Neutrophils; Oxaprozin; Propionates; Rabbits
PubMed: 11858617
DOI: 10.1089/108076802317233234 -
Journal of Tongji Medical University =... 2001The efficacy and safety of leflunomide (LEF) in the treatment of rheumatoid arthritis (RA) were evaluated and the comparison with methotrexate's (MTX's) was performed in... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
The efficacy and safety of leflunomide (LEF) in the treatment of rheumatoid arthritis (RA) were evaluated and the comparison with methotrexate's (MTX's) was performed in a 12-week, single-blind, randomized, parallel trial for treating 81 patients with RA. There were 56 cases in LEF group and 25 cases in MTX group. The dose of LEF was 20 mg per day and MTX 15 mg per week. All patients took oxaproxin simultaneously at the 4th to 6th week after the trail. The results showed that the general effective rate and notable effective rate were 94.64% and 73.21% in LEF group, 72% and 44% in MTX group, respectively, with the differences being statistically significant between the two groups (P < 0.05). LEF and oxaprozin could obviously improve the symptoms, signs and joint functions. The incidence of side reactions was lower in LEF group (17.86%) than in MTX group (40.00%, P < 0.05). LEF had a good therapeutic effect for RA, especially for refractory RA and had slight side reactions, and could be regarded as a superior immunosuppressive agent used in the treatment of RA and other connective tissue diseases.
Topics: Adolescent; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Rheumatoid; Female; Humans; Isoxazoles; Leflunomide; Male; Methotrexate; Middle Aged; Oxaprozin; Propionates; Single-Blind Method
PubMed: 11523255
DOI: 10.1007/BF02888043 -
Journal of the American Geriatrics... May 2001Gastrointestinal (GI) complications are the most-common serious adverse reactions associated with nonsteroidal anti-inflammatory drugs (NSAIDs). We quantified the effect...
OBJECTIVES
Gastrointestinal (GI) complications are the most-common serious adverse reactions associated with nonsteroidal anti-inflammatory drugs (NSAIDs). We quantified the effect of specific NSAIDs on the rate of GI hospitalizations among older people living in long-term care.
DESIGN
Retrospective cohort study.
SETTING
All Medicare/Medicaid certified nursing homes in four states (Maine, Minnesota, New York, and South Dakota).
PARTICIPANTS
We identified 125,516 newly admitted residents from a database of all residents (1992-1996) of all Medicare/Medicaid certified nursing homes in four states. Using the federally mandated Minimum Data Set, which includes information on all drugs received (prescription and over-the-counter), we identified patients who received at least one prescription for aspirin (n = 19,101) or NSAIDs (n = 9,777). The control population consisted of all institutionalized persons who did not receive these drugs.
MEASUREMENTS
From Health Care Financing Administration inpatient claims, we identified the first hospitalization for GI perforation, ulcer, or hemorrhage that occurred during the year of follow up (ICD9-CM discharge codes: 531-534, 578). Cox proportional hazards models provided adjusted estimates of rate ratios.
RESULTS
NSAID exposure increased the GI-event-related hospitalization rate in both men (rate ratios (RR) = 2.64; 95% confidence interval (CI) = 1.17-5.99) and women (RR = 3.23; 95% CI = 1.85-5.65). The rate of GI hospitalizations for both men and women taking sulindac, naproxen, or indomethacin was higher than for nonusers. The risk of GI-event-related hospitalizations was greatest among women exposed to diflunisal (RR = 6.08; 95% CI = 2.27-16.26) or oxaprozin (RR = 6.03; 95% CI = 2.49-14.58).
CONCLUSIONS
Despite the high background rate of GI events, most NSAIDs increased the risk of GI hospitalization. Careful attention to choice of agent and dosing is needed in prescribing NSAIDs in this frail, older population.
Topics: Age Distribution; Aged; Anti-Inflammatory Agents, Non-Steroidal; Centers for Medicare and Medicaid Services, U.S.; Databases, Factual; Female; Gastrointestinal Diseases; Health Services Research; Hospitalization; Humans; Insurance Claim Reporting; Long-Term Care; Maine; Male; Medicaid; Medicare; Minnesota; New York; Nursing Homes; Proportional Hazards Models; Retrospective Studies; Risk Factors; Sex Distribution; South Dakota; United States
PubMed: 11380750
DOI: 10.1046/j.1532-5415.2001.49117.x -
The Journal of Rheumatology Sep 2000This 8 week randomized, double blind clinical trial compared the effect of a combined home based progressive exercise program and treatment with the nonsteroidal... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
OBJECTIVE
This 8 week randomized, double blind clinical trial compared the effect of a combined home based progressive exercise program and treatment with the nonsteroidal medication oxaprozin to treatment with oxaprozin alone on pain and physical functioning in older community dwelling patients with unilateral knee osteoarthritis (OA).
METHODS
Efficacy variables measured before and after 8 weeks included (1) pain using the Western Ontario McMaster (WOMAC) pain, physical disability, and stiffness subscales and a 10 point visual analog scale (VAS) before and after self-paced walking (SPW) and stepping (SPS) functional tasks; (2) physical function using the time to complete a self-paced 40 m walk (SPW) and 20 cycles of 2 steps (SPS): (3) physical activity level using the Physical Activity Scale for Elderly (PASE); (4) clinical measures of knee functioning (range of motion). One hundred seventy-nine men and women (mean age 74 +/- 6 yrs) with radiographic evidence of mild/moderate medial compartment OA were randomized to either a progressive home based knee exercise program (n = 88) or a control program (n = 89). All patients were given oxaprozin 1,200 mg per os daily.
RESULTS
We observed significant reduction from baseline in activity related pain (VAS); and improvement in SPW and SPS test time, passive range of motion, and PASE after 8 weeks in both groups. These changes were significantly greater (p < 0.05) in the exercise versus sham group.
CONCLUSION
Addition of a progressive exercise program to nonsteroidal antiinflammatory therapy in patients with knee OA can improve measures of activity and activity related pain more than medication alone.
Topics: Aged; Disability Evaluation; Double-Blind Method; Exercise Therapy; Female; Home Care Services; Humans; Male; Motor Activity; Osteoarthritis, Knee; Treatment Outcome
PubMed: 10990236
DOI: No ID Found -
Seminars in Arthritis and Rheumatism Apr 2000
Topics: Acquired Hyperostosis Syndrome; Adult; Anti-Inflammatory Agents, Non-Steroidal; Antirheumatic Agents; Drug Therapy, Combination; Female; Humans; Magnetic Resonance Imaging; Oxaprozin; Propionates; Sacroiliac Joint; Sulfasalazine; Treatment Outcome
PubMed: 10805358
DOI: 10.1016/s0049-0172(00)80020-7