Drugs Naproxen Research Articles

Complexation of the Non-steroidal Anti-inflammatory Drug Nabumetone with Modified and Unmodified Cyclodextrins

The inclusion of the anti-inflammatory drug, Nabumetone, in α-, β- and hydroxypropyl-β-cyclodextrin (CDs) is studied using UV-VIS absorption and steady-state fluorescence emission. Binding constants and thermodynamic parameters of complex formation are determined by spectrofluorimetry. The inclusion phenomena of Nabumetone with the three cyclodextrins is compared with that of the well known similar anti-inflammatory drug Naproxen. In the case of Nabumetone pronounced differences are observed in the complexation process with each cyclodextrin whereas the respective Naproxen complexes are nearly identical. 1H-NMR experiments show that the inclusion process in Nabumetone can occur either through the substituents in the -2 (butanone) or -6 (methoxy) positions in the naphthalene ring.

Novel esters and amides of nonsteroidal antiinflammatory carboxylic acids as antioxidants and antiproliferative agents.

A series of phenolic antioxidant ester and amide derivatives of the nonsteroidal antiinflammatory drug naproxen was designed to have both antiinflammatory and cytoprotective activity. Compounds were evaluated in vitro both for antioxidant activity, as assessed indirectly by thiobarbituric acid reactive substance (TBARS) formation in a membrane lipid peroxidation assay, and for antiproliferative activity, as indexed by the inhibition of DNA synthesis in cultured human vascular endothelial cells. Compounds of this series exhibited potent antioxidant activity, with IC50 values (1.6-11.63 microM) 2-6-fold lower than that of Trolox (6-hydroxy-2,5, 7,8-tetramethylchroman-2-carboxylic acid) and 400-1300-fold lower than that of vitamin E. Structural modifications of the ester or amide substructure (5a and 6a) did not affect antioxidant activity, but methylation of the 6-hydroxy substituent resulted in compound 6f which was devoid of antioxidant activity. Although indistinguishable in antioxidant activity, the amide derivatives tended to be more potent as antiproliferative agents than the corresponding esters. The IC50's for the amide derivatives (3, 5a-e, 8) ranged from 2 to 7 microM, while the IC50's for the structurally related esters (1, 2a-c, 6a-e) ranged from 9 to 22 microM. Moreover, studies with compound 6a indicate that the observed inhibition of DNA synthesis is reversible, suggesting that the antiproliferative activity is due to a cytostatic rather than cytotoxic activity of the compounds. Thus, the antioxidant-naproxen derivatives represent a novel series of agents that both protect against free-radical damage and possess cytostatic activity in vascular endothelial cells. Studies are in progress to assess the utility of these compounds as potential components of an ocular irrigating solution.

Renal targeting of a non-steroidal anti-inflammatory drug: effects on renal prostaglandin synthesis in the rat.

1. Renal specific targeting of the non-steroidal anti-inflammatory drug naproxen was obtained by coupling to the low-molecular-mass protein lysozyme. A previous study showed that conjugation to lysozyme resulted in a 70-fold increase of naproxen accumulation in the kidney with a subsequent renal release of the active metabolite naproxen-lysine.2. In the present study we questioned whether naproxen-lysozyme is active in the rat kidney, inhibiting the urinary excretion of prostaglandin E2 and renal sodium and water excretion in salt-restricted baseline conditions as well as during frusemide treatment.3.A high dose of free naproxen (10 mg.day-1. kg-1) did not affect prostaglandin E2 excretion in baseline conditions (naproxen, 11+/-1 ng/8 h; vehicle, 13+/-4 ng/8 h), whereas sodium and water excretion were, respectively, 3.0 and 1.6 times lower in the naproxen group (P<0.05). Naproxen completely prevented the frusemide-induced increase (3-fold) in prostaglandin E2 excretion (naproxen 6.6+/-1.1 ng/8 h, vehicle 40+/-12 ng/8 h, P<0. 005). Frusemide-stimulated natriuresis and diuresis were, respectively, 1.6 (P<0.05) and 1.8 times (P<0.005) lower in the naproxen group.4.A dose of 2 mg.day-1.kg-1 lysozyme-conjugated naproxen did not affect prostaglandin E2 excretion in baseline conditions (conjugate, 18+/-2 ng/8 h; vehicle, 24+/-5 ng/8 h). The conjugate also had no effect on sodium and water excretion. However, the naproxen conjugate completely prevented the frusemide-induced increase (2-fold) in prostaglandin E2 excretion (conjugate, 16+/-3 ng/8 h; vehicle, 48+/-13 ng/8 h, P<0.05). Surprisingly, frusemide-induced natriuresis and diuresis were not affected by the conjugate.5. In conclusion, a renal specific delivery of the non-steroidal anti-inflammatory drug naproxen using lysozyme results in an inhibitory effect on renal prostaglandin E2 synthesis but does not affect the excretion of sodium and water, in contrast to free naproxen.

Contribution of cAMP to the inhibitory effect of non‐steroidal anti‐inflammatory drugs in rat uterine smooth muscle

1. The effect of the non-steroidal anti-inflammatory drugs naproxen, mefenamic acid, phenylbutazone, piroxicam and tolmetin on the vanadate (0.3 mM)-induced tonic contraction, as well as the modifications of these effects by the G-protein inhibitor pertussis toxin, and the inhibitors of protein kinase A, Rp-cAMPS (Rp-Adenosine 3',5'-cyclic monophosphothioate triethylamine salt) and protein kinase C, H-7 [1(5-isoquinolynilsulfonyl)-2-methyl-piperazine], have been assayed to study the possible nature of intracellular mediators contributing to the inhibitory effects of NSAIDs in rat uterine smooth muscle incubated in medium lacking calcium plus EDTA. The effect of phorbol 12,13-dibutyrate on vanadate contraction and its modification with H-7 has also been examined. 2. Naproxen (6-600 microM), mefenamic acid (6-300 microM), phenylbutazone (6-300 microM), piroxicam (6-600 microM) and tolmetin (6-600 microM) produced concentration-dependent relaxation of vanadate-induced tonic contraction. The potency order, in accordance with their respective IC50 values was: phenylbutazone > or = mefenamic acid > or = naproxen > tolmetin > or = piroxicam. 3. The relaxant effects of naproxen, phenylbutazone, piroxicam and tolmetin were significantly antagonized with pertussis toxin (50 ng ml-1), Rp-cAMPS (100 microM) and H-7 (1 microM). However, the effect of mefenamic acid was unmodified by the three drugs. This suggests that the effect of mefenamic acid and other NSAIDs occur by different mechanisms. 4. Phorbol 12,13-dibutyrate relaxed the vanadate contraction but the maximal relaxation achieved (54.8 +/- 8.3%, n = 4) was lower than those induced with the NSAIDs. On the other hand, H-7 (1 microM) did not modify the relaxant effect of phorbol 12,13-dibutyrate. This suggests that H-7 behaves as a PKA, but not a PKC inhibitor, under the present experimental conditions. 5. The relaxation by naproxen, phenylbutazone, piroxicam and tolmetin is presumably produced by increasing cAMP because the effects of these are antagonized with Rp-cAMPS and H-7, and by pertussis-toxin-sensitive mechanisms.

Targeting of Naproxen Covalently Linked to HSA to Sinusoidal Cell Types of the Liver

The kinetic behaviour of a naproxen human serum albumin conjugate (Nap23-HSA) was investigated in rats and in isolated perfused rat livers (IPRL), as compared to its active metabolite naproxen-lysine (Nap-lysine) and free naproxen. Through covalently linking the antiinflammatory drug naproxen to HSA, this drug can be selectively delivered to non parenchymal cells of the liver. Liver endothelial and Kupffer cells play an important role in the pathogenesis of inflammatory liver diseases. Targeting naproxen to these cells might increase its efficacy and reduce the side effects.The altered kinetic properties of Nap23-HSA, after i.v. injection of 22 mg.kg−1, as compared to an equimolar amount of the uncoupled drug, were demonstrated in vivo by a decrease in the steady state volume of distribution (41 ± 5 vs. 134 ± 19 ml.kg−1), a decrease in its clearance (0.48 ± 0.05 vs. 0.63 ± 0.1 ml.min−1.kg−1), a shorter plasma half life (60 ± 11 vs. 152 ± 44 min) and a sustained biliary excretion.Liver targeting of Nap23-HSA was clearly demonstrated: drug content of the liver 180 min after injection was about 30 times higher for Nap23-HSA as compared to naproxen itself. The IPRL experiments showed that the Vmax of hepatic removal of the conjugate was 40 μg.min−1.g liver−1. With doses below receptor saturation a rapid removal of the conjugate (t1/2 = 6 min) from the perfusion medium was found.In conclusion, this study demonstrates the saturable uptake of Nap23-HSA and its lysosomal degradation in both in vivo and IPRL experiments. Covalently linked naproxen is released as Nap-lysine. This active metabolite accumulates in Kupffer and endothelial cells in which it reaches therapeutic concentrations. Release from these cells leads to rapid uptake by hepatocytes and carrier mediated excretion into bile. Levels of Nap-lysine in bile and plasma reflect the slowest step in its generation: the proteolytic release in endothelial and Kupffer cells.

Staphylococcal septic arthritis: antibiotic and nonsteroidal anti-inflammatory drug treatment in a rabbit model.

This study evaluated the effects of combining antibiotic therapy with the application of a nonsteroidal anti-inflammatory drug on the degradation of articular cartilage for an animal model of Staphylococcal septic arthritis. Rabbits were infected intra-articularly with Staphylococcus aureus. Antibiotic treatment started 18 hours after infection and continued for 7 days. Treatment with the nonsteroidal anti-inflammatory drug naproxen sodium started 24 hours before infection and continued for either 3 or 7 weeks. The cartilage matrix of uninfected and infected knees was quantified by analysis of glycosaminoglycan and collagen content. Three weeks after infection, the combined treatment of the nonsteroidal anti-inflammatory drug and antibiotics reduced the loss of glycosaminoglycan and collagen from the cartilage of the infected knee by 15 and 30%, respectively, compared with antibiotic treatment alone. Continuing treatment with naproxen sodium for 7 weeks reduced the loss of collagen by 50% when compared with antibiotic treatment alone. The longer period of treatment with naproxen sodium showed little further effect on the loss of glycosaminoglycan than that observed for the 3-week treatment. Treatment with this drug and antibiotics reduced swelling of the knee and levels of prostaglandin E2 in the synovial fluid. The data support the hypothesis that decreasing post-infectious inflammation by adding the drug to a standard antibiotic regimen reduces cartilage damage from Staphylococcal septic arthritis.

Determination of the Enantiomeric Purity of Naproxen: An Organic Chemistry Laboratory Experiment

Recent availability of and publicity surrounding the antiinflammatory drug naproxen presents an opportunity for an organic chemistry laboratory experiment of great up-to-the-minute interest.

Estimation of the relative contribution of the transcellular and paracellular pathway to the transport of passively absorbed drugs in the Caco-2 cell culture model.

The objective of this investigation was to determine, using the Caco-2 cell culture model, the extent to which the paracellular and transcellular routes contributed to the transport of passively absorbed drugs. An effort was also made to determine the controlling factors in this process. We selected a heterologous series of drugs with varying physicochemical parameters for the investigation. Effective permeability coefficients of the model drugs (naproxen, phenytoin, salicylic acid, chlorothiazide, furosemide, propranolol, diltiazem, ephedrine, and cimetidine), at pH 7.2 and pH 5.4, were estimated using confluent monolayers of Caco-2 cells. The biophysical model approach, based on molecular size restricted diffusion within an electrostatic field of force, used by Adson et al. (1,2), was employed to estimate the permeability coefficients of the ionized and unionized forms of the drugs for the paracellular and transcellular route. The permeability coefficients of the acidic drugs was greater at pH 5.4, whereas that of the basic drugs was greater at pH 7.2 and the transcellular pathway was the favored pathway for most drugs, probably due to its larger accessible surface area. The paracellular permeability of the drugs was size and charge dependent. The permeability of the drugs through the tight junctions decreased with increasing molecular size. Further, the pathway also appeared to be cation-selective, with the positively charged cations of weak bases permeating the aqueous pores of the paracellular pathway at a faster rate than the negatively charged anions of weak acids. Thus, the extent to which the paracellular and transcellular routes are utilized in drug transport is influenced by the fraction of ionized and unionized species (which in turn depends upon the pKa of the drug and the pH of the solution), the intrinsic partition coefficient of the drug, the size of the molecule and its charge.

(Glyco)-protein drug carriers with an intrinsic therapeutic activity: The concept of dual targeting

Dual targeting can in principle be achieved by using intrinsically active carriers that not only deliver the conjugated drug but also otherwise influence the pathological process. Potential carriers of this kind are monoclonal antibodies, certain interferons and interleukins, as well as certain enzymes, peptide hormones and antivirally active (glyco)-proteins. The low molecular weight protein lysozyme, that is easily filtered and reabsorbed in kidney tubular cells, was used as a carrier for renal delivery of various drugs including anti-bacterial agents. The carrier itself can add to the anti-infective effect through its lysing effect on bacterial cell walls. Albumins derivatized with various sugars were used for delivery of the anti-inflammatory drug naproxen to hepatocytes, endothelial cells and Kupffer cells. Naproxen-albumin exhibited a potent hepatoprotective effect if delivered to sinusoidal cell types. Negatively charged and enzymatically active protein carriers can contribute to therapeutic effects, among others, through receptor antagonism and detoxification of endotoxins. Some (glyco)-proteins, designed as a drug carrier for anti-HIV agents, exhibited an intrinsic antiviral activity even without coupling of antiviral drugs. This activity was caused by an increased negative charge of the particular (glyco)-proteins. The in vitro IC 50 values of some of these polyanionic proteins were in the nanomolar concentration range. The mechanism of action was found to be inhibition of a post binding virus/cell fusion event. The particular negatively charged albumins (NCAs) showed, in the therapeutic dose range, favorable pharmacokinetics with regard to lymphatic distribution and residence time in the blood stream. They have little acute toxicity and, in contrast to other polyanionic compounds, such as dextran sulfate are readily biodegradable. The NCAs lack an anticoagulant activity and exhibit low immunogenicity. Importantly, a high activity against primary clinical HIV isolates was observed. We detected a high affinity binding to the V3 loop of the envelope glycoprotein gpl20, explaining the potent effect on virus/cell fusion and HIV-I replication as well as the significant activity on syncytium-inducing HIV variants. The particular antiviral proteins can in principle be applied as intrinsically active drug carriers for the targeting of nucleoside analogues such as AZT, protease inhibitors and glycosidase inhibitors. A major advantage would be the concomitant blocking of sequential steps in the viral replication process with the aims to obtain synergism and prevention of drug resistance.

In vitro displacement of phenytoin from protein binding by nonsteroidal antiinflammatory drugs tolmetin, ibuprofen, and naproxen in normal and uremic sera.

Displacement of phenytoin (90% bound to albumin) by other highly albumin-bound drugs like salicylate has been well documented. Other widely used nonsteroidal antiinflammatory drugs like tolmetin, ibuprofen, and naproxen are also strongly bound to albumin and can potentially displace phenytoin. However, phenytoin-ibuprofen interaction has been poorly studied in the past, and interaction of phenytoin with tolmetin or naproxen has not been studied before. For normal serum pool (albumin 3.7 g/dl), we observed significant increases in free phenytoin concentrations only with antiinflammatory drug concentrations at the upper end of therapeutic or above therapeutic concentrations. However, for the uremic pool (albumin 2.9 g/dl), displacement of phenytoin was significant even at the lower end of therapeutic concentrations of those antiinflammatory drugs. Of the three antiinflammatory drugs we studied, ibuprofen caused the highest displacement of phenytoin.

Inhibition of tolbutamide 4-methylhydroxylation by a series of non-steroidal anti-inflammatory drugs in V79-NH cells expressing human cytochrome P4502C10.

1. To study the role of cytochrome P4502C10 in the metabolism of the non-steroidal antiinflammatory drugs (NSAIDs) diclofenac, phenylbutazone, fenoprofen, ibuprofen, flurbiprofen, ketoprofen and naproxen, a cell line was developed stably expressing CYP2C10 cDNA. A retroviral vector construct, containing a human CYP2C10 cDNA, was transfected in V79-NH Chinese hamster lung cells by calcium phosphate co-precipitation. Sublines stably expressing human cytochrome P450 cDNA were established by selection with the neomycin analogue G418. 2. Enzymatic activity of CYP2C10 was detected by 4-methylhydroxylation of tolbutamide. This activity was inhibited to background levels by preincubation with the CYP2C9/10 inhibitor sulphaphenazole. 3. Preincubations with the NSAIDs ketoprofen, phenylbutazone, flurbiprofen and diclofenac (all 250 microM) caused a decrease in 4-methylhydroxylation of tolbutamide (500 microM), significantly different from control values (p < 0.05). Inhibition of this activity was not seen in preincubations with the NSAIDs fenoprofen, ibuprofen and naproxen (250 microM). 4. The V79-NH CYP2C10 cell line we have developed has been shown to be a useful tool to predict drug-drug interactions.

Comparison between active and passive drug transport in human intestinal epithelial (caco-2) cells in vitro and human jejunum in vivo

Drug transport rates in Caco-2 monolayers were compared with those obtained in the human jejunum in vivo. Permeability coefficients unbiased by the hydrodynamic conditions were calculated in order to allow direct comparison of the two models. The rapidly (passively) transported drugs naproxen, antipyrine and metoprolol had comparable permeability coefficients in Caco-2 cells and in human jejunum. The permeability coefficients of the slowly (passively) transported, hydrophilic drugs, terbutaline and atenolol, 79- and 27-fold lower, respectively, in Caco-2 cells than in jejunum. The carrier-mediated transport rates of L-dopa, L-leucine and D-glucose were also much slower in Caco-2 cells than in human jejunum. The lower permeability of the actively transported compounds and of atenolol and terbutaline is consistent with the colonic origin of the Caco-2 cells. The results indicate that Caco-2 monolayers can be used to predict passive drug transport in humans, while prediction of transport by carrier-mediated systems may require a scaling factor, due to a low expression of carriers in this cell line.

Column liquid chromatography with diode laser-induced fluorescence detection of carboxylic acids after pre-column derivatisation

Several pre-column approaches to fluorescence derivatisation of carboxylic acids, compatible with diode laser-induced fluorescence (DIO-LIF) detection, were compared. For this purpose red-absorbing labels containing hydrazide, bromoacetamide and iodoacetamide functionalities were studied. The sensitivity of DIO-LIF detection is illustrated by the (3–10) × 10 −12 M (75–250 amol) detection limit for various derivatised carboxylic acids. The real-life detection limit for the carboxylic acids is 3 × 10 −8 M , because derivatisation is not quantitative at lower concentrations. Derivatised n-alkylcarboxylic acids and non-steroidal anti-inflammatory drugs are easily separated by column liquid chromatography, despite the attachment of the bulky red-absorbing labels. The determination of the anti-inflammatory drug naproxen in saliva is shown as an example.

Thin layer chromatography—mass spectrometry using infrared lase desorption

The infrared laser desorption of the drug naproxen from silica thin layer chromatography (TLC) plates is described. Desorbed neutral molecules were ionized by two-photon ionization at a wavelength of 266 nm and mass spectra were recorded using a time-of-flight mass spectrometer. Particular features investigated were the sensitivity attainable and the effect of repeated irradiation of the same area of the TLC plate.

Simultaneous determination of naproxen and its desmethyl metabolite in human serum by second-derivative synchronous fluorescence spectrometry

A simple, rapid, sensitive and selective method for the simultaneous determination of the non-steroidal anti-inflammatory drug naproxen (NAP) and its main metabolite the 6-demethylated derivative (DNAP) in human serum is described. The method is based on the intrinsic fluorescence of both acids in alkaline aqueous solution. The broad-band overlapping conventional spectra of both compounds are resolved by means of second-derivative synchronous fluorescence spectrometry, thus obviating the need for pre-analysis sample separation techniques. NAP and DNAP are determined in serum supernatant solution after removal of proteins with acetonitrile at pH 11.7. Recoveries from sera spiked with NAP (5–70 μg ml −1) and DNAP (0.25–5 μg ml −1) ranged from 95 to 106% (mean 99.6%) and from 95 to 104% (mean 100.1%), respectively.

Esters of naproxen as potential prodrugs for skin penetration. 1. Synthesis and physico-chemical properties

Several esters of the nonsteroidal antiinflammatory drug Naproxen [2-(6-methoxy-2-naphthyl)propionic acid] were synthesized by standard procedures. Melting points and enthalpies of melting were obtained by differential scanning calorimetry. Solubilities in water were measured using HPLC. The partition coefficients (octanol/water) were calculated according to Rekker and Mannhold and Rm-values were determined by RP-TLC. The two latter parameters were correlated with high significance.

Low molecular weight proteins as carriers for renal drug targeting: naproxen coupled to lysozyme via the spacer L-lactic acid.

Low molecular weight proteins (LMWPs) are potential carriers for targeting drugs to the kidney. To test whether ester bonds are suitable for the reversible drug conjugation, the antiinflammatory drug naproxen (Nap) was conjugated to the LMWP lysozyme (LYSO) via an ester bond using an L-lactic acid spacer (Nap-lact-LYSO, 1:1:1). The distribution and degradation of the conjugate in rats were compared to those of an equimolar mixture of free drug and LMWP and of a directly coupled conjugate without spacer (Nap-LYSO). The plasma clearance of Nap-lact-LYSO closely resembled that of Nap-LYSO and LYSO itself. Its major accumulation site appeared to be the kidney as demonstrated by extracorporal gamma-camera counting of the LMWP. Renally released naproxen was excreted in the urine as 6-desmethyl-naproxen-sulfate (6-DMN-S). Apparently the kidneys represent the main sites of demethylation and sulfation after administration of the LMWP-coupled drug. In addition, the renal excretion of naproxen (including its metabolites) was significantly delayed and sustained as compared to that after injection of uncoupled naproxen. Using the L-lactic acid spacer LMWP conjugation, the renal selectivity of Nap was increased 5.6 +/- 0.41-fold. Additional in vitro studies with Nap-lact-LYSO revealed that renal generation of the parent drug coincided with formation of low molecular weight catabolites, mainly as naproxen-L-lactic acid-lysine (Nap-lact-Lys). This indicated that in vitro the rate of cleavage of the ester bond is significantly slower than digestion of the carrier backbone itself.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of?-cyclodextrin complexation on the photohaemolitic activity induced by Ketoprofen and Naproxen sensitization

Red blood cell lysis photosensitized by two non-steroidal anti-inflammatory drugs Naproxen (NAP) and Ketoprofen (KPF) was investigated in the presence of β-cyclodextrin (β-Cyd). The photohaemolysis was inhibited by the addition of β-Cyd both for NAP and, to a lesser extent, for KPF. The protective action was found only in a restricted range of concentration of β-Cyd. Higher amounts of β-Cyd interfered with the resistance of the cell to the osmotic shock induced by the photosensitization process. The complexing action of β-Cyd was ascertained through UV-vis absorption spectroscopy, induced circular dichroism and emission spectroscopy. The isolated complexes Naproxen-β-Cyd (NAP-β-Cyd) and Ketoprofen-β-Cyd (KPF-β-Cyd) were found to protect from the photosensitized membrane damage induced by the two drugs, even if it occurred only in a limited range of concentration. This suggests a valid tool in alleviating thein vitro phototoxic consequences caused by these compounds, even if care has to be taken in therapeutic administration due to the presence of the uncomplexed β-Cyd.

Simultaneous quantitative determination of naproxen, its metabolite 6-O-desmethylnaproxen and their five conjugates in plasma and urine samples by high-performance liquid chromatography on dynamically modified silica

The glucuronides of the anti-inflammatory drug naproxen and its metabolite 6-O-desmethylnaproxen have been produced on a preparative scale by enzymatic synthesis. 6-O-Desmethylnaproxen, the glycine conjugate of naproxen and the O-sulphate of 6-O-desmethylnaproxen were prepared by chemical synthesis. Naproxen and the purified metabolite and conjugates were used as standards for the analytical investigation of the metabolic pattern of naproxen in humans. A reversed-phase high-performance liquid chromatographic method based on bare silica dynamically modified with cetyltrimethylammonium ions has been developed. The system was optimized to give a separation of naproxen, 6-O-desmethylnaproxen and five conjugates. Using this method it is also possible to deduce the relationship between the amount of the intact ether-glucuronide and acyl-glucuronide of 6-O-desmethylnaproxen.

Inhibition of alveolar bone loss in beagles with the NSAID naproxen

The non-steroidal anti-inflammatory drug(NSAID) naproxen was studied in 11 beagle dogs over a 13-month period to determine its effect on the progression of periodontitis. Following a 6-month pretreatment period, 5 dogs received naproxen daily at a dosage of 2.0 mg/kg for 1 month, then 0.2 mg/kg for 6 months. Six control dogs received a gelatin capsule daily as placebo. Standardized radiographs were used to measure the rate of bone loss during the pretreatment and treatment periods. In the control dogs, the rate of bone loss was seen to increase during the treatment period although the increase was not statistically significant. In dogs treated daily with naproxen, the rate of bone loss in the treatment period was significantly less at 4 months of treatment; however, at 7 months the difference, though lower than pretreatment rate, was not significant. When the percent change in rate of bone loss during the overall 7-month treatment period was compared with pretreatment rate, the control dogs demonstrated a 38% increase in rate of bone loss during the treatment period contrasting with a 61% decrease in bone loss rate in naproxen-treated dogs. The data indicate that the non-steroidal anti-inflammatory drug naproxen can significantly inhibit alveolar bone loss in beagles. At 4 months of treatment the rate of bone loss in the naproxen-treated dogs was significantly less than pretreatment, but at 7 months of treatment the rate was no longer statistically significantly less than baseline. This probably reflects a dose response to naproxen treatment for, after 30 days of the treatment period, the naproxen dosage was reduced 10-fold due to tolerance by the beagle.