Potent Non-steroidal Anti-inflammatory Drug Research Articles

Optimisation of the Treatment of Acute Gout

Most of the drugs prescribed to treat acute gouty attacks were used before the introduction of modern clinical trials. Thus, there are few well-designed studies available to evaluate these drugs. Nevertheless, worldwide clinical experience supports the use of most nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine and corticosteroids in the treatment of acute gout. Colchicine has been widely used but toxicity, especially gastrointestinal adverse effects, are a major concern. Therapeutic regimens involving hourly or 2-hourly administration were based on the short initial half-life of colchicine in plasma. Other therapy schedules, such as early 8-hourly administration, may be equally effective and have fewer adverse effects. Unfortunately, comparative studies to investigate this have not been performed. Colchicine should not be prescribed to patients with either severe renal insufficiency or combined hepatic-renal insufficiency. Doses should be halved in patients with moderate renal function impairment. NSAIDs are the most widely prescribed drugs in the treatment of acute gout. Few comparative data are available, but any of the most potent NSAIDs are probably useful in the control of pain and inflammatory signs of acute gouty arthritis. Pharmacokinetic properties should be taken into account when selecting an NSAID for the treatment of gout, as rapid absorption and a short half-life may help to avoid accumulation in patients with subclinical renal function impairment. Comorbidities should always be kept in mind when prescribing NSAIDs. Patients with previous or recent gastrointestinal bleeding, those receiving anticoagulant therapy or with haemorrhage diathesis, and those with renal insufficiency are at risk of developing severe adverse effects from NSAID administration. Corticosteroids are probably a reasonable choice for patients in whom colchicine and NSAIDs may be hazardous or for those with a history of previous intolerance to these drugs. Few trials using prednisone, prednisolone or triamcinolone acetonide are available, and dosages are prescribed following empirical data. Corticotropin has also been used to treat acute gout. Although it has been proven to be as effective as other corticosteroids or indomethacin, the need for multiple doses, parenteral administration and the high cost are major limitations for its use. Currently, the choice of a drug for the treatment of acute gout will depend on the balance between its efficacy and the potential adverse effects in a particular patient.

Inhibition of diclofenac formulated in hyaluronan on angiogenesis in vitro and its intraocular tolerance in the rabbit eye.

To investigate the effect of diclofenac, a potent nonsteroidal anti-inflammatory drug, formulated in hyaluronan (diclofenac/HA) on angiogenesis in vitro and its intraocular toxicity in vivo. The effect of diclofenac/HA on angiogenesis was determined by choriocapillary endothelial cells on Matrigel stimulated by vascular endothelial growth factor (VEGF). The tube areas were quantified by image digital analysis. For toxicity study, diclofenac/HA was injected intravitreally with a dose range from 100 to 1080 microg in 26 rabbits following gas compression vitrectomy. Potential toxicity was assessed by indirect ophthalmoscopy and by histological studies (light and electron microscopy). Retinal function was monitored by electroretinography (ERG) in six rabbits that received 400 microg of diclofenac/HA. Diclofenac/HA, 180, 90 microg/ml, inhibited tube formation to 24% and 55% of the standard group (Media Ham's F12 plus 5% fetal calf serum and 50 ng/ml VEGF) respectively (P<0.01). Intravitreal injection of 540 microg or higher doses of diclofenac/HA resulted in ocular toxicity in the rabbit, demonstrated as cataract, vitreous haze and retinal damage observed by indirect ophthalmoscopy and light- and electron-microscopic examinations. No toxicity was observed in the eyes that received 400 microg or less diclofenac/HA, which was further supported by the normal ERG examined at 4 and 25 days post injection. Diclofenac/HA inhibits tube formation in vitro and is non-toxic to the rabbit retina at concentrations that are inhibitory to tube formation. Our results suggest diclofenac/HA may be an effective candidate to inhibit ocular neovascularisation related to granulomatous reaction in the eye.

Approach towards an integrative drug treatment of Alzheimer's disease.

At present pharmacotherapy of Alzheimer's disease (AD) is limited to acetylcholinesterase inhibitors. These drugs produce small, but consistent improvements of memory and global function, some are also positively influencing activities of daily living. This therapeutic approach neglects the complexity of AD and the fact that most of the degenerating neurons are not cholinergic. Acetylcholinesterase inhibitors are symptomatic drugs, with no influence on disease progression. There is a need for disease modifying compounds, or preventive drugs. Data are indicating that vitamin E has some ability to influence the disease progression. The potency of non-steroidal anti-inflammatory drugs (NSAIDs) or estrogen as preventive agents has to be explored further in prospective clinical studies. The initial hope in the use of naturally occurring neurotrophic factors, like nerve growth factor, to rescue cholinergic neurons from degeneration and to restore cognitive function has been disappointed in first, small clinical studies. The peptidergic drug Cerebrolysin exhibiting neurotrophic stimulation, neuroimmunotrophic regulation and induction of BBB glucose transporter expression, might be able to address the pathological changes of AD at different levels simultaneously. In addition to an impressive preclinical database, results from 3 placebo-controlled, double-blind studies demonstrate significant improvements of cognitive performance, global function and activities of daily living in AD patients. In all studies persisting improvements, up to 6 months after drug withdrawal, indicate a powerful disease modifying activity.

Lornoxicam, a new potent NSAID with an improved tolerability profile.

Lornoxicam is a member of the oxicam group of nonsteroidal antiinflammatory drugs (NSAIDs). Oxicams have potent antiinflammatory and analgesic effects, but their use is associated with a high risk of gastrointestinal adverse effects. Lornoxicam has been shown to be at least as effective as comparative NSAIDs and more effective than 10 mg morphine when used at doses > or = 8 mg to control pain after oral surgery. In addition, oral doses of lornoxicam of 16-24 mg daily have been more effective than tramadol 300 mg daily in pain following knee surgery. Lornoxicam combines the high therapeutic potency of oxicams with an improved gastrointestinal toxicity profile as compared to naproxen, for example. This is probably due to the short half-life of lornoxicam as compared to the other oxicams. The clinical trials published so far, mostly comparative, clearly do- cument the efficacy of lornoxicam as a potent analgesic with excellent antiinflammatory properties in a range of painful and/or inflammatory conditions, including postoperative pain and rheumatoid arthritis.

Influence of sex on the pharmacokinetics of tolmetin in the rat

The purpose of this study was to investigate sex-related differences in the pharmacokinetics of tolmetin, a potent nonsteroidal anti-inflammatory drug, in the rat. Male and female Wistar rats received oral tolmetin at two dose levels, 3.2 and 10 mg/kg. Blood samples were drawn at selected times after drug administration, and tolmetin concentration in whole blood was determined. Tolmetin was rapidly absorbed in all cases. C max increased with the dose, but was similar in both sexes. Notwithstanding, tolmetin half-life was significantly prolonged in females compared with males. As a result of the prolonged half-life, area under the curve values were significantly higher in females than in males. Tolmetin clearance was significantly reduced in females. The present results strongly suggest sex-related differences in the pharmacokinetics of tolmetin in the rat. Tolmetin elimination appears to be impaired in females, compared with males. The existence of sex-related differences in tolmetin pharmacokinetics in other species, including humans, requires further investigation.

Aspirin induced apoptosis in gastric cancer cells

Aspirin has been well known for its anti-pyretic and anti-inflammatory action over the past century. Its main action in the gastro-intestinal tract has always been associated with erosion and ulceration. However in recent years, there has been evidence suggesting that aspirin and the more potent non-steroidal anti-inflammatory drugs (NSAIDs), could reduce the risk of gastric and colon cancer. One of the possible mechanisms in chemo-prevention is the ability to induce apoptosis in epithelial cells of the gastro-intestinal origin. This article introduces the role of apoptosis in the body and the gastro-intestinal tract. Evidence on the chemo-preventive role of aspirin and NSAIDs are listed, and the mechanisms of action discussed.

Copper(II) complexes of a nonsteroidal anti-inflammatory drug niflumic acid. Synthesis, crystal structure of tetrakis-μ-(2-[3-(trifluoromethyl)phenyl]aminonicotinato)bis(dimethylsulfoxide)dicopper(II) complex at 190 K. Anti-inflammatory properties

The synthesis and characterization of three complexes with a potent nonsteroidal anti-inflammatory drug niflumic acid {2-[3-(trifluoromethyl)phenyl]aminonicotinic acid} with formula [Cu(niflumato) 2L] (L=H 2O, DMSO=dimethylsulfoxide, DMF= N, N-dimethylformamide) were investigated. The crystal and molecular structure of the {Cu(niflumato) 2(DMSO)} 2 was reported. Crystallographic data are as follows: monoclinic system, space group P2 1/ n, Z=2, a=11.1318(8), b=17.513(2), c=15.336(1) Å, β=103.316(8)°, V=2909.4(4) Å 3. The structure was refined to R=0.030 and w R=0.037 for 3702 reflections with I> σ( I). It consists of centrosymmetric binuclear units with the Cu–Cu i (symmetry code i: 1− x, − y, 1− z) distance between two centrosymmetrically related ions of 2.6272(5) Å. Each Cu(II) ion in [Cu 2(DMSO) 2(μ-niflumato) 4] is coordinated to an apical dimethylsulfoxide O atom on the one hand and to the equatorial carbonyl and carboxylic O atoms of two crystallographically independent niflumate moieties and their centrosymmetric counterparts on the other hand. In spite of the low-temperature (190 K) crystal measurements, one –CF 3 grouping exhibits some disorder. The biological activities of these complexes were compared to that of niflumic acid. Niflumic acid and its various copper complexes significantly inhibited polymorphonuclear leukocyte (PMNL) oxidative metabolism, as assessed by chemiluminescence and O − 2 generation measurement. This effect was dose-dependent. All copper complexes exerted a similar inhibiting effect which was always significantly higher than that exerted by the parent drug.

Structural requirements for the binding of non-steroidal anti-inflammatory drugs to the 78 kDa gastrin binding protein

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the proliferation of colorectal carcinoma cell lines in vitro and reduce the risk of colorectal carcinoma in vivo. The good correlation observed between the potency of NSAIDs as inhibitors of colorectal carcinoma cell proliferation and as antagonists of a 78 kDa gastrin binding protein (GBP) suggested that blockade of the GBP might contribute to the anti-proliferative effects of NSAIDs [G.S. Baldwin, V.J. Murphy, Z. Yang, T. Hashimoto, J. Pharmacol. Exp. Ther. 286 (1998) 1110–1114]. The most potent NSAID investigated was sulindac sulphide, which had an IC 50 value of 40 μM. In order to investigate the structural requirements for binding to the GBP, 26 analogues of sulindac sulphide and sulindac sulphoxide were tested for their ability to inhibit the binding of iodinated gastrin to the GBP. Six of the analogues inhibited gastrin binding by more than 50% at a concentration of 1 mM. The IC 50 values estimated by computer fitting of titration data were in the range of 280–940 μM. Comparison of the analogue structures suggests that a substituent with a carboxyl group is preferred in the R 2 position. In addition the location of the NSAID binding site within the GBP structure was investigated. NSAIDs bound to both the N- and C-terminal halves of the GBP, and the affinities determined were similar to the values previously reported for the full-length GBP. The results reported herein represent the first step in the rational design of more potent GBP antagonists, some of which may be useful for the treatment of colorectal carcinoma.

Anti-inflammatory and analgesic effects of a novel pyrazole derivative, FR140423

The pharmacological profile of a novel and newly discovered non-steroidal anti-inflammatory and analgesic compound, 3-(difluoromethyl)-1-(4-methoxyphenyl)-5-[4-(methylsulfinyl)phenyl]pyrazole (FR140423), was investigated. In recombinant human cyclooxygenase enzyme assays, the inhibition of prostaglandin E 2 formation by FR140423 was 150 times more selective for cyclooxygenase-2 than cyclooxygenase-1. Oral administration of FR140423 dose dependently reduced carrageenin-induced paw edema and adjuvant arthritis. These effects were two- to three-fold more potent than those of indomethacin. Unlike indomethacin, FR140423 did not induce mucosal lesions in the stomach. FR140423 showed dose-dependent anti-hyperalgesic effects in the yeast-induced hyperalgesic model. This effect was five-fold more potent than that of indomethacin. Furthermore, FR140423 increased the pain threshold in non-inflamed paws and, unlike indomethacin, it produced an analgesic effect in the tail-flick test. These analgesic effects were blocked by the μ-opioid antagonist naloxone. These results suggest that FR140423, a selective cyclooxygenase-2 inhibitor, is a potent non-steroidal anti-inflammatory drug (NSAID) without gastrointestinal side effects and is a unique compound having morphine-like analgesic effects.

Combination oral antiangiogenic therapy with thalidomide and sulindac inhibits tumour growth in rabbits.

Neovascularization facilitates tumour growth and metastasis formation. In our laboratory, we attempt to identify clinically available oral efficacious drugs for antiangiogenic activity. Here, we report which non-steroidal anti-inflammatory drugs (NSAIDs) can inhibit corneal neovascularization, induced by basic fibroblast growth factor (bFGF) or vascular endothelial growth factor (VEGF). This antiangiogenic activity may contribute to the known effects of NSAIDs on gastric ulcers, polyps and tumours. We found that sulindac was one of the most potent antiangiogenic NSAIDs, inhibiting bFGF-induced neovascularization by 50% and VEGF-induced neovascularization by 55%. Previously, we reported that thalidomide inhibited growth factor-induced corneal neovascularization. When we combined sulindac with thalidomide, we found a significantly increased inhibition of bFGF- or VEGF-induced corneal neovascularization (by 63% or 74% respectively) compared with either agent alone (P< 0.01). Because of this strong antiangiogenic effect, we tested the oral combination of thalidomide and sulindac for its ability to inhibit the growth of V2 carcinoma in rabbits. Oral treatment of thalidomide or sulindac alone inhibited tumour growth by 55% and 35% respectively. When given together, the growth of the V2 carcinoma was inhibited by 75%. Our results indicated that oral antiangiogenic combination therapy with thalidomide and sulindac may be a useful non-toxic treatment for cancer. © 1999 Cancer Research Campaign

Non-Steroidal Antiinflammatory Drugs

1. Non-steroidal antiinflammatory drugs (NSAIDs) are among the most frequently prescribed medications and are used primarily to control pain, stiffness, and reduce inflammation. 2. One of the most common adverse effects of NSAID therapy is gastrointestinal (GI) problems, specifically indigestion, nausea, dyspepsia, diarrhea, constipation, and gastritis. 3. Considerations in chronic pain management include non-pharmacologic treatment options (i.e., physical therapy, behavioral therapy, etc.), use of misoprostol for clients at high risk for NSAID induced GI problems, and monitoring blood and urine every 3 months to 1 year with chronic NSAID therapy to detect liver, kidney, and hematologic problems. 4. Current research is focused on development of a prostaglandin H synthetase (PGHS-2) inhibitor which should offer efficacy equal to the most potent NSAIDs with minimal side effects, including gastric safety.

Blockade of long chain fatty acid oxidation by non-steroidal anti-inflammatory drugs may contribute to inhibition of proliferation of human colorectal carcinoma cell lines

Non-steroidal anti-inflammatory drugs (NSAIDs) reduce the growth of colorectal carcinoma (CRC) cell lines. Although the mechanism appears to be independent of cyclooxygenases, the inhibitory target has not previously been defined. We now report for the first time that NSAIDs inhibit oxidation of the long chain fatty acid palmitate in human CRC cell lines with potencies which are in good agreement with the potencies of NSAIDs as inhibitors of cell proliferation. The absence of inhibition of acetate oxidation rules out an effect on mitochondrial functions. We conclude that the long chain fatty acid oxidation pathway may be a novel target for some of the inhibitory effects of NSAIDs on the growth of CRC cell lines.

Comparison of the cyclooxygenase-1 inhibitory properties of nonsteroidal anti-inflammatory drugs and selective COX-2 inhibitors, using sensitive microsomal and platelet assays

Two forms of cyclooxygenase (COX) activity are involved in the synthesis of prostaglandins, prostacyclins, and thromboxanes in mammalian cells. There is now convincing evidence, obtained with a number of structurally distinct inhibitors, that selective COX-2 inhibitors possess anti-inflammatory effects with an improved gastrointestinal tolerability compared with conventional nonsteroidal anti-inflammatory drugs (NSAIDs) affecting both COX-1 and COX-2. As more selective COX-2 inhibitors are being developed, assays with a high degree of sensitivity to inhibition are needed to compare the relative effects of compounds on COX-1 activity. In the present report, we describe a sensitive assay for the inhibition of human COX-1 based on the production of prostaglandin E2 by microsomes from U937 cells incubated with a subsaturating concentration of arachidonic acid. More than 45 NSAIDs and selective COX-2 inhibitors were tested in this assay. IC50 values ranged from 1 nM for flunixin and flurbiprofen to about 200-500 microM for salicylate and acetaminophen. Potent and nonselective NSAIDs such as sulindac sulfide, diclofenac, and indomethacin showed IC50 values of < 20 nM. Among the compounds that have been reported to show selectivity for COX-2, the rank order of potency against COX-1 was DuP 697 > SC-58451 > celecoxib > nimesulide-meloxicam-piroxicam-NS-398-RS-57067 > SC-57666 > SC-58125 > flosulide > etodolac > L-745,337 > DFU-T-614, with IC50 values ranging from 7 nM to 17 microM. A good correlation was obtained between the IC50 values for the inhibition of microsomal COX-1 and both the inhibition of TXB2 production by Ca2+ ionophore challenged platelets and the inhibition of prostaglandin E2 production by CHO cells stably expressing human COX-1. However, the microsomal assay was more sensitive to inhibition than cell-based assays and allowed the detection of inhibitory effects on COX-1 for all NSAIDs and selective COX-2 inhibitors examined with discrimination of their potency under conditions of limited availability of arachidonic acid.

New approaches to pain control in patients with cancer

Pain affects most patients with malignant disease, and the prevalence of severe pain increases in the advanced stages of the condition. One in 5 patients with cancer has uncontrolled pain, even after 10 years of the use of the World Health Organization programme for cancer pain control and its 'three-step ladder' for the rational use of analgesics including morphine. Morphine has long been the 'gold standard' for the treatment of severe cancer pain. However, its side-effects, particularly sedation, cognitive impairment and myoclonus at high doses, have provoked the use of 'opioid rotation' to alternatives such as methadone and hydromorphone. The new 72-h transdermal patch for fentanyl also offers advantages of reduced side-effects and increased convenience over oral morphine. Intravenous strontium-89 and bisphosphonate therapy are effective for both short- and long-term control of metastatic bone pain. The spinal N-methyl-D-aspartate (NMDA) receptor is important in modulating the plasticity of the central nervous system and in aggravating chronic pain through the phenomenon of 'wind-up'. The NMDA antagonist ketamine, an anaesthetic, can be used at low doses for the management of refractory and neuropathic pains. Among adjuvant drugs, ketorolac has emerged as a potent non-steroidal anti-inflammatory drug. Palliative care is gaining acceptance as a new discipline in healthcare. Its strategic role is being reviewed as an adjunct to cancer therapy at all stages and its use is no longer confined to the terminal phase of disease after curative treatment has failed. Pain control and other aspects of symptom control are, therefore, viewed as an integral part of cancer management.

Treatment of biliary colic with diclofenac: A randomized, double-blind, placebo-controlled study

BACKGROUND & AIMS: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been used to relieve biliary colic. Follow-up was limited in previous studies, and the role of NSAIDs in the natural history of biliary colic has not been clarified. The purpose of this study was to evaluate the efficacy of diclofenac, a potent NSAID, in the the immediate symptomatic relief of biliary colic and the prevention of cholelithiasis-related complications. METHODS: Fifty-three patients with cholelithiasis and biliary colic were enrolled in this randomized, double-blind, placebo-controlled study. They received a single 75-mg (3 mL) intramuscular injection of diclofenac (n = 27) or similarly administered 3 mL of saline (n = 26). All patients were followed up for at least 3 days. The effect of either treatment was assessed by changes in the severity of pain and the development of cholelithiasis-related complications. RESULTS: Complete relief of pain was obtained in 21 diclofenac and in 7 placebo patients; progression to acute cholecystitis was observed in 4 and 11 patients, respectively. Fewer overall complications were observed in the diclofenac group. CONCLUSIONS: In patients with cholelithiasis who present with biliary colic, a single 75-mg intramuscular dose of diclofenac can provide satisfactory pain relief and decrease substantially the rate of progression to acute cholecystitis. (Gastroenterology 1997 Jul;113(1):225-31)

Comparison of the cyclooxygenase-1 inhibitory properties of nonsteroidal anti-inflammatory drugs and selective COX-2 inhibitors, using sensitive microsomal and platelet assays

Two forms of cyclooxygenase (COX) activity are involved in the synthesis of prostaglandins, prostacyclins, and thromboxanes in mammalian cells. There is now convincing evidence, obtained with a number of structurally distinct inhibitors, that selective COX-2 inhibitors possess anti-inflammatory effects with an improved gastrointestinal tolerability compared with conventional nonsteroidal anti-inflammatory drugs (NSAIDs) affecting both COX-1 and COX-2. As more selective COX-2 inhibitors are being developed, assays with a high degree of sensitivity to inhibition are needed to compare the relative effects of compounds on COX-1 activity. In the present report, we describe a sensitive assay for the inhibition of human COX-1 based on the production of prostaglandin E2 by microsomes from U937 cells incubated with a subsaturating concentration of arachidonic acid. More than 45 NSAIDs and selective COX-2 inhibitors were tested in this assay. IC50 values ranged from 1 nM for flunixin and flurbiprofen to about 200-500 microM for salicylate and acetaminophen. Potent and nonselective NSAIDs such as sulindac sulfide, diclofenac, and indomethacin showed IC50 values of < 20 nM. Among the compounds that have been reported to show selectivity for COX-2, the rank order of potency against COX-1 was DuP 697 > SC-58451 > celecoxib > nimesulide-meloxicam-piroxicam-NS-398-RS-57067 > SC-57666 > SC-58125 > flosulide > etodolac > L-745,337 > DFU-T-614, with IC50 values ranging from 7 nM to 17 microM. A good correlation was obtained between the IC50 values for the inhibition of microsomal COX-1 and both the inhibition of TXB2 production by Ca2+ ionophore challenged platelets and the inhibition of prostaglandin E2 production by CHO cells stably expressing human COX-1. However, the microsomal assay was more sensitive to inhibition than cell-based assays and allowed the detection of inhibitory effects on COX-1 for all NSAIDs and selective COX-2 inhibitors examined with discrimination of their potency under conditions of limited availability of arachidonic acid.

Predictability of the clinical potency of NSAIDs from the preclinical pharmacodynamics in rats.

Relevance of the preclinical pharmacodynamic, toxicity and pharmacokinetic parameters predicting the clinical potency of nonsteroidal antiinflammatory drugs (NSAIDs) was evaluated. Data for oral potencies of 24 NSAIDs in rats were collected from the literature and from New Drug Applications with respect to the following parameters: antiinflammatory, analgesic, antipyretic, acute ulcerogenic activities, acute toxicity, in vitro inhibition of prostaglandin synthesis, acid dissociation constant (pKa), octanol-water partition coefficient and elimination half-life. Data for most of the in vivo parameters in rats were collected following single dose administration with the exception of adjuvant arthritis. Single and daily clinical doses were considered. All of these NSAIDs have been approved for marketing although not all have been sold in the USA. The preclinical data were compared to human dose (unit or daily doses) using single and multiple stepwise regression analyses. Analyses suggest that NSAIDs are effective in all models of preclinical tests for fever, pain and inflammation, however, carrageenin-induced rat paw edema model is clearly the best predictor of human dose. Rank order of preclinical models for predicting human dose is carrageenin > yeast induced fever > pressure induced pain = adjuvant arthritis in rats. The analysis suggested that the pain and adjuvant arthritis models in rats may also involve a prostaglandin independent mechanism. Of the two physicochemical factors tested, pKa contributed best to the carrageenin model towards predicting the clinical potency of NSAIDs. Mathematical relationships between human dose, carrageenin ED50 and pKa were established that may assist in the future clinical development of NSAIDs. Carrageenin-induced paw edema model in rats is the most robust predictor of the clinical potency of NSAIDs. Acid dissociation constant (pKa) appears to be a secondary contributor to the potency of NSAIDs. The relevance of the data analyses for developing cyclooxygenase-2 (COX-2) selective NSAIDs is discussed.

Percutaneous absorption of ketoprofen. I. In vitro release and percutaneous absorption of ketoprofen from different ointment bases

Ketoprofen (KP) is a potent non-steroidal anti-inflammatory drug which is used for the treatment of rheumatoid arthritis. The oral administration of KP can cause gastric irritation and renal adverse effects. Topical application of the drug can bypass gastrointestinal disturbances and provide relatively consistent drug levels at the site of action. Since the efficacy of an ointment depends on the type of ointment base and the concentration of the drug, four different bases (white petrolatum, cold cream, hydrophilic ointment and Carbopol 940 gel) were used at 1, 3, 5, 7 and 10% concentrations of KP to evaluate the effect of ointment base and concentration. The general rank order of the drug release was found to be: Carbopol gel > hydrophilic ointment > cold cream > white petrolatum. There was a positive correlation between the concentration of KP and release rate for all bases except Carbopol gel. The in vivo percutaneous absorption of KP from different ointment bases at 3% concentration was studied by carrageenan-induced paw edema in mice. The rank order of the percent edema inhibition was as follows: Carbopol gel ≥ hydrophilic ointment > cold cream > white petrolatum. There was a good correlation between the in vitro and in vivo results.

Meloxicam: A toxicology overview

Meloxicam is a new potent non-steroidal anti-inflammatory drug (NSAID), which in animal tests exhibits potential antiarthritic action and has a wider spectrum of anti-inflammatory activity than currently available NSAIDs. Toxicological testing of meloxicam in animals suggests that acute oral overdosage is unlikely to cause severe toxicity in man. Compared with other NSAIDs, meloxicam has a relatively weak effect on gastric acid secretion and on ulceration in the rat stomach. Whereas most NSAIDs can cause parenchymal kidney damage in animals at low plasma levels and over relatively short periods, meloxicam only induces such damage in the rat over the longer term. Meloxicam preferentially inhibits cyclooxygenase-2 (COX-2), rather than cyclooxygenase-1 (COX-1), which may explain its good gastric and renal tolerability. Meloxicam was chondroneutral in long-term studies in rats and mice. It was significantly less phototoxic in vitro than diclofenac, ketoprofen and naproxen, but similar to piroxicam and tenoxicam. There was no evidence of mutagenic, clastogenic, teratogenic or tumorigenic activity on immunogenic potential.

The use of ketorolac tromethamine oral rinse for the treatment of periodontitis in adults

Periodontitis is a chronic infectious and inflammatory disease which afflicts approximately three quarters of the world’s adult population over the age of thirty-five. Recently published studies have demonstrated that long-term administration (>-6 months) of non-steroidal anti-inflammatory drugs (NSAIDs) can halt the progressive loss of alveolar bone associated with this disease. The safe and efficacious twice daily use for six months of 0.1% ketorolac tromethamine oral rinse for the prevention of periodontal disease progression in adults has recently been demonstrated. This presentation summarizes our results to date regarding the pharmacokinetics, pharmacodynamics, safety and efficacy of the topical oral rinse form of this potent NSAID in patients with periodontitis.