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PubMed2001

Enantioselective inhibition of the binding of rac-profens to human serum albumin induced by lithocholate.

The reversible binding of lithocholate to human serum albumin determines a decrease of the binding of rac-ketoprofen. The process was followed by displacement chromatography using increasing concentrations of the competitor, i.e., lithocholate, in the mobile phase. The inhibition of rac-ketoprofen binding resulting was enantioselective and greater displacement was observed for the (S) enantiomer. The displacement process resulting was competitive in nature, the two enantiomers of ketoprofen binding to the same binding site as the modifier. The investigation was extended to other nonsteroidal antiinflammatory drugs. The enantioselective binding inhibition was larger in the case of rac-naproxen and rac-suprofen with respect to the phenomenon observed in the case of rac-ketoprofen. The difference in circular dichroism spectroscopy was also used to characterize the binding of lithocholate to human serum albumin. This bile acid was proven to bind to site II on human serum albumin. The results, as obtained by displacement chromatography and difference circular dichroism spectroscopy, strongly support the hypothesized role of bile acids in inducing the enantioselective inhibition of ketoprofen binding to human serum albumin in patients suffering from liver diseases.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1984

Differential contractile responsiveness of isolated rabbit arteries from different vascular beds to cyclooxygenase inhibitors and PGI2.

The actions of three, structurally unrelated cyclooxygenase inhibitors and PGI2 on the contractile responses to electrical stimulation and to noradrenaline of strips of rabbit coeliac, ear, pulmonary, carotid, femoral arteries and the aorta were studied. Indomethacin (3 mumol/l), suprofen (0.8 mumol/l) and meclofenamic acid (0.2 mumol/l) potentiated the adrenergically induced contractions of coeliac arteries by 126-165%. The contractile responses of ear arteries were increased by these three substances by 87-91%, and the responses of pulmonary arteries by 26-33%. All of these changes were statistically significant. Prostacyclin produced a dose-related inhibition of the stimulation-induced contractions of the coeliac, ear and pulmonary arteries; its IC50 values were 10.4, 212 and 433 nmol/l, respectively. In contrast to effects in the above arteries, the evoked contractions of aortic and carotid strips were not affected by any of the prostaglandin synthesis inhibitors used; the responses of femoral vessels were reduced by all of the inhibitors (by 13-23%; P less than 0.05). Low concentrations of PGI2 did not affect the evoked contractions of aortic, carotid and femoral strips whereas higher concentrations increased baseline tone and potentiated contractions. The results indicate that there are considerable difference in the sensitivities of the arteries from different vascular beds to inhibitors of cyclooxygenase and to prostacyclin.

Animals↗
PubMed1981

Prostaglandins /PGs/ and peristalsis.

The effect of some inhibitors of PG-synthesis /Aspirin, Indomethacin and Suprofen/ on the small intestine peristalsis and the PG-like activity in mice was investigated. It was found that the three drugs examined in the applied doses did not affect the small intestine peristalsis but they significantly decreased the PG-like activity. The role of PGs in the physiological peristalsis of the small intestine is discussed.

Animals↗
PubMed1995

The substrate binding site of human liver cytochrome P450 2C9: an approach using designed tienilic acid derivatives and molecular modeling.

Biochemical experiments, using the well-defined human liver CYP2C9 expressed in yeast, and molecular modeling techniques were used to derive a predictive model for substrates of CYP2C9. The ability of 10 2-aroylthiophenes related to tienilic acid to act as substrates for CYP2C9 was studied. Four of them were original compounds that were synthesized and completely characterized by several spectroscopic techniques. In these 10 compounds various chemical functions, such as ester, amide, alcohol, phenol, ether or tetrazole functions, replaced the OCH2COOH function of tienilic acid. Among them, only the derivatives containing an acidic function (carboxylic acids, phenol, and tetrazole whose pKaS are 4.8, 6.3, and 3.8, respectively) underwent a 5-hydroxylation of their thiophene ring like tienilic acid. Despite their close structural analogy with tienilic acid, all of the other compounds not only did not undergo any 5-hydroxylation of their thiophene ring but also failed to act as inhibitors of CYP2C9. These results strongly suggested that the presence, at pH 7.4, of a negative charge on the substrate is a very important feature in its recognition by CYP2C9. In fact, the four new substrates of CYP2C9 described in this study, a carboxylic acid, phenol, and tetrazole derivative, each of which is related to tienilic acid, and the antiinflammatory drug, suprofen (with Km between 12 and 130 microM and kcat between 0.2 and 1.3 min-1), as well as almost all CYP2C9 substrates reported in the literature, exhibit a pKa below 7 (except phenytoin whose pKa is 8.1). They mainly exist as anions at physiological pH. By using molecular modeling techniques, 12 CYP2C9 substrates were superimposed with respect to their hydroxylation site and fitted onto templates, which were rigid molecules such as (S)-warfarin and phenytoin. It was thus possible to arrange them in order that all their anionic sites were at a distance around 4 A from a common point (a putative cationic site of the protein) in space. These results provide a model of the substrate binding site of CYP2C9, in which substrates interact through their anionic site A- with a cationic residue of the CYP2C9 protein C+. In that model, the distance between the hydroxylation site (Hy) and the anionic site (A-) is 7.8 +/- 1.6 A, and the <HyA-C+ angle is 82 +/- 15 degrees.

Aryl Hydrocarbon Hydroxylases↗
PubMed2001

Antibodies directed to drug epitopes to investigate the structure of drug-protein photoadducts. Recognition of a common photobound substructure in tiaprofenic acid/ketoprofen cross-photoreactivity.

Drug-induced photoallergy is an immune adverse reaction to the combined effect of drugs and light. From the mechanistic point of view, it first involves covalent binding of drug to protein resulting in the formation of a photoantigen. Hence, determination of the structures of drug-protein photoadducts is of great relevance to understand the molecular basis of photoallergy and cross-immunoreactivity among drugs. Looking for new strategies to investigate the covalent photobinding of drugs to proteins, we generated highly specific antibodies to drug chemical substructures. The availability of such antibodies has allowed us to discriminate between the different modes by which tiaprofenic acid (TPA), suprofen (SUP), and ketoprofen (KTP) photobind to proteins. The finding that the vast majority of the TPA photoadduct can be accounted for by means of antibody anti-benzoyl strongly supports the view that the drug binds preferentially via the thiophene ring, leaving the benzene ring more accessible. By contrast, selective recognition of SUP-protein photoadducts by antibody anti-thenoyl evidences a preferential coupling via the benzene ring leaving the thiophene moiety more distant from the protein matrix. In the case of KTP, photoadducts are exclusively recognized by antibody anti-benzoyl, indicating that the benzene ring is again more accessible. As a result of this research, we have been able to identify a common substructure that is present in TPA-albumin and KTP-albumin photoadducts. This is remarkable since, at a first sight, the greatest structural similarities can be found between TPA and SUP as they share the same benzoylthiophene chromophore. These findings can explain the previously reported observations of cross-reactivity to KTP (or TPA) in patients photosensitized to TPA (or KTP).

Animals↗
PubMed1984

Effects of cyclooxygenase inhibitors, prostaglandins F2 alpha and I2, on isolated coeliac and basilar arteries of alloxan-diabetic dogs.

The effects of prostaglandin synthetase inhibitors PGF2 alpha and PGI2 on the tone of isolated basilar and coeliac arteries were studied in healthy and alloxan-diabetic dogs. PGF2 alpha (1 mumol 1-1) produced a significantly higher tone in diabetic basilar arteries (1.15 +/- 0.16 mN) than in normal cerebral vessels (0.7 +/- 0.10 mN). By contrast, the contractile responses of normal and diabetic coeliac arteries to PGF2 alpha did not differ. The cyclooxygenase inhibitors indomethacin (3 mumol 1-1) and suprofen (0.58 mumol 1-1) potentiated the PGF2 alpha-evoked contractions in all of the vessels studied. The percent potentiation was greater (50-60%) in the basilar arteries from alloxan-treated dogs than in normal basilar vessels (22-30%). There was not such a difference between diabetic and normal coeliac arteries. Prostacyclin produced a concentration-related relaxation in the presence of indomethacin or indomethacin + PGF2 alpha. The relaxant potencies of PGI2 were similar in the vessels from metabolically healthy and diabetic dogs. The IC50 values for PGI2 were 11.6 +/- 1.3 and 11.8 +/- 1.8 nmol 1-1 in normal and diabetic basilar arteries, respectively; they were 25.4 +/- 3.2 and 26.2 +/- 3.9 nmol 1-1 in control and alloxan-treated coeliac vessels. These results indicate that normal and diabetic vessels may have differential reactivity to cyclooxygenase inhibitors, this difference being dependent on the vascular region.

Animals↗
PubMed1979

Skin sensitizing properties of arylalcanoic acids and their analogues.

While participating in a clinical trial of suprofen, a new antiphlogistic agent, a 32-year-old atopic woman developed a severe contact dermatitis reaction of the hands to this substance. To check for cross-reactivity patterns, patch tests were performed with similar arylalcanoic acid derivatives. Positive reactions were obtained for ibuprofen, ketoprofen, fenoprofen, naproxen, alclofenac, and metiazinic acid, which are all antiphlogistic and anti-inflammatory agents for systemic use, and chlorambucil, which is an antineoplastic agent. The antigenic determinant seems to correspond to a very well-defined structure: the carboxyl group (-COOH) has to be separated from the aryl structure by at least one C atom (substituted or not). Furthermore, the aryl group must be substituted with different chemical groups but not in the orthopositions.

Adult↗
PubMedDate not supplied

Non-steroidal anti-inflammatory drugs as the first step in cancer pain therapy: double-blind, within-patient study comparing nine drugs.

The efficacy and tolerability of acetylsalicylic acid, paracetamol, diclofenac, ibuprofen, indomethacin, pirprofen, sulindac, naproxen and suprofen were compared in the treatment of cancer pain. In a double-blind, within-patient randomized study, each drug was given for 1 week to eight patients and for another week to a further eight patients. A total of 65 patients were effectively treated; only 48 completed week 1 and 41 completed week 2. Naproxen, diclofenac and indomethacin were highly effective in pain relief (tested by means of a 100 mm visual analogue scale) and were relatively well tolerated. It is concluded that these non-steroidal anti-inflammatory drugs can be considered as first choice in the treatment of cancer pain.

Acetaminophen↗
PubMed1984

Arachidonic acid metabolism in inflamed gingiva and its inhibition by anti-inflammatory drugs.

Prostaglandin (PG) synthetase inhibitors are tissue-selective. Therefore, the action of four nonsteroidal anti-inflammatory drugs (NSAID) was tested against PG synthesis from 14C-arachidonic acid by gingival homogenate. Suprofen and tolmetin sodium did not significantly inhibit PGs at any of the three concentration levels used (10(-7), 10(-5), 10(-3) M), whereas flurbiprofen and zomepirac sodium did significantly inhibit PG formation at millimolar concentration. The results, coupled with our previous study on indomethacin, piroxicam and ibuprofen open the way for future tests of NSAIDs in treatment of gingival inflammation and periodontal disease.

Anti-Inflammatory Agents↗
PubMed1988

Metabolic chiral inversion of anti-inflammatory 2-arylpropionates: lack of reaction in liver homogenates, and study of methine proton acidity.

1. Enrichment in the (S)-enantiomers for (R)-flurbiprofen, (R)-naproxen, (R)-suprofen and (R;S)-ibuprofen was investigated in various subcellular hepatic preparations containing coenzyme A. While such preparations were able to form hippuric acid from benzoic acid, the chiral inversion was never seen. 2. Using 2-dimethylaminoethanethiol 2-phenylpropionate (DEPP) as a model acyl thioester, the acidity of the methine proton was investigated by monitoring the proton/deuterium exchange occurring in deuterated solvents using high-resolution n.m.r. The compound was inert up to 22 h in D2O at 37 degrees C and pD 7.4. In pure methanol or a methanol-water mixture, only solvolysis was seen. In contrast, competitive hydrolysis (k = 0.005 h-1) and proton/deuterium exchange (k = 0.09 h-1) were seen in a CD3CN/D2O (50:50) mixture at 37 degrees C. 3. It is speculated that the failure to characterize chiral inversion of 2-arylpropionates in subcellular preparations may be due to the absence of a microenvironment of adequately moderate polarity.

Animals↗
PubMed1990

Chronic electrical stimulation of sympathetic nerves: effects on blood-aqueous barrier.

The effect of electrical stimulation of the sympathetic nerves on the blood-aqueous barrier was investigated in rabbits. The permeability of the barrier was assessed during either acute, chronic or following chronic nerve stimulation. During acute and chronic stimulation of the sympathetic nerves, fluorescein entered the anterior chamber at a rate significantly slower than in control eyes. After chronic stimulation, both the rate of entry of fluorescein and the aqueous humor protein concentration were much greater than in control eyes indicating breakdown of the blood-aqueous barrier. Treatment with the non-steroidal anti-inflammatory drugs, indomethacin and suprofen, completely blocked the breakdown of the blood-aqueous barrier. These results indicate that sympathetic nerve stimulation can cause the local synthesis of prostaglandins and that these can affect the blood-aqueous barrier.

Animals↗
PubMed1993

Non-steroidal anti-inflammatory drug and endotoxin induced uveitis.

Suprofen eye drop was instilled into one eye of 10 pigmented rabbits and then anterior uveitis was induced by intraperitoneal injection of endotoxin of Shigella flexneri serotype 1A to evaluate the effects of non-steroidal anti-inflammatory drug on endotoxin induced uveitis. The pupillary diameters were measured, and aqueous cell and flare gradings were recorded in 20 eyes of 10 rabbits for one week at an interval of 12 hours for the first 24 hours and then every 24 hours for a week. A difference between the treated and control groups were investigated. All the above parameters showed greatest changes at 12 or 24 hours after injection and became normal by one week. The two groups demonstrated statistically significant difference at 12 hours, day 1 and day 2 as for pupillary diameter, at day 1 and day 2 as for cell and at 12 hours and day 1 as for flare. Thus, it can be concluded that prostaglandins play a role in miosis, in the appearance of inflammatory cells and flare in endotoxin induced uveitis and the topical administration of non-steroidal anti-inflammatory drug can alleviate signs of anterior uveitis. Specific relationship between leukotriene B4 and aqueous cell was not demonstrated.

Administration, Topical↗
PubMed2004

Synthesis of precursor of anti-inflammatory agents by using highly reactive zinc.

Highly reactive zinc metal was prepared by electrolysis of a N,N-dimethylformamide (DMF) solution containing naphthalene and a supporting electrolyte in a one-compartment cell fitted with a platinum cathode and a zinc anode. This highly reactive electrogenerated zinc (EGZn/Naph) was used for transformation of ethyl 2-bromoacrylate into the corresponding organozinc compound, which can not be achieved by the use of usual zinc metals. Reaction of the organozinc compounds thus prepared with various aryl halides in the presence of 5 mol% of palladium catalyst gave the corresponding cross-coupling products in high yields. These cross-coupling reactions were successfully applied to a synthesis of the precursor of anti-inflammatory agents such as ibuprofen, naproxen, cicloprofen and suprofen.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1987

Action of a prostaglandin synthetase inhibitor on IUD associated uterine bleeding.

The Authors treated twenty-eight women using IUD, who suffered from increased menstrual blood loss and pelvic pain, with a prostaglandin synthetase inhibitor, Suprofen, in an attempt to reduce their symptomatology, in a double blind crossover study. The drug produced an important reduction of the menstrual blood loss and pains. These observations suggest that prostaglandins are involved in the etiology of excessive menstrual blood loss and pains, and that prostaglandin inhibitors may be useful for reducing these symptoms.

Clinical Trials as Topic↗
PubMed1979

The effect of prostaglandin E1 on acetylcholine release from the cat brain.

Cerebral ventricular perfusion with prostaglandin E1 (PGE1, 1.4 X 10(-8) M) reduced the release of acetylcholine (ACh) into the ventriculo-cisternal perfusate of the unanaesthetized cat's brain. The samples of effluent were assayed on the isolated guinea-pig ileum. Neither a halving (1.07 X 10(-3) M) nor a threefold rise (6.45 X 10(-3) M) in the calcium concentration of the perfusate had any effect on the spontaneous release of the cholinergic transmitter. The action of PGE1 was counteracted by decreasing and potentiated by increasing the extracellular calcium concentration. Polyphloretin phosphate (PPP, 10(-4) g/ml) in itself did not significantly affect the ACh outflow. Preperfusion however, with this drug readily antagonized the depressant effect of PGE1. Ouabain (2.0 X 10(-5) M) added to the perfusion fluid increased the ACh output from the cat brain, and PGE1 prevented this effect of ouabain. A single intraventricular injection of 6-hydroxydopamine (1 mg) counteracted the inhibitory effect of PGE1 on spontaneous ACh release. A perfusion with the potent PG synthesis inhibitor suprofen (3.8 X 10(-7) M) did not influence change the mean output of the transmitter. Our data indicate that PGE1 reduces ACh release in the CNS via a pre- or postsynaptic modification of monoaminergic neurotransmission.

Acetylcholine↗
PubMed1984

Effects of cyclooxygenase inhibitors and PGI2 on the adrenergic contractions of isolated rabbit arteries.

The effect of three cyclooxygenase inhibitors (indomethacin, suprofen, meclofenamic acid) and PGI2 on the contractile responses to noradrenaline (NA) and to nerve stimulation (TNS) of strips of rabbit coeliac-, pulmonary-, ear-, carotid-, femoral arteries and the aorta were studied. The equipotent concentration (0.1 X EC50) of NA were calculated from dose-response curves. The stimulation parameters (Hz, duration) varied according to the responsiveness of the tissue. Both NA and TNS caused 7-23% of maximum response. In the presence of cyclooxygenase inhibitors (COI's) NA and TNS produced significantly greater proportion (15-30%) of maximum contraction in coeliac-, ear-, and pulmonary arteries. Contractions of the other 3 vessels were not influenced by COI's. The inhibitory potency of PGI2 was determined on contractions produced by equipotent concentration (EC50) of NA. PGI2 was highly effective in coeliac arteries, it was less potent in pulmonary- and ear arteries and had no effect on the responses of the other vessels.

Animals↗
PubMed1981

[Effect of alpha-(p-thenoylphenyl)-propionic acid (TN-762) on acute inflammatory reactions and prostaglandin biosynthesis].

A series of compounds with the general structure of phenylpropionic acid was originally synthesized for anti-inflammatory screening. The title compound, TN-762, showed marked anti-inflammatory and analgesic activities and was less toxic. This compound was the same as suprofen which was reported by Janssen to have potent anti-inflammatory and anti-writhing activities. Effects of TN-762 on acute inflammatory reactions and prostaglandin biosynthesis were investigated in animal models and findings compared to those of ketoprofen and indomethacin. TN-762 showed a dose-dependent inhibition at low doses of 5-20 mg/kg, p.o. on an increased vascular permeability induced by histamine in rats and by acetic acid in mice and carrageenin-induced paw edema in rats. The anti-inflammatory activity of TN-762 was much the same as that of ketoprofen and indomethacin. The inhibitory effect of TN-762 on carrageenin-induced paw edema was not affected by successive administration for 14 days and/or by adrenalectomy. The compound was more active than the two reference compounds in inhibiting ultraviolet erythema in guinea pigs. TN-762 inhibited markedly the arachidonic acid potentiation of carrageenin-induced edema in rat paw, the sudden death following intraveneous administration of arachidonic acid to rabbits and the diarrhea produced by endotoxin in mice, all considered to be induced by biosynthetic prostaglandins. The activities of TN-762 were the same or were more potent than those of ketoprofen and indomethacin. On the contrary, the ulcerogenic activity of TN-762 on the gastrointestinal tract in rats was significantly less than that of ketoprofen and indomethacin. From the above results, TN-762 proved to be a potent inhibitor of acutely-induced inflammation and of prostaglandin biosynthesis, however, the ulcerogenic effects were comparatively diminished.

Animals↗
PubMed1998

Inhibition of pilocarpine-induced aqueous humor flare, hypotony, and miosis by topical administration of anti-inflammatory and anesthetic drugs to dogs.

OBJECTIVE: To investigate the mechanism by which pilocarpine causes increased aqueous humor (AH) flare, hypotony, and miosis in dogs. ANIMALS: 6 dogs with normal eyes. PROCEDURE: Both eyes of each dog were treated topically with a 2% solution of pilocarpine, and 1 eye of each dog was additionally treated with commercially available ophthamic solutions. Breakdown of the blood-aqueous barrier (BAB) was quantitated in each eye, using laser flaremetry to measure AH flare. Intraocular pressure and pupil size were also measured. RESULTS: Pilocarpine caused increased flare from BAB breakdown that was inhibited by the drugs tested. Inhibition (most to least) of BAB breakdown was flurbiprofen more than diclofenac, proparacaine, or suprofen, which were more than 0.125 or 1.0% prednisolone. Inhibition appeared dose-dependent and caused consensual inhibition in the contralateral eye. Intraocular pressure was decreased only in proparacaine-treated eyes and increased in eyes treated with nonsteroidal anti-inflammatory drugs (NSAID). Flurbiprofen and proparacaine were the most effective at blocking miosis. CONCLUSIONS: Pilocarpine produced a predictable, reproducible BAB breakdown in dogs. Miosis and increased AH flare were inhibited equally by proparacaine or NSAID, suggesting that these signs were caused by neuropeptide release into the AH from antidromic stimulation, which subsequently triggers prostaglandin production. Hypotony was inhibited only by anti-inflammatory drugs. CLINICAL RELEVANCE: Proparacaine in combination with pilocarpine would be the best choice for treating dogs with acute glaucoma. Topical administration of NSAID should not be used to treat dogs with acute glaucoma, because they increase intraocular pressure and negate the effects of pilocarpine.

Administration, Topical↗