ER-34122, a novel dual 5-lipoxygenase/cyclooxygenase inhibitor with potent anti-inflammatory activity in an arachidonic acid-induced ear inflammation model

OBJECTIVE AND DESIGN: To investigate the effect of ER-34122, a novel pyrazole derivative, on 5-lipoxygenase (LOX) and cyclooxygenase (COX) metabolite production in vitro, ex vivo and in vivo. MATERIAL: In vitro, lysate of rat basophilic leukemia cells, the microsome fraction of sheep seminal vesicles, human polymorphonuclear leukocytes, human synovial cells, and human monocytes. Ex vivo and in vivo, male Balb/c mice or SD rats. TREATMENT: In ex vivo study, ER-34122 (0.03-1 mg/kg) was orally administered 1 h before withdrawal of blood samples. In carrageenin-induced paw edema, ER-34122 (3-100 mg/kg) and indomethacin (1-10mg/kg) were orally administered 1 h before carrageenin injection. In arachidonic acid-induced ear inflammation, ER-34122 (0.3-10mg/kg), zileuton (10-100mg/kg) and indomethacin (0.3-3mg/kg) were orally administered 1 h before arachidonic acid application. METHODS: 5-Hydroxyeicosatetraenoic acid and other eicosanoids were determined by using an HPLC method and enzyme immunoassay, respectively. Rat hind paw edema and mouse ear edema were assessed by measuring paw volume and ear thickness, respectively. Myeloperoxidase (MPO) activity and eicosanoid content of the ear tissue were also determined. RESULTS: ER-34122 inhibited both LOX and COX product generation in vitro, and ex vivo. ER-34122 and indomethacin inhibited carrageenin-induced paw edema formation. In the arachidonic acid-induced ear inflammation, ER-34122 inhibited inflammatory responses (edema formation and MPO accumulation) as well as eicosanoids (LTB4, LTC4 and PGE2) generation. A representative LOX inhibitor, zileuton, also inhibited these inflammatory responses, while a COX inhibitor, indomethacin, did not suppress them though it completely inhibited PGE2 generation. CONCLUSIONS: The anti-inflammatory characteristics of ER-34122 are considered to be superior to those of COX inhibitors such as indomethacin, because in addition to its inhibitory activity on the COX pathway, ER-34122 inhibits LOX products generation, as revealed by the inhibition of edema formation or polymorphonuclear leukocyte infiltration in the arachidonic acid-induced ear inflammation model.     

Effects of tepoxalin, a dual inhibitor of cyclooxygenase/5-lipoxygenase, on events associated with NSAID-induced gastrointestinal inflammation

The purpose of this study is to evaluate the diagnostic efficacy of ultrasonography in stage I posterior tibial tendon dysfunction. Fourteen of the 17 consecutive patients who underwent tenosynovectomy for stage I posterior tibial tendon dysfunction were included in this study. The preoperative diagnosis was based primarily on the clinical suspicion of dysfunction, which was confirmed by ultrasonography. Two measurements were obtained at the midpoint between the insertion site and the medial malleolus in both feet of the 14 patients: the diameter of the posterior tibial tendon and the diameter of the tendon sheath measured from its inner walls. The mean diameter of the tendon was 4.61 +/- 0.50 mm and that of the tendon sheath in the symptomatic foot was 7.24 +/- 0.75. In the unaffected foot, the mean diameter of the tendon was 3.30 +/- 0.34 mm and that of the tendon sheath was 3.64 +/- 0.35 mm, respectively. In the symptomatic tendon, the increase of peritendinous space was significantly higher than the increase in the tendinous portion (P < 0.0001). Surgical findings proved the accuracy of diagnosis in all patients. Although many cases of stage I posterior tibial tendon dysfunction remain undiagnosed owing to the mild clinical symptoms, this series indicates that ultrasonography is a valuable adjunctive diagnostic tool in the clinical examination and assists in achieving an accurate diagnosis of stage I posterior tibial tendon dysfunction, allowing early treatment.     

Effect of a 5-lipoxygenase inhibitor, ZM 230487, on cutaneous allergic inflammation in the guinea-pig

1. Leukotrienes have potent biological effects in vitro and in vivo and are found in tissue and in biological fluids in various pathological conditions including allergic diseases. Leukotriene B4 (LTB4) is a potent stimulus for eosinophil accumulation and activation and there is much interest in determining its importance in mediating the accumulation of eosinophils at sites of allergic inflammation in vivo. In this study, we investigated the effects of a potent 5-lipoxygenase inhibitor, ZM 230487, on the accumulation of eosinophils and on local oedema formation in cutaneous inflammation in the guinea-pig. 2. The i.d. injection of increasing concentrations of arachidonic acid (AA) led to a dose-dependent accumulation of 111In-eosinophils but oedema formation was only significant at the top dose of AA tested (3 x 10(-8) mol per site). Co-injection of ZM 230487 with AA inhibited 111In-eosinophil accumulation up to 99% but the small oedema response to AA was only partially inhibited. AA-induced oedema formation was only effectively inhibited when a combination of a PAF antagonist, an antihistamine and ZM 230487 was used. 3. Local administration of the cyclo-oxygenase inhibitor, ibuprofen, partially inhibited AA-induced oedema formation suggesting that vasodilator prostaglandins may be released following i.d. injection of AA. AA-induced 111In-eosinophil accumulation was also partially inhibited by ibuprofen. 4. PAF-induced 111In-eosinophil accumulation was partially suppressed by local administration of ZM 230487. In contrast, LTB4-induced 111In-eosinophil accumulation was enhanced by ZM 230487. These data suggest that locally-released leukotrienes may modulate mediator-induced eosinophil accumulation. ZM 230487 had no effect on PAF- or LTB4-induced oedema formation. 5. ZM230487 significantly inhibited the accumulation of 111 In-eosinophils, but did not affect local oedema formation, in a passive cutaneous anaphylaxis (PCA) reaction. However, the PAF antagonist WEB 2086 either alone or in combination with ZM 230487 had no effect on "'In-eosinophil accumulation or oedema formation in the PCA reaction.6. In conclusion, it appears that a product of 5-lipoxygenase, probably LTB4, is important for the accumulation of "'In-eosinophils, but not local oedema formation, in the PCA reaction in guinea-pigskin. These data support a major role for LTB4 in allergic inflammation in the guinea-pig and make this animal (and the PCA model) suitable for studying the effects of inhibitors of leukotriene synthesis or action in vivo.     

Ursolic acid from Plantago major, a selective inhibitor of cyclooxygenase-2 catalyzed prostaglandin biosynthesis

A hexane extract of Plantago major was investigated by bioactivity-directed fractionation, using an in vitro cyclooxygenase-2 (COX-2) catalyzed prostaglandin biosynthesis inhibition assay, and resulted in the isolation of ursolic acid (1). This triterpenoid showed a significant COX-2 inhibitory effect, directly on the enzyme activity, with an IC50 value of 130 microM and a COX-2/COX-1 selectivity ratio of 0.6. The structural isomer oleanolic acid (2) was found to be less active than 1, with an IC50 value of 295 microM, but showed a similar selectivity ratio (0.8). Furthermore, no significant inhibition on COX-2 or COX-1 was observed by the triterpenoid, 18beta-glycyrrhetinic acid (3). The direct inhibitory effect of 1 and 2 on COX-2 catalyzed prostaglandin biosynthesis increased with preincubation, indicating a time-dependent inhibition, while the effect on COX-1 was found to be independent of preincubation time.     

New cyclooxygenase-2/5-lipoxygenase inhibitors. 2. 7-tert-butyl-2,3-dihydro-3,3-dimethylbenzofuran derivatives as gastrointestinal safe antiinflammatory and analgesic agents: variations of the dihydrobenzofuran ring

A series of 5-keto-substituted 7-tert-buty1-2,3-dihydro-3,3- dimethylbenzofurans (DHDMBFs) were found to be nonsteroidal antiinflammatory and analgesic agents. These compounds are inhibitors of 5-lipoxygenase (5-LOX) and cyclooxygenase (COX) with selectivity for the COX-2 isoform. A series of analogues were prepared to investigate the scope of this lead. Five ketone side chains from active DHDMBFs were used to investigate the effects of changes in the DHDMBF "core": the size and identity of the heterocycle and the substituent requirements of the heterocycle and phenyl ring. Biological testing showed that a variety of structural changes can be accommodated, but no structure was clearly superior to the DHDMBF structure.     

New cyclooxygenase-2/5-lipoxygenase inhibitors. 1. 7-tert-buty1-2,3-dihydro-3,3-dimethylbenzofuran derivatives as gastrointestinal safe antiinflammatory and analgesic agents: discovery and variation of the 5-keto substituent

A series of 5-keto-substituted 7-tert-buty1-2,3-dihydro-3,3- dimethylbenzofurans (DHDMBFs) were prepared and evaluated as potential nonsteroidal antiinflammatory and analgesic agents. Interest in this class of compounds arose when a DHDMBF was found to be an active metabolite of the di-tert-butylphenol antiinflammatory agent tebufelone. We have now found that a variety of 5-keto-substituted DHDMBFs have good in vivo antiinflammatory and analgesic activity after oral administration. These compounds inhibit both cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) in vitro. The cyclooxygenase inhibition was found to be selective for the cyclooxygenase-2 isoform, and this combination of COX-2/5-LOX inhibition may be responsible for the gastrointestinal safety of compounds such as 30.     

Regulation of 5-lipoxygenase activity in mononuclear phagocytes: characterization of an endogenous cytosolic inhibitor

The proinflammatory leukotrienes (LT) play important roles in host defense and disease states. However, no endogenous mechanisms to downregulate 5-lipoxygenase (5-LO), the enzyme catalyzing LT synthesis, have been described. We observed that the cytosolic fraction of rat alveolar macrophages (AMs) and peritoneal macrophages (PMs), and of peripheral blood monocytes (PBMs) contain substantial amounts of 5-LO protein, but little detectable 5-LO activity. We therefore examined these mononuclear phagocyte (MNP) cytosolic fractions for inhibitory activity against 5-LO. MNP cytosol dose-dependently reduced the 5-LO activity in neutrophil (PMN) cytosol and AM membrane. Furthermore, MNP cytosol dose-dependently prolonged the lag phase of soybean lipoxygenase (LO) without affecting the rate of product formation. This effect was overcome by subsequent addition of 13(S)-hydroperoxy-9-cis-11-trans-octadecadienoic acid (13-HpOD), suggesting that the active factor scavenges hydroperoxides. Inactivation by boiling and roteinase K suggest that is a protein. We speculate that this cytosolic factor(s) may serve as an endogenous means for the down-regulation of 5-LO in macrophages.     

Effects of cyclooxygenase-2 selective and nitric oxide-releasing nonsteroidal antiinflammatory drugs on mucosal ulcerogenic and healing responses of the stomach

Effects of selective cyclooxygenase-2 (COX-2) inhibitors (NS-398) and nitric oxide (NO) -releasing aspirin (NO-ASA) on gastric ulcerogenic and healing responses were examined in comparison with nonselective COX inhibitors such as indomethacin and aspirin (ASA). Hypothermic stress (28-30 degrees C, 4 hr) induced gastric lesions in anesthetized rats with an increase of acid secretion. The lesions induced by hypothermic stress were markedly worsened by subcutaneous administration of both indomethacin and ASA but were not affected by either NS-398 or NO-ASA, although the increased acid secretion during hypothermia was not affected by any of the drugs. On the other hand, the healing of gastric ulcers induced in mice by thermal cauterization (70 degrees C, 15 sec) was significantly delayed by daily subcutaneous administration of indomethacin and ASA as well as NS-398, but not by NO-ASA. COX-2 mRNA was not detected in the intact mucosa but was positively expressed in the ulcerated mucosa, most potently on day 3 after ulceration. Prostaglandin contents in the intact mouse stomach were reduced by indomethacin, ASA, and NO-ASA, while the increased prostaglandin generation in the ulcerated mucosa was inhibited by all drugs including NS-398. After subcutaneous administration of NO-ASA to pylorus-ligated rats and mice, high amounts of NOx were detected in both the gastric contents and serum. In addition, both NS-398 and NO-ASA showed an equipotent antiinflammatory effect against carrageenan-induced paw edema in rats as compared with indomethacin and ASA. These results suggest that both indomethacin and ASA not only increased the mucosal ulcerogenic response to stress but impaired the healing response of gastric ulcers as well. The former action was due to inhibition of COX-1, while the latter effect was accounted for by inhibition of COX-2 and was mimicked by the COX-2-selective inhibitor NS-398. NO-ASA, although it inhibited both COX-1 and COX-2 activity, had no deleterious effects on gastric ulcerogenic and healing responses.     

Comparison of indomethacin and nimesulide, a selective cyclooxygenase-2 inhibitor, on key pathophysiologic steps in the pathogenesis of nonsteroidal anti-inflammatory drug enteropathy in the rat

OBJECTIVE: To examine the differences between independent and behavior-dependent stressful life events and chronic adversities in child psychiatric patients, community controls, and children with asthma. METHOD: The Psychosocial Assessment of Childhood Experiences was used to assess recent severe events (life events with high long-term threat) and major adversities (long-term experiences with high negative impact on child) in children attending a psychiatric clinic (n = 99), community controls (n = 26), and children with chronic asthma (n = 94). RESULTS: In the previous year, the psychiatric patients had, on average, experienced significantly more independent and behavior-dependent severe events and major adversities than either the controls or the asthmatic patients. The differences were most pronounced in relation to behavior-dependent high-threat life events and long-term-experiences. Among the psychiatric patients, one third of all severe events and one quarter of all major adversities were dependent on the child's behavior. The corresponding proportions in the controls and children with asthma were between one fifth and one twelfth. CONCLUSIONS: Psychiatrically disturbed children have an increased risk of experiencing behavior-dependent life events and long-term adversities compared with their peers in the community at large and compared with children suffering from a chronic physical illness such as asthma. Future studies need to examine the possible contributions of such experiences to the development and maintenance of psychiatric and physical illness in children.     

Studies on 5-lipoxygenase inhibitors. II. Discovery, optical resolution and enantioselective synthesis of FR110302, a highly potent non-redox type 5-lipoxygenase inhibitor

A novel series of 2,2-dialkyl-5-(2-quinolylmethoxy)-1,2,3, 4-tetrahydro-1-naphthols was synthesized and evaluated as 5-lipoxygenase (5-LO) inhibitors. Systematic optimization led to identification of several highly potent non-redox type 5-LO inhibitors with nanomolar IC50s as racemic mixtures. Optical resolution of racemate 50 indicated that its 5-LO inhibitory activity was enantiospecific and due to the (+)-enantiomer. An efficient synthetic route to the (+)-enantiomers via asymmetric reduction of tetralone intermediates was established. The best compound, (+)-2,2-dibutyl-5-(2-quinolylmethoxy)-1,2,3,4-tetrahydro-1-naphtho l (FR110302, (+)-50), showed potent inhibitory activity against leukotriene (LT) biosynthesis by intact neutrophiles in rats (IC50 4.9 nM) and in humans (IC50 40 nM). Furthermore oral administration of FR110302 significantly inhibited neutrophil migration in the rat air pouch model at 1 mg/kg.     

Chemopreventive effects of nimesulide, a selective cyclooxygenase-2 inhibitor, on the development of rat urinary bladder carcinomas initiated by N-butyl-N-(4-hydroxybutyl)nitrosamine

The chemopreventive potential of a selective cyclooxygenase-2 inhibitor, nimesulide (NIM), against the development of rat superficial urinary bladder carcinomas after initiation with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) was examined. Six-week-old Fischer 344 male rats were given 0.05% BBN in their drinking water for 8 weeks, followed by diets supplemented with 0, 100, 200, or 400 ppm NIM for 12 weeks, and they were then sacrificed. NIM decreased, in a dose-dependent manner, the incidence of transitional cell carcinoma (TCC) to 12 of 20 (60.0%), 8 of 16 (50.0%), and 5 of 19 (26.3%) and the multiplicity of TCCs to 0.75 +/- 0.79, 0.56 +/- 0.63, and 0.37 +/- 0.78 per rat at 100, 200, and 400 ppm, respectively, as compared with the BBN alone group values of 18 of 20 (90.0%) and 2.35 +/- 1.23. NIM did not significantly affect the cell differentiation or invasiveness of TCCs. These results indicate clear chemopreventive potential of a selective cyclooxygenase-2 inhibitor against postinitiation development of superficial rat urinary bladder carcinomas.     

Synthesis, biological activity, and molecular modeling of selective 5-HT(2C/2B) receptor antagonists

The synthesis and biological activity are reported for a series of analogues of the previously published indole urea 2 (SB-206553), designed to probe the 5-HT(2C) receptor binding site. Small molecule modeling studies have been used to define a region in space which is allowed at the 5-HT(2C) receptor but disallowed at the 5-HT(2A) receptor. In a complementary approach, docking of 2 into our model of the 5-HT(2C) receptor has allowed us to propose a novel primary binding interaction for this series of diaryl ureas, involving a potential double hydrogen-bonding interaction between the urea carbonyl oxygen of the ligand and two serine residues in the receptor. The difference of two valine residues in the 5-HT(2C) receptor for leucine residues in the 5-HT(2A) receptor is believed to account for the observed 5-HT(2C)/5-HT(2A) selectivity with 2.     

Possible participation of cyclooxygenase-2 in the recurrence of allergic inflammation in rats

The possible involvement of purines and/or nitric oxide (NO) in the gamma-aminobutyric acid (GABA)A receptor-mediated effects on the spontaneous activity of isolated preparations from longitudinal and circular muscles of cat terminal ileum was investigated. GABA had biphasic effects, which were neurogenic and muscarinic. ATP and adenosine dose dependently inhibited the activity of the muscles. A contractile response evoked by the nucleotide only was also observed. The effects of the purines were equipotent and resistant to Nomega-nitro-L-arginine (L-NNA), tetrodotoxin and to desensitization by alpha,beta-methylene adenosine 5'-triphosphate (alpha,beta-meATP), except for the contractile effect of ATP, which was abolished by alpha,beta-meATP. Pretreatment of the preparations with ATP or adenosine produced: (i) desensitization to the effects of the respective purinoceptor agonist only; and (ii) suppression of the GABA-induced responses of longitudinal and circular muscles. Hemoglobin and L-NNA greatly reduced or completely blocked the GABA(A)-induced relaxation and decreased the GABA(A)-induced contraction. Our results indicate that purines and NO, to a different extent, mediate the relaxant phase of the GABA effects in both layers. Interactions between muscarinic cholinoceptors and GABA-nitrergic pathway and a concomitant activation of postjunctional P1 and P2y purinoceptors are suggested to explain the prejunctional biphasic effects of GABA.     

Effect of a novel 5-lipoxygenase activating protein inhibitor, BAYx 1005, on asthma induced by cold dry air

BACKGROUND: Leukotrienes have been implicated in the mediation of airway obstruction induced by hyperventilation of cold dry air in asthmatic subjects. The effect of a novel inhibitor of 5-lipoxygenase activating protein, BAYx 1005, on the bronchospastic response to cold dry air hyperventilation was investigated in asthmatic patients. METHODS: After a screening cold dry air hyperventilation challenge to document cold air responsiveness, 16 asthmatic subjects (baseline forced expiratory volume in one second (FEV1) > 60% of predicted) underwent cold air challenge three hours after receiving 750 mg of BAYx 1005 or placebo using a randomised, double blind, crossover design. Leukotriene synthesis inhibition was estimated by measuring the concentration of leukotriene B4 in whole blood stimulated with calcium ionophore A21387. RESULTS: Treatment with BAYx 1005 produced a 34% (95% CI 11 to 63) increase in the amount of cold air minute ventilation required for a 10% decrease in FEV1 (PD10VE) compared with placebo (mean (SE) 37.6 (1.12) 1/min compared with 28.0 (1.13) 1/min, p < 0.006). The PD20VE increased 19% (95% CI 8 to 31) after treatment with BAYx 1005 compared with placebo (57.3(1.10)1/min versus 48.1 (1.10) 1/min, p < 0.002). Treatment with BAYx 1005 produced a 15.4% decrease in ionophore-stimulated LTB4 production, while treatment with placebo produced a 7.1% increase in ex vivo LTB4 (p < 0.02). CONCLUSIONS: Treatment with BAYx 1005, a novel inhibitor of leukotriene synthesis, produced a significant blunting of cold dry air responsiveness consistent with the hypothesis that leukotrienes mediate part of the bronchoconstriction induced by hyperventilation of cold dry air.     

Identification of the human liver cytochrome P450 enzymes involved in the in vitro metabolism of a novel 5-lipoxygenase inhibitor

In vitro studies were conducted to identify the hepatic cytochrome P450 (CYP) forms involved in the oxidative metabolism of [14C]ABT-761 and its N-dehydroxylated metabolite, [14C]ABT-438, by human liver microsomes. The two compounds were metabolized by parallel pathways, to form the corresponding methylene bridge hydroxy metabolites. There was no evidence of sulfoxidation and/or ring hydroxylation. Over the ABT-761 and ABT-438 concentration ranges studied (1-300 microM), the rate of NADPH-dependent hydroxylation was linear with respect to substrate concentration ([S]) and did not conform to saturable Michaelis-Menten kinetics. Under these conditions ([S] < KM), the intrinsic clearance (Vmax/KM) of ABT-438 was 10-fold higher than that of ABT-761 (1.7 +/- 0.8 vs. 0.17 +/- 0.06 microl/min/mg, mean +/- SD, N = 3 livers). The hydroxylation of both compounds was shown to be highly correlated (r = 0.83, p < 0.01, N = 11 different human livers) with CYP3A-selective erythromycin N-demethylase activity, and the correlation between ABT-761 hydroxylation and tolbutamide hydroxylase (CYP2C9-selective) activity (r = 0.63, p < 0.05, N = 10) was also statistically significant. Ketoconazole (2.0 microM), a CYP3A-selective inhibitor, inhibited the hydroxylation of both compounds by 53-67%, and sulfaphenazole (CYP2C9-selective) decreased activity by 10-20%. By comparison, alpha-naphthoflavone, a known activator of CYP3A, stimulated the hydroxylation of ABT-761 (8-fold) and ABT-438 (4-fold). In addition, the abundance-normalized rates of cDNA-expressed CYP-dependent metabolism indicated that hydroxylation was largely mediated (66-86%) by CYP3A(4). Therefore, it is concluded that the hydroxylation of ABT-761 and ABT-438 (相似文献   

Antiepileptic effects of tiagabine, a selective GABA uptake inhibitor, in the rat kindling model of temporal lobe epilepsy

PURPOSE: We determined the antiepileptic profile of tiagabine (TGB), a selective gamma-aminobutyric acid (GABA) uptake inhibitor, in the rat kindling model of temporal lobe epilepsy (TLE). METHODS: The anticonvulsant and adverse effects of TGB were examined in amygdala- or hippocampal-kindled rats and compared with those of other GABA uptake inhibitors (SKF89976A and NNC-711) and conventional antiepileptic drugs [AEDs: valproate (VPA) and carbamazepine (CBZ)]. In addition, the antiepileptogenic effects of TGB on amygdala kindling development were examined. RESULTS: TGB (2.5-40 mg/kg intraperitoneally, i.p.) had potent and dose-dependent anticonvulsant effects on both amygdala- and hippocampal-kindled seizures. The order of anticonvulsant potency of the three GABA uptake inhibitors tested was: NNC-711 > TGB > SKF-89976A and paralleled the in vitro GABA uptake efficacy. In addition, daily treatment with TGB 10 mg/kg for 10 days significantly retarded kindling development. Although adverse effects of TGB on motor systems were significantly less than those of VPA and CBZ, high toxic doses of TGB often caused EEG paroxysm and myoclonus. CONCLUSIONS: Our results indicate the clinical usefulness of TGB for treatment of drug-resistant TLE.     

Evaluation of the novel anti-inflammatory agent tetrandrine as a pulpotomy medicament in a canine model

Tetrandrine, a bisbenzylisoquinoline alkaloid with unique broad-spectrum anti-inflammatory properties, was evaluated as a pulpotomy medicament in a canine model. Histological sections were evaluated after three days (acute inflammation) and six weeks (chronic inflammation) by two criteria: 1) intensity and degree of inflammation, and 2) extent of pulp involvement. The results of the three-day dressings revealed significant neutrophil infiltration in only 30% of teeth treated with tetrandrine, compared with 81%, 84%, and 100% of teeth treated with Ledermix, (Lederle Pharmaceuticals, Wolfrathausen, Germany), formocresol (Creighton Pharmaceuticals, Sydney, Australia) and saline (controls) respectively (P < 0.01). After six weeks, there was significant lymphocyte infiltration in only 30% of teeth treated with tetrandrine, compared with 66%, 90%, and 100% on teeth treated with Ledermix, formocresol, and saline controls respectively. (P < 0.01). In both three-day and six-week specimens in tetrandrine-treated teeth the extent of inflammation was limited to less than one-third of the coronal section of the pulp, whereas teeth treated with Ledermix or formocresol showed cellular infiltration extending to greater than two-thirds of the pulp (P < 0.01). Comparative studies with berbamine, a natural analog of tetrandrine, showed that it was less potent than tetrandrine, but significantly better than Ledermix and formocresol on both acute and chronic pulp inflammation (P < 0.05 and P < 0.01 respectively). These results suggest that tetrandrine may have value as a pulpotomy medicament.     

Effect of SC-41930, a potent selective leukotriene B4 receptor antagonist, in the guinea pig model of middle ear inflammation

Arachidonic acid metabolites such as prostaglandins and leukotrienes have been shown to play an important role in the pathogenesis of otitis media (OM). Among these mediators, leukotriene B4 (LTB4) is one of the most potent inducers of inflammatory processes. SC-41930 has been shown to be a specific LTB4 receptor antagonist both in vitro and in vivo. In this study, anti-inflammatory effects of SC-41930 were investigated in a guinea pig model of OM induced by middle ear (ME) inoculation of killed Staphylococcus aureus. Outcome of treatment was determined by measurement of myeloperoxidase activity in the samples of ME mucosa, evaluation of temporal bone histopathology, and presence of ME fluids. Myeloperoxidase activity in the SC-41930-treated group was found to be significantly lower than that in the control group. Histopathology of temporal bones indicated decreased inflammation in the treated group as compared to the controls. In addition, ME fluids were absent in four out of six treated animals. These results demonstrate that SC-41930 can produce significant anti-inflammatory effects in this model of OM.     

(+/-)-trans-2-[3-methoxy-4-(4-chlorophenylthioethoxy)-5-(N-methyl-N- hydroxyureidyl)methylphenyl]-5-(3,4, 5-trimethoxyphenyl)tetrahydrofuran (CMI-392), a potent dual 5-lipoxygenase inhibitor and platelet-activating factor receptor antagonist

By incorporating an N-hydroxyurea functionality onto diaryltetrahydrofurans, a novel series of compounds was investigated as dual 5-lipoxygenese (5-LO) inhibitor and platelet-activating factor (PAF) receptor antagonist. These dual functional compounds were evaluated in vitro for 5-LO inhibition in RBL cell extracts and human whole blood, and PAF receptor antagonism in a receptor binding assay. PAF-induced hemoconcentration and arachidonic acid- and TPA-induced ear edema in mice were used to determine in vivo activities. The structure-activity relationship analysis to define a preclinical lead is presented. (+/-)-trans-2-[3-methoxy-4-(4-chlorophenylthioethoxy)-5-(N-methyl- N-h ydroxyureidyl)methylphenyl]-5-(3,4, 5-trimethoxyphenyl)tetrahydrofuran (40, CMI-392) was selected for further study. In the arachidonic acid-induced mouse ear edema model, 40 was more potent than either zileuton (a 5-LO inhibitor) or BN 50739 (a PAF receptor antagonist), and it demonstrated the same inhibitory effect as a physical combination of the latter two agents. These results suggest that a single compound which both inhibits leukotriene synthesis and blocks PAF receptor binding may provide therapeutic advantages over single-acting agents. The clinical development of compound 40 is in progress.