Rat Passive Cutaneous Anaphylaxis Test Research Articles

Study of adjuvant effect of model surfactants from the groups of alkyl sulfates, alkylbenzene sulfonates, alcohol ethoxylates and soaps

The sodium salts of representatives of anionic surfactants, dodecylbenzene sulfonate (SDBS), dodecyl sulfate (SDS) and coconut oil fatty acids, and a nonionic surfactant, dodecyl alcohol ethoxylate, were studied for adjuvant effect on the production of specific IgE antibodies in mice. The surfactants were injected subcutaneously (sc) in concentrations of 1000, 100, 10 or 1 mg/l, respectively, together with 1 μg of ovalbumin (OVA). In addition, groups of mice received OVA in saline (control group) or in Al(OH) 3 (positive adjuvant control group). After the primary immunization the mice were boosted up to three times with OVA (0.1 μg sc) in saline. OVA-specific IgE antibodies were determined by the heterologous mouse rat passive cutaneous anaphylaxis test. The results were confirmed by a specific ELISA method. After the first booster, the Al(OH) 3 group and the 10 mg/l SDS group showed a statistically significant increase in OVA specific IgE levels. After two boosters, a statistically significant suppression in OVA-specific IgE production occurred with SDS (1000 mg/l), SDBS (1000 and 100 mg/l), coconut soap (1000 mg/l) and the alcohol ethoxylate (10 mg/l). This study suggests that a limited number of surfactants possess an adjuvant effect whereas all surfactants at certain levels can suppress specific IgE production.

Antigenicity studies of prulifloxacin (NM441)

Antigenicity of prulifloxacin, a new antibacterial agent, and that of its active metabolite (NM394) were investigated using guinea pigs and mice in this study. In the study with guinea pigs, the animals were immunized with prulifloxacin by oral administration, the predetermined clinical route, and with prulifloxacin alone or emulsified with Freund's complete adjuvant (FCA) by s.c. When active systemic anaphylaxis (ASA) test and passive cutaneous anaphylaxis (PCA) test of these animals were conducted by eliciting with NM394 alone or protein conjugate (NM394-GPSA) of NM394 and guinea pig serum albumin (GPSA), no ASA and PCA reactions were observed. When guinea pigs were immunized subcutaneously with protein conjugate (NM394-BSA) of NM394 and bovine serum albumin (BSA) together with FCA, ASA and PCA reactions were positive by eliciting with NM394-GPSA or NM394-BSA, but were negative by eliciting with NM394 alone. In the study with mice, the animals were immunized orally with prulifloxacin and intraperitoneally with prulifloxacin alone or suspended with aluminum hydroxide gel (alum). When rat PCA test of sera from these mice was conducted by eliciting with NM394 or NM394-GPSA, no positive PCA reaction was observed. When mice were immunized intraperiotneally with NM394-BSA together with alum, PCA reactions were positive by eliciting with NM394-GPSA or NM394-BSA, but were negative by eliciting with NM394 alone. These results show that prulifloxacin has no immunogenicity to guinea pigs and mice, and NM394 as its active form has no eliciting potential to anti-NM394-BSA antibody.

Studies on antiulcer agents. II. Antiulcer properties of N-(1H-tetrazol-5-yl)-2-anilino-5-pyrimidinecarboxamides inhibiting release of histamine from passively sensitized rat peritoneal mast cells.

With the aim of applying mast cell-stabilizing agents as antiulcer agents, N-(1H-tetrazol-5-yl)-2-anilino-5-pyrimidinecarboxamides were synthesized, and initially evaluated pharmacologically for activity in the rat passive cutaneous anaphylaxis test by oral administration. The most active compound 6 was proved to inhibit potently the release of histamine from passively sensitized rat peritoneal mast cells in vitro. When compared with other mast cell-stabilizing agents and an antiulcer agent, compound 6 was found to show excellent gastric mucosal protection and gastric antisecretion activities. Furthermore, compound 6 revealed good activity against acidified aspirin ulcer in rats and water-immersion stress ulcer in rats.

Synthesis and antiallergic activity of 11-(aminoalkylidene)-6,11-dihydrodibenz[b,e]oxepin derivatives

A new series of 11-substituted 6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid derivatives was synthesized and demonstrated to be orally active antiallergic agents. These compounds are structurally related to 1 (KW-4994), which we had reported previously to be a new antiallergic agent. Most compounds synthesized exhibited potent inhibitory effects on 48-h homologous passive cutaneous anaphylaxis (PCA) in rats and on IgG1-mediated bronchoconstriction in guinea pigs. Additionally, compounds possessing a terminal carboxyl group at the 2-position of the dibenz[b,e]oxepin ring system exhibited inhibitory effects on specific [3H]pyrilamine binding to guinea pig cerebellum histamine H1 receptors, whereas these demonstrated negligible effects on specific [3H]QNB binding to rat striatum muscarinic acetylcholine M1 receptors. Structure-activity relationship studies revealed that the following key elements were required for enhanced antiallergic activities: (1) a 3-(dimethylamino)propylidene group as the side chain at the 11-position, (2) a terminal carboxyl moiety at the 2-position, and (3) a dibenzoxepin ring system. Among the compounds synthesized, (Z)-11-[3-(dimethylamino)propylidene]-6,11-dihydrodibenz [b,e]oxepin-2-acetic acid hydrochloride (16) was selected for further evaluation. It had an ED50 value of 0.049 mg/kg po in the PCA test in rats and an ID50 value of 0.030 mg/kg po in inhibiting anaphylactic bronchoconstriction in guinea pigs. Furthermore, it had a Ki value of 16 +/- 0.35 nM for the histamine H1 receptor, while it exhibited negligible CNS side effects up to a dose of 600 mg/kg po. Compound 16 is now under clinical evaluation as KW-4679.

A New Series of Antiallergic Agents. I. Synthesis and Activity of 11-(2-Aminoethyl)thio-6,11-dihydrodibenz(b, e)oxepin Derivatives.

A new series of 11-substituted 6,11-dihydrodibenz[b,e]oxepin derivatives was synthesized and evaluated for antiallergic activity. Convenient methods for the preparation of sulfides from alcohols were developed. Structure-activity relationships are described. Compound 7, 11-[2-(dimethylamin)ethyl]thio-6,11-dihydrodibenz[b,e] oxepin-2-carboxylic acid hydrochloride, was the most potent in the rat passive cutaneous anaphylaxis test (ED50 = 0.92 mg/kg p.o.). It had a potent inhibitory effect on anaphylactic bronchoconstriction in guinea pigs (ED50 = 0.029 mg/kg p.o.) and H1 receptor antagonistic effect (Ki = 14 nM) with few central nervous system side effects. Additionally, an antagonistic effect against prostaglandin D2-induced contraction of isolated guinea pig trachea (pA2 = 5.73) was an attractive mechanism of action of the new antiallergic agent. Compound 7 was selected for further evaluation as KW-4994.

Acrylamide derivatives as antiallergic agents. 2. Synthesis and structure activity relationships of N-[4-[4-(diphenylmethyl)-1-piperazinyl]butyl]-3-(3-pyridyl)acrylamides

A new series of 3-(3-pyridyl)acrylamides 16, 17, 19, and 26, and 5-(3-pyridyl)-2,4-pentadienamides 20-25 were prepared and evaluated for their antiallergic activity. Several of these compounds exhibited more potent inhibitory activities than the parent compound 1a [(E)-N-[4-[4-(diphenylmethyl)-1-piperazinyl]butyl]-3- (3-pyridyl)acrylamide] against the rat passive cutaneous anaphylaxis (PCA) reaction and the enzyme 5-lipoxygenase. Particularly, (E)-N-[4-[4-(diphenylmethyl)-1-piperazinyl]butyl]-3- (6-methyl-3-pyridyl)acrylamide (17p) showed an ED50 value of 3.3 mg/kg po in the rat PCA test, which was one-fifth of ketotifen and oxatomide. As compared with ketotifen and oxatomide, compound 17p (AL-3264) possessed a better balance of antiallergic properties due to inhibition of chemical mediator release, inhibition of 5-lipoxygenase, and antagonism of histamine.

Studies on antiallergy agents. III. Synthesis of 2-anilino-1,6-dihydro-6-oxo-5-pyrimidinecarboxylic acids and related compounds.

A series of 2-anilino-1,6-dihydro-6-oxo-5-pyrimidinecarboxylic acids with various substituents was synthesized and evaluated in the rat passive cutaneous anaphylaxis test for antiallergic activity. High activity by intraperitoneal and oral administrations was observed for the 3-trifluoromethyl and 2-alkoxyanilino derivatives (64, 79, 81, 82 and 85). Structure-activity relationships are discussed.

Pro-drugs for the oral delivery of disodium cromoglycate.

Bifunctional pro-drugs of disodium cromoglycate (DSCG), incorporating both lipophilic and hydrophilic pro-moieties, were desined to improve the oral absorption of DSCG, an antiallergic agent used clinically. The synthesized pro-drugs were found to prossess the desired properties for an orally active pro-drug. Among the pro-drugs tested, KY-556 (carrying twin ethyl pro-moieties and an L-lysyl pro-moiety) was particularly well absorbed orally and, as expected, displayed good antiallergic activity in the rat passive cutaneous anaphylaxis test.

Studies on antiallergy agent. I. Synthesis of 1,4-dihydro-4-oxo-3-quinolinecarboxylic acids

A series of 1, 4-dihydro-4-oxo-3-quinolinecarboxylic acids with a variety of substituents was prepared and evaluated in the rat passive cutaneous anaphylaxis test for antiallergic activity. The introduction of alkoxy group into 8 position of quinoline nucleus provided significantly active compounds. However, the conversion to 3-quinolinecarboxylic acids with alkoxy group at 6 or 7 position and the replacement of alkoxy group with alkylthio, alkylsulfonyl and other groups resulted in substantial reduction or loss of activity. Among the analogues, 8-butoxy-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid (69) was found to possess remarkably potent activity by oral administration. Structure-activity relationships are discussed.

The pharmacological profile and initial clinical evaluation of tiacrilast (Ro 22-3747): a new antiallergic agent

Tiacrilast (Ro 22-3747) is an allergic mediator release inhibitor which has demonstrated potent oral activity in two IgE-mediated animal models of immediate hypersensitivity: the rat passive cutaneous anaphylaxis test (ID50 of 0.65 mg/kg) and a model in which anaphylactic bronchospasm is induced in passively sensitized rats (ID50 of 0.022 mg/kg). In addition to oral efficacy, in the latter model Ro 22-3747 was 23-fold more potent than cromoglycate by the aerosol (nebulization) route of administration. In vitro studies have confirmed that the mechanism of action of Ro 22-3747 in the in vivo models is through allergic mediator release inhibition since Ro 22-3747 was a potent inhibitor of antigen-induced (IgE-mediated) histamine release from passively sensitized rat peritoneal cells in vitro (IC50 values of 0.25 and 1.5 microM for Ro 22-3747 and cromoglycate, respectively), and Ro 22-3747 did not display end organ antagonism to histamine, serotonin, or the leukotrienes. Clinical evaluations of Ro 22-3747 at a 350 mg oral dose have been conducted in patients with allergic asthma and allergic rhinitis. In a limited study in allergic asthmatics, Ro 22-3747 demonstrated significant inhibitory activity relative to placebo in reducing acute airway responses to inhaled pollen extracts in patients with ragweed sensitivity (measured by changes in log PD20 FEV1 and log PD35 SGaw). The activity seen, however, was less than that observed with cromoglycate (20 mg) administered by inhalation.(ABSTRACT TRUNCATED AT 250 WORDS)

IgE ANTIBODY AGAINST HEPATITIS B SURFACE ANTIGEN IN MICE

Hepatitis B surface antigen (HBs antigen) was examined for elicitation of IgE production by injection into mice. The Prausnitz-Küstner (PK)-type skin test in the rat was employed for detection of IgE antibody to HBs antigen, because no sufficient purified HBs antigen was available as the challenging antigen for the passive cutaneous anaphylaxis (PCA) test in rats. The positive PK test was considered to be due to IgE antibody, since the active principle was inactivated by heating the sera at 56 C for 30 min, did not bind to protein A and was eliminated by anti-mouse IgE antisera. These data indicate that the PK-type test in rats can be used for detection of mouse IgE antibody when the amount of a test sample is not sufficient for the PCA test in rats.

Synthesis of the metabolites and degradation products of 2-amino-7-isopropyl-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-3- carboxylic acid (Amoxanox).

The metabolites and degradation products of 2-amino-7-isopropyl-5-oxo-5H-[1] benzopyrano-[2, 3-b] pyridine-3-carboxylic acid (Amoxanox, AA-673, 1), a promising drug for the treatment of bronchial asthma, were synthesized to confirm the proposed structures and to determine their activity in the rat passive cutaneous anaphylaxis test.

ChemInform Abstract: SYNTHESIS AND ANTIALLERGY ACTIVITY OF 10‐OXO‐10H‐PYRIDO(1,2‐A)THIENO(3,2‐D)PYRIMIDINES AND 10‐OXO‐10H‐PYRIDO(1,2‐A)THIENO(3,4‐D)PYRIMIDINES

AbstractTetrazolylsubstituierte Carbonsäureamide (III) und Heterocyclen (VI) erhält man direkt aus der Carbonsäure (II) oder über die Derivate (IV) und (V).

Nitrogen bridgehead compounds. 33. New antiallergic 4H-pyrido[1,2-a]pyrimidin-4-ones. 2.

A series of 9-hydrazono-4H-pyrido[1,2-a]pyrimidin-4-ones was prepared. The compounds were evaluated in the rat passive cutaneous anaphylaxis test for antiallergic activity. Structure-activity relationship studies revealed that the presence of a monosubstituted hydrazone moiety in position 9 and an unsubstituted 2-position are necessary for the intravenous activity.

Allergic hypersensitivity to the herbicide 2,4-D in BALB/c mice.

Following several reports of human allergic hypersensitivity, the ability of 2,4-D (2,4-dichlorophenoxyacetic acid) to elicit 2,4-D-specific IgE antibodies and delayed-type hypersensitivity in BALB/c mice was studied. 2,4-D-specific IgE antibodies were detected in mouse sera following the second intraperitoneal immunization with 1, 10, or 100 micrograms 2,4-D-keyhold limpet hemocyanin conjugate with aluminum hydroxide adjuvant. Specific IgE was determined with the rat passive cutaneous anaphylaxis test using a conjugate of 2,4-D with bovine serum albumin for challenge. The highest antibody titers and a measurable response in all mice were seen in the group that received 1 microgram of 2,4-D conjugate. Dinitrophenyl-specific IgE was measured at all intervals examined in mice immunized with a dinitrophenyl-keyhole limpet hemocyanin conjugate. 2,4-D applied epicutaneously on 2 d or over 4 wk failed to elicit delayed-type hypersensitivity as measured by change in ear thickness, incorporation of 5-[125I]iodo-2'-deoxyuridine, or histology following challenge on the ear. No 2,4-D-specific IgE antibodies were detected in serum during the 4-wk sensitization period. Similar treatment with a known sensitizer, dinitrofluorobenzene, produced delayed hypersensitivity. Following 4 wk of dosing, low titers of dinitrophenyl-specific IgE antibodies were elicited.

Synthesis and antiallergy activity of 4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidines.

A series of 4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidines with substitutions in the 2, 3, and 7 positions was prepared. The compounds were evaluated in the rat passive cutaneous anaphylaxis test for antiallergy activity. Several compounds had potent oral activity and were found to be superior to disodium cromoglycate and doxantrazole. Structure-activity relationships are discussed.

ChemInform Abstract: DEVELOPMENT OF ETHYL 3,4‐DIHYDRO‐4‐OXOPYRIMIDO(4,5‐B)QUINOLINE‐2‐CARBOXYLATE, A NEW PROTOTYPE WITH ORAL ANTIALLERGY ACTIVITY

AbstractDie aus der Carbonsäure (I) oder dem Aldehyd (IV) zugänglichen Carbonsäureamide (III) bzw. (VI) werden zu den Carbonsäureestern (VIII) cyclisiert, deren Verseifung die Carbonsäuren (IX) liefert.

Development of ethyl 3,4-dihydro-4-oxopyrimido[4,5-b]quinoline-2-carboxylate, a new prototype with oral antiallergy activity.

Structural modification of 3,4-dihydro-4-oxoquinazoline-2-carboxylic acid leading to ethyl 3,4-dihydro-4-oxopyrimido[4,5-b]quinoline-2-carboxylate, a new prototype with oral antiallergy activity of the disodium cromoglycate type, is described. This prototype is 10 times more potent than disodium cromoglycate in the rat passive cutaneous anaphylaxis test. Structure-activity studies indicate that a carboxylic acid moiety directly attached to the 2 position of the pyrimidine ring is most favorable for intravenous activity while esters of this acid are preferred for oral activity. The oral activity of ethyl 3,4-dihydro-4-oxopyrimido[4,5-b]quinoline-2-carboxylate (ED50 = 3 mg/kg) places this ester among the more potent orally active antiallergy agents reported to date.

ChemInform Abstract: SYNTHESIS AND ANTIALLERGIC ACTIVITY OF 2‐HYDROXY‐3‐NITRO‐1,4‐NAPHTHOQUINONES

AbstractAus den Naphthochinonen (I) erhält man nach Addition von Anilin über (II) mit Schwefelsäure die Hydroxy‐Verbindungen (III), die auch bei der Autoxidation der Tetralone (IV) erhalten werden können.

Some properties of Ascaris suum allergen A.

The stability of <i>Ascaris suum </i>allergen A to chemical and enzymatic agents has been studied. The allergenic activity measured in the rat passive cutaneous anaphylaxis test was found to be stable to heat at 100 °C, hot acid and periodate at 4 °C but to be destroyed completely by hot alkali. The allergen showed various degrees of resistance to treatment by the proteolytic enzymes trypsin, papain, chymotrypsin, elastase, subtilisin and pronase but was hydrolysed readily by pepsin. The effect of alkali on the allergen has been further studied by thin-layer gel filtration, ultracentrifugation, electrophoresis and amino acid analysis. Although the amino acid composition and sedimentation coefficients remained the same as the native allergen after this treatment, the isoelectric point and electrophoretic mobility were changed.