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At least 415 records · Page 23Linked to original sources
PubMed2001

Effect of TAK-637, a tachykinin NK1-receptor antagonist, on lower urinary tract function in cats.

The effect of TAK-637 ((aR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H[1,4]diazocino[2,1g][1,7]naphthyridine-6,13-dione), a tachykinin NK1-receptor antagonist, on lower urinary tract function was investigated in cats. TAK-637 (0.1, 0.3, 1 and 3 mg/kg, i.v.) produced a dose-dependent increase in bladder capacity without any significant reduction in voiding efficiency in decerebrate cats. The maximal increase in bladder capacity was 94%. By contrast, oxybutynin at 1 and 3 mg/kg (i.v.) produced a 18% and 35% increase in bladder capacity, respectively, with a 47% and 45% reduction in voiding efficiency. TAK-637 (3 mg/kg, i.v.) did not inhibit the micturition reflex induced by electrical stimulation of the rostral brainstem near the locus coeruleus, indicating that it does not impair the well-organized micturition reflex (bladder contraction and urethral relaxation). These results suggest that TAK-637 increases bladder storage capability without inhibiting the voiding function of the lower urinary tract, presumably by inhibiting the afferent pathway of the micturition reflex, rather than the efferent pathway.

Animals↗
PubMed2006

Direct involvement of orexinergic systems in the activation of the mesolimbic dopamine pathway and related behaviors induced by morphine.

In this study, we investigated the role of orexinergic systems in dopamine-related behaviors induced by the mu-opioid receptor agonist morphine in rodents. Extensive coexpression of tyrosine hydroxylase with orexin receptors was observed in the mouse ventral tegmental area (VTA). The levels of dopamine and its major metabolites in the nucleus accumbens were markedly increased by the microinjection of orexin A and orexin B into the VTA. The subcutaneous morphine-induced place preference and hyperlocomotion observed in wild-type mice were abolished in mice that lacked the prepro-orexin gene. An intra-VTA injection of a selective orexin receptor antagonist SB334867A [1-(2-methylbenzoxazol-6-yl)-3-[1.5]naphthyridin-4-yl urea] significantly suppressed the morphine-induced place preference in rats. Furthermore, the increased level of dialysate dopamine produced by morphine in the mouse brain was significantly decreased by deletion of the prepro-orexin gene. These findings provide new evidence that orexin-containing neurons in the VTA are directly implicated in the rewarding effect and hyperlocomotion induced by morphine through activation of the mesolimbic dopamine pathway in rodents.

Animals↗
PubMed1999

Trovafloxacin: an overview.

Trovafloxacin, a new synthetic naphthyridine fluoroquinolone antibiotic, is a broad-spectrum agent available orally and intravenously. It was recently approved by the Food and Drug Administration for the treatment of selected pulmonary, surgical, intraabdominal, gynecologic, pelvic, skin, and urinary tract infections. Its spectrum of activity includes aerobic gram-positive and gram-negative organisms as well as anaerobic pathogens. It is rapidly absorbed after oral administration, achieves good tissue and cerebrospinal fluid penetration, and has a half-life that allows once-daily dosing. It is hepatically metabolized, and dosage adjustments are necessary for patients with severe hepatic dysfunction but not for those with mild or moderate dysfunction or renal dysfunction. The drug has a favorable safety profile, and a high tendency for transient first-dose dizziness and/or lightheadedness in young women. Similar to other quinolones, trovafloxacin should not be taken with antacids that contain aluminum or magnesium, sucralfate, or ferrous sulfate. Trovafloxacin may prove beneficial as it allows for oral or intravenous monotherapy against indicated infections that normally require multidrug, broad-spectrum antibiotic coverage.

Anti-Infective Agents↗
PubMed1993

In vitro and in vivo immunopharmacological profile of Sch 40120.

Sch 40120 (10-(3-chlorophenyl) - 6,8,9,10- tetrahydrobenzo [b] [1,8] naphthyridin-5 (7H)-one) is a leukotriene inhibitor that is also a potent inhibitor of acute inflammatory responses in rodent systems. In the present study, we have evaluated the effects of this drug on immune function as well as its activity in models of immune mediated chronic inflammatory disease. Sch 40120 was particularly effective in suppressing T cell proliferative responses in vitro. Antigen-specific and poly-clonally-induced in vitro antibody responses were also inhibited by the drug. However, the in vivo potency of Sch 40120 in suppressing immune responses and in inhibiting the pathological changes seen in rodent models of autoimmune disease (EAE and adjuvant arthritis) was somewhat less than that previously observed in models of acute inflammation. Nevertheless, the spectrum of activities exhibited by Sch 40120 suggests that it will be particularly useful in the treatment of psoriasis where T lymphocytes have been implicated in the development of disease and leukotrienes appear to have a role in the persistence of psoriatic plaques.

Animals↗
PubMed2004

In vitro efficacy of new antiprotozoals against Philasterides dicentrarchi (Ciliophora, Scuticociliatida).

Philasterides dicentrarchi is a histiophagous ciliate that causes severe losses in turbot and sea bass farming. This study investigated the in vitro efficacy against P. dicentrarchi of 85 newly synthesized compounds and 12 commercial compounds, of which 2 are fluoroquinolones (norfloxacine and lomefloxacine) with known antibacterial activity. Seventeen of the newly synthesized compounds (2 naphthyridines, 2 pyridothienodiazines and 13 pyridothienotriazines) and the fluoroquinolone norfloxacin showed good activity. The most promising compound was the pyridothienotriazine 12k, with activity similar to that of the salicylanilides niclosamide and oxiclozanide (MLC 0.8 mg l(-1) in PBS, 1.5 mg l(-1) in seawater; MLC = minimum 24 h lethal concentration).

Animals↗
PubMed1983

Appraisals of compounds of diverse chemical classes for capacities to cure infections with sporozoites of Plasmodium cynomolgi.

Compounds (265) of widely diverse structures were appraised for radical curative activity in rhesus monkeys infected with sporozoites of the B strain of Plasmodium cynomolgi, using an evaluation system that provided a preliminary assessment with from 0.1-1.0 g of compound and tests against one to five active infections. None of 32 compounds in a miscellaneous structure category, none of seven agents of antibiotic origin, none of 12 1,5-naphthyridines, and none of seven 7-aminoquinolines exhibited curative activity at the largest test doses. There was a suggestion that one of 12 newly synthesized pyrocatechols was curative. Two of 20 6-aminoquinolines effected cure at or near maximum tolerated doses. In contrast, 90 of 174 newly synthesized 8-aminoquinolines effected cure; 18 of the 90 being as active as primaquine, eight twice as active, and six four times as active. There were major disagreements between the above results and those recorded by others in mice inoculated with sporozoites of P. berghei yoelii or P. yoelii nigeriensis. These discrepancies were of serious dimensions in evaluations of the 8-aminoquinolines. This, plus previous near flawless performances of P. cynomolgi in identifying agents that would cure naturally acquired P. vivax infections, led to the suggestion that the abbreviated simian model employed in these studies be used hereafter in primary screening of new agents for radical curative activity.

Aminoquinolines↗
PubMed2001

Effects of TAK-637, a novel neurokinin-1 receptor antagonist, on colonic function in vivo.

Substance P (SP) is an important neurotransmitter that mediates various gut functions; however, its precise pathophysiological role remains unclear. In this study, we investigated the effect of SP on colonic function and the effect of TAK-637 [(aR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]naphthyridine-6,13-dione] a new neurokinin-1 (NK1) receptor antagonist, on colonic responses to SP or stress in Mongolian gerbils. SP and the selective NK1 agonist [pGlu6]SP6-11 significantly increased fecal pellet output. TAK-637 reduced [pGlu6]SP6-11-induced defecation, but did not significantly affect neurokinin A-, 5-hydroxytryptamine- or carbachol-stimulated defecation. Oral TAK-637 decreased restraint stress-stimulated fecal pellet output with an ID50 value of 0.33 mg/kg. Ondansetron and atropine, but not the peripheral kappa-receptor agonist trimebutine, also reduced restraint stress-stimulated defecation. TAK-637 inhibited the increase in fecal pellet output stimulated by intracerebroventricular injection of corticotropin-releasing factor, but did not affect the stress-induced increase in plasma adrenocorticotropic hormone levels. Denervation of the sensory neurons with capsaicin did not affect stress-stimulated defecation. These results suggest that NK1 receptors in the enteric plexus play an important role in stress-induced changes in colonic function, and that TAK-637 may be useful in the treatment of functional bowel diseases such as irritable bowel syndrome.

Adrenocorticotropic Hormone↗
PubMed1992

Actions of a 5-lipoxygenase inhibitor, Sch 40120, on acute inflammatory responses.

Sch 40120 (10-(3-chlorophenyl)-6,8,9,10-tetrahydrobenzo[b] [1,8]naphthyridin-5(7H)-one) is an inhibitor of the 5-lipoxygenase enzyme in rat neutrophils, human neutrophils and the the MC9 murine mast cell clone with IC50 values of 8, 4 and 7 microM, respectively. The drug was examined for its effects on acute inflammatory responses in the paw and pleural cavity of rats. The drug suppressed paw inflammation triggered by a reverse passive Arthus reaction or a subplantar injection of the polysaccharide carrageenan with p.o. ED50 values of 0.2 and 1.5 mg/kg, respectively. In reverse passive Arthus reaction and carrageenan pleurisy models, Sch 40120 was found to suppress both the cellular and fluid components of the acute inflammation. The p.o. ED50 values for inhibition of cells and fluid in pleurisy models were in the range of 0.1 to 0.7 mg/kg. When applied locally to the ears of mice, the drug blocked an arachidonic acid-induced and leukotriene-mediated ear inflammation with an ED50 of 0.072 mg/ear. These findings suggest that Sch 40120 is a potent anti-inflammatory agent that may be particularly useful in the treatment of inflammatory diseases such as psoriasis in which leukotrienes appear to be major mediators of the pathological symptoms that characterize the disease state.

Acute Disease↗
PubMed2003

Characterization of ARC-111 as a novel topoisomerase I-targeting anticancer drug.

8,9-Dimethoxy-5-(2-N,N-dimethylaminoethyl)-2,3-methylenedioxy-5H-dibenzo[c,h][1,6] naphthyridin-6-one (ARC-111, topovale) is a new synthetic antitumor agent. In the current study, we show that ARC-111 is highly potent in scid mice carrying human tumor xenografts. ARC-111 was shown to be as active as camptothecin (CPT)-11 in the HCT-8 colon tumor model, and compared favorably with CPT-11 and topotecan in the SKNEP anaplastic Wilms' tumor model. In tissue culture models, ARC-111 exhibited low nM cytotoxicity against a panel of cancer cells. ARC-111 cytotoxicity as well as ARC-111-induced apoptosis was reduced >100-fold in CPT-resistant topoisomerase I (TOP1)-deficient P388/CPT45 cells as compared with P388 cells. Similarly, ARC-111 cytotoxicity was greatly reduced in CPT-resistant CPT-K5 and U937/CR cells, which express CPT-resistant mutant TOP1, suggesting that the cytotoxic target of ARC-111 is TOP1. Indeed, ARC-111, like CPT, was shown to induce reversible TOP1 cleavage complexes in tumor cells as evidenced by specific reduction of the TOP1 immunoreactive band in a band depletion assay, as well as elevation of small ubiquitin modifier-TOP1 conjugate levels and activation of 26S proteasome-mediated degradation of TOP1. Unlike CPT, ARC-111 is not a substrate for the ATP-binding cassette transporter breast cancer resistance protein. In addition, ARC-111 cytotoxicity was not significantly reduced in the presence of human serum albumin. These results suggest that ARC-111 is a promising new TOP1-targeting antitumor drug with a different drug resistance profile than CPT.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1991

Pharmacological profile of UP 5145-52, an original antiulcer and antisecretory agent.

The gastric and antiulcer effects of UP 5145-52, a new naphthyridinone derivative (1-phenyl-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl)-4-acetoxy butane, were studied in rats. UP 5145-52 dose dependently prevented the formation of gastric lesions induced by a necrotizing agent such as absolute ethanol, indomethacin or stress (ED50 values were 0.065, 1.26 and 0.72 mg/kg p.o., respectively). A beneficial action was also observed against indomethacin-induced intestinal lesions. UP 5145-52 inhibited total acid output in the pylorus-ligated rat (ED50 on total acid output was 0.16 mg/kg p.o.) and in the rat chronic gastric fistula model. The mechanism of antisecretory activity currently remains unknown as UP 5145-52 fails to bind to receptors involved in gastric secretion (H2 or muscarinic) and to inhibit H+/K+ adenosine triphosphatase. The ability of UP 5145-52 (1 mg/kg p.o.) to restore synthesis of gastric acid glycoproteins depressed by previous administration of absolute ethanol suggests that cytoprotection could play a role in the antiulcer efficacy of the drug.

Adenosine Triphosphatases↗
PubMedDate not supplied

Wy-46,300 and Wy-46,531: vascular smooth muscle relaxant/antihypertensive agents with combined Ca2+ antagonist/myosin phosphorylation inhibitory mechanisms.

1,4,5,6,7,8-hexahydro-2-methyl-5-oxo-4-(pentafluorophenyl)-1,7- naphthyridine-3-carboxylic acid methyl ester hydrochlorides with either a 3-phenoxy-2-hydroxypropyl (Wy-46,300) or 2-hydroxy-4-phenylbutyl (Wy-46,531) substituent at the 7 position are structurally novel vascular relaxant compounds which lower blood pressure by approximately 35 mm Hg at 25 mg/kg p.o. in spontaneously hypertensive rats (SHR) or perinephritic hypertensive beagles. In contrast to standard Ca2+ blockers, both agents also directly inhibit myosin phosphorylation and actin-myosin interactions in Triton-purified arterial actomyosin. The potency of Wy-46,300 (IC50 = 28 microM) in this system is similar to the calmodulin antagonist W-7, whereas Wy-46,531 (IC50 = 18 microM) is more potent. Inhibition of both parameters is attenuated in the presence of maximal Ca2+-calmodulin, consistent with calmodulin antagonism as the mechanism for myosin phosphorylation inhibition. In intact smooth muscle, these agents inhibit K+-depolarized contractions of rabbit aortic strips in a biphasic manner (0.1-10 microM, 30-40% inhibition; 10 microM-100 microM, 90% inhibition). In contrast to comparable inhibition of force by standard Ca2+ blockers, this latter phase of inhibition is not reversible with the Ca2+ agonist Bay K 8644. Moreover, significantly greater inhibition of receptor-mediated contractions (norepinephrine, angiotensin II, histamine) than that observed with nifedipine is apparent with Wy-46,300. In paced rabbit atria, both Wy-46,300 and Wy-46,531 are 10-100 times less potent as negative inotropic agents (IC25 = 3-5 microM) when compared with standard Ca2+ blockers.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Antiallergy activity of Sch 37224, a new inhibitor of leukotriene formation.

Sulfidopeptide leukotrienes (LTs) C4, D4 and E4 are important mediators in the pathophysiology of bronchial asthma. Sch 37224, 1-(1,2-dihydro-4-hydroxy-2-oxo-1-phenyl-1,8-naphthyridin-3-yl) pyrrolidinium, hydroxide inner salt, has been found to inhibit the formation of these autocoids. Although Sch 37224 did not inhibit 5-lipoxygenase, cyclooxygenase or phospholipase A2, it inhibited LTD4 and thromboxane B2 release by anaphylactic guinea pig lung (IC40 = 3.9 and 1.9 microM, respectively). At 5 microM Sch 37224 also inhibited superoxide anion radical generation from activated human polymorphonuclear neutrophilic leukocytes. When administered p.o. to guinea pigs, Sch 37224 decreased a LT-mediated allergic bronchospasm (ED40 = 1.1 mg/kg) for 6 hr and did not exhibit tolerance. In addition to its activities in allergen-induced bronchospasm in guinea pigs, Sch 37224 also inhibited hyperventilation-induced bronchospasm in guinea pigs at 0.5 to 5 mg/kg and anaphylactic bronchospasm in rats at 0.1 to 10 mg/kg. Sch 37224 was weak or ineffective as an antagonist of histamine, methacholine, serotonin, LTC4 or platelet activating factor induced bronchospasms in guinea pigs. Also, Sch 37224 was not a bronchodilator or calcium influx blocker and had only weak relaxant activity on guinea pig trachea in vitro (IC40 = 51 microM). Sch 37224 is, therefore, a potential antiallergic agent that inhibits LT release. It is p.o. effective in animal models of allergic and nonallergic-mediated bronchospasms.

Animals↗
PubMed1989

[General pharmacology of T-3262, a new pyridonecarboxylic acid].

General pharmacological activities of (+/-)-7-(3-amino-1-pyrrolidinyl)-6-fluoro-1-(2,4-difluorophenyl)-1,4- dih ydro- 4-oxo-1,8-naphthyridine-3-carboxylic acid p-toluenesulfonate hydrate (T-3262), which is a new pyridonecarboxylic acid, were examined with the following results. 1. Central nervous system: T-3262 did not show any significant pharmacological effects at oral doses of 100-1,000 mg/kg but caused slow waves in spontaneous EEG in cats at intravenous doses of 10-30 mg/kg. 2. Respiratory and cardiovascular system: T-3262 produced little effect in normotensive rats and anesthetized rabbits at oral doses of 100-1,000 mg/kg and intravenous doses of 3-30 mg/kg, respectively. But T-3262 caused, dose-dependently, an increase of respiratory rate, hypotension, decrease of heart rate and changes in ECG patterns (elevation of T waves, slow amplitudes of QRS complexes and prolongation of RR interval, etc.) in anesthetized dogs at intravenous doses of 3-10 mg/kg. 3. Renal functions: T-3262 increased electrolyte excretions at oral doses of 300-1,000 mg/kg but did not affect PSP excretion in rats. 4. Autonomic nervous system and smooth muscle organs: T-3262 exerted slight inhibition of gastric output in rats and slight miosis in mice at an oral dose of 1,000 mg/kg. But T-3262 did not affect the contraction of nictitating membrane in anesthetized cats at intravenous doses of 1-30 mg/kg. T-3262 increased spontaneous motilities of isolated stomach, ileum and uterus, but decreased that of isolated colon at concentrations of 10(-5)-10(-4) g/ml. 5. Hematological examinations: T-3262 did not show any significant effects on bleeding time, blood coagulation, platelet aggregation and blood glucose level in rats at oral doses of 100-1,000 mg/kg. 6. Miscellaneous effects: T-3262 exerted slight inhibitions of gastric secretion and of carrageenin-induced hind paw edema in rats at a dose of 1,000 mg/kg administered intraduodenally and orally, respectively. T-3262 did not affect neuromuscular junction and bile secretion in rats at intravenous doses of 3-30 mg/kg and oral doses of 100-1,000 mg/kg, respectively. From these results, it can be assumed that T-3262 has a wide safety margin as an oral antibacterial agent.

4-Quinolones↗
PubMed1987

Comparison of the effects of the new anxiolytic suriclone and benzodiazepines on motor function and electroencephalogram.

(6-(7-Chloro-1,8-naphthyridin-2-yl)-7-oxo-2,3,6,7-tetrahydro-5H- 1,4- dithiino[2,3-c]pyrrol-5-yl)-4-methyl-1-piperazinecarboxylate (suriclone, RP 31264), a new anxiolytic, produced behavioral effects similar to those of diazepam and lorazepam, had a protective effect against electroshock convulsion and potentiated the sleeping effect of hexobarbital in mice. It inhibited crossed extensor reflexes in chicks and augmented the dorsal root reflex potential, the increase of which is considered to be an index of increased GABAergic presynaptic inhibition. Suriclone produced high-amplitude slow waves in the amygdala and cerebral cortex and desynchronization of theta waves in the hippocampus in rat electroencephalogram (EEG). These observations were quantitatively confirmed by power spectrum analysis of EEG. The mechanisms of action of suriclone on the CNS are discussed in relation to those of benzodiazepines.

Animals↗
PubMed1987

Pharmacological effects of the antianxiety compound suriclone and its principal metabolites.

The pharmacodynamic effects of 4-methyl-1-piperazinecarboxylic acid ester with (+/-)-6-(7-chloro-1,8-naphthyridin-2-yl)-2,3,6,7-tetrahydro-7-h ydr oxy-5H-p- dithiino[2,3-c]pyrrol-5-one (suriclone, RP-31264) and its principal metabolites M1 and M2 on respiration, cardiovascular system, autonomic nervous system, smooth muscle and other physiological parameters were investigated in various animal species. Suriclone, 1 mg/kg i.v., increased the amplitude of respiratory movement, decreased the respiratory rate and blood pressure and increased the heart rate in conscious rabbits. The respiratory and depressor effects were more evident in pentobarbital anesthetized rabbits. In anesthetized dogs, suriclone, 0.05 or 0.5 mg/kg i.v., produced essentially the same effects as seen in the anesthetized rabbits. The ECG pattern was not significantly changed in any animal. Such effects on respiration and on the cardiovascular system of metabolites M1 and M2 in the rabbits were weak. In the isolated guinea-pig atria, suriclone, 10(-6) g/ml, had no effect but increased contractility and decreased heart rate at a high concentration of 10(-5) g/ml. Both M1 and M2 had weak effects. Suriclone had no action on flow rate of the perfusate through the blood vessels of the isolated rabbit ear. In anesthetized dogs, suriclone 0.5 mg/kg i.v., did not affect the responses to vagal stimulation or to pre- and postganglionic stimulation of cardiac ganglion. Suriclone instilled onto the eye or i.v. had no appreciable effect on pupillary diameter or the miotic response in rabbits, but an abnormal oculogyration was evoked when the drug was given i.v. at 1 mg/kg. M1 or M2 had no such effect. Suriclone did not exert analgesic effects in mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

[Therapeutic prospects of new fluoroquinolones].

Fluoroquinolones are new synthetic derivatives with a broad spectrum and a potent antibacterial activity this permits to assimilate these molecules as antibiotics. These compounds are characterized by a quinoline or a naphthyridine nucleus with a fluorine atom in position 6 and a piperazine or a pyrrole nucleus in position 7. The combination of their antibacterial properties and the good absorption and tissue distribution allows their use in the treatment of the main infections caused by sensitive strains. The clinical and biological tolerance of these drugs are usually excellent.

Anti-Infective Agents↗
PubMed1988

Protective action of SCH 12223 against experimentally induced gastric and intestinal lesions.

The gastrointestinal protective action of SCH 12223 [3-(n-butyl)-4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one hydrate, sodium salt] against various noxious stimuli was characterized in rats. SCH 12223 inhibited the ethanol-induced gastric lesions when given p.o. (0.3-3 mg/kg) or i.v. (1 and 3 mg/kg). Indomethacin pretreatment (10 mg/kg p.o.) did not interfere with this effect. SCH 12223 was also active p.o. in five gastric erosion models: aspirin (1-10 mg/kg), aspirin + acid (1-30 mg/kg), indomethacin (1-10 mg/kg), stress (1 and 3 mg/kg) and reserpine (0.3-10 mg/kg)-induced erosions. The compound lacked antisecretory activity in the pylorus-ligated rats (10 mg/kg p.o.) but increased total gastric mucus (N-acetylneuraminic acid measurements) (1-10 mg/kg p.o.). SCH 12223 (10 and 30 mg/kg p.o.) attenuated intestinal lesions provoked by indomethacin (20 mg/kg p.o. or s.c.) and the protected animals showed better weight gain and food intake than controls. In a 38-day study, SCH 12223 also improved survival from indomethacin lethality (6 of 16 vs. 16 of 16 in the control, P less than .05). The protection cannot be attributed to changes in biliary excretion and plasma levels of indomethacin. We conclude that SCH 12223 is a unique agent which protects both gastric and intestinal epithelia from noxious stimuli, a feature shared by prostaglandins.

Administration, Oral↗