The 5-lipoxygenase inhibitors ZD2138 and ZM230487 are potent and selective inhibitors of several antigen-induced guinea-pig pulmonary responses.

The non-redox 5-lipoxygenase inhibitor Zeneca ZD2138 (6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxy- methyl]-1-methyl-2-quinolone) was evaluated for its ability to inhibit antigen-induced leukotriene release from guinea-pig lung in vitro and antigen-induced increases in pulmonary resistance in guinea pigs in vivo. ZD2138 inhibited antigen-induced release of leukotriene D4 and leukotriene B4 with IC50 values of 0.3 +/- 0.06 microM and 0.4 +/- 0.09 microM, respectively. At about ten times higher concentrations, ZD2138 had no effect on antigen-induced release of thromboxane B2, indicating selectivity for inhibition of 5-lipoxygenase vs. phospholipase A2, cyclooxygenase, or thromboxane synthetase. Similarly, ZD2138 did not inhibit histamine release, indicating that the compound did not have a generalized effect on the mediator release processes. Zeneca ZM230487-(6-[(3-fluoro-5-[4-methoxy- 3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxymethyl]-1-ethyl-2-quinolone), the N-ethyl analog of ZD2138, was approximately equipotent toward inhibition of antigen-induced leukotriene D4 release, with an IC50 of 0.2 +/- 0.08 microM. The so-called 5-lipoxygenase activating protein (FLAP) inhibitor, MK-886 (3-[1-(p-chlorobenzyl)-5-(isopropyl)-3-tert-butylthioindol-2-yl]-2 ,2- dimethylpropanoic acid), and the iron ligand 5-lipoxygenase inhibitor zileuton (N-(1-benzo[b]thien-2-ylethyl)-N-hydroxy-urea) were also active, but less potent than ZD2138 with IC50 values for inhibition of antigen-induced leukotriene release in vitro of 9.3 +/- 3.2 microM and 14.8 +/- 1.8 microM, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Tachykinin-induced dyspnea in conscious guinea pigs.

Aerosol administration of neurokinin A (NKA) or substance P (SP) to conscious guinea pigs produced labored abdominal breathing (dyspnea). Time to onset of dyspnea was inversely related to tachykinin concentration. Aerosol administration of the neutral endopeptidase inhibitor thiorphan significantly potentiated tachykinin-induced dyspnea without affecting responses to leukotriene D4 (LTD4), carbachol, histamine, platelet activating factor or serotonin (5-HT), indicating selectivity for tachykinins rather than a nonspecific effect on agonist reactivity. The rank order of potency for producing dyspnea was LTD4 greater than or equal to NKA (with thiorphan) much greater than SP (with thiorphan) greater than 5-HT = carbachol greater than histamine greater than platelet-activating factor. Pretreatment with propranolol, phentolamine, methysergide, pyrilamine or the peptide leukotriene antagonist, ICI 198,165, did not alter dyspnea induced by NKA or SP. The dose-response curves for NKA and SP were shifted to small degrees (less than 3-fold) to the right by atropine and to the left by indomethacin. Also, pretreatment with capsaicin did not affect responses to NKA or SP, indicating that they do not cause dyspnea by activating capsaicin sensitive C-fibers. These results suggest primarily direct effects of NKA and SP. This model may be useful for in vivo evaluation of tachykinin antagonists.

Inhibition by REV-5901 of leukotriene release from guinea-pig and human lung tissue in vitro.

The 5-lipoxygenase inhibitor REV-5901 [alpha-pentyl-3-(2-quinolinylmethoxy)benzene-methanol] was evaluated for effects on mediator release in vitro from fragmented guinea-pig and human lung. In guinea-pig lung, REV-5901 inhibited the antigen-induced release of immunoreactive leukotriene D4 (iLTD4) with an IC50 of 9.6 +/- 2.9 microM and immunoreactive leukotriene B4 (iLTB4) with an IC50 of 13.5 +/- 2.2 microM. REV-5901 also inhibited the calcium ionophore-induced release of immunoreactive leukotrienes from human lung in vitro with IC50 values of 11.7 +/- 2.2 MicroM versus peptide leukotrienes and 10.0 +/- 1.1 microM versus iLTB4. The inhibition of release of iLTD4 and iLTB4 with similar IC50 values suggests that REV-5901 acts by inhibiting 5-lipoxygenase in this system. At concentrations as high as 50 microM, REV-5901 did not inhibit the release of thromboxane B2 (TxB2), 6-keto-prostaglandin-F1 alpha (6-keto-PGF1 alpha), or histamine from either lung. The lack of effect on TxB2 and 6-keto-PGF1 alpha indicates that REV-5901 did not inhibit phospholipase A2, cyclooxygenase, or thromboxane synthetase. Inhibition of leukotriene release by REV-5901 could not be reversed by washing. Among various 5-lipoxygenase inhibitors, the order of potency for inhibition of iLTD4 release from guinea-pig lung was AA-861 greater than REV-5901 greater than phenidone greater than nafazatrom greater than NDGA greater than BW755C. These findings suggest that REV-5901 is a selective and relatively potent inhibitor of leukotriene release from lung tissue in vitro.

Treatment of abdominal nerve entrapment syndrome using a nerve stimulator.

Seventy-six patients treated at York Pain Relief Clinic for Abdominal Nerve Entrapment Syndrome (ANES) between 1982 and 1986, using aqueous phenol and nerve stimulator control are reviewed. A questionnaire was sent to all the patients who had been discharged from the clinic to try to confirm that the initial improvements had been maintained and 60 patients replied. Group A (n = 44) had been diagnosed with confidence; 95% had gained complete or partial relief of symptoms. Group B (n = 32) had other symptoms making the diagnosis less certain; 50% gained some relief. Clinical presentation of ANES and the method of treatment are described.

Interleukin-1 induces chondrocyte protease production: the development of collagenase inhibitors.

Supernatants from the P388D1 macrophage cell line as well as human interleukin-1 (IL-1) stimulated primary rabbit articular chondrocytes to produce collagen- (C-ase) and proteoglycan- (PG-ase) degrading proteases. The P388D1 derived factor had a molecular weight of 16,000-20,000 and a pI of 4.5-5.0. Both protease activities were metal dependent and inhibited by EDTA, phenanthroline, and alpha 2-macroglobulin but not by PMSF, TLCK, pepstatin, or alpha 1-antitrypsin. Size exclusion chromatography indicated the molecular weights for latent PG-ase and C-ase were 44,000-56,000 and 34,000-44,000, respectively. Chemical synthesis efforts produced two classes of C-ase inhibitors--thiols and hydroxamic acids. The former had IC50 values of 10(-5)-10(-6) M while the latter approached 10(-7) M.

Alexia without agraphia and associated disorders: importance of recognition in the rehabilitation setting.

Alexia without agraphia is readily recognized in its pure (without other neurologic findings) but rare form. However, this deficit is more common when associated with other behavioral disturbances that result from trauma or cerebral infarction to the posterior cerebral hemispheres. Two cases presented with alexia without agraphia following infarction within the posterior cerebral artery territory. Because of initial confusion and disorientation the patients were diagnosed as demented and unsuitable for rehabilitation. Both subjects had a visual field deficit and color agnosia. Prosopagnosia, simultanagnosia, and ataxia of visual-motor control were also present. The second case was unusual because of pure word blindness associated with a right occipital lobe lesion. Only a few such cases have been reported in the literature worldwide. This paper demonstrates that careful delineation of cognitive deficits permits greater understanding of functional disorders with improved rehabilitation outcome.

Interleukin-1 stimulates the secretion of proteoglycan- and collagen-degrading proteases by rabbit articular chondrocytes.

Supernatants from the P388D1 murine macrophage cell line as well as commercially prepared human interleukin-1 (IL-1) stimulated primary rabbit articular chondrocytes to produce collagen- and proteoglycan-degrading proteases. The P388D1-derived factor had a molecular weight of 16,000-20,000 and a pI of 4.5-5.0, and was sensitive to phenylglyoxal treatment. Human IL-1 and the P388D1 supernatants enhanced glycosaminoglycan (GAG) release from bovine nasal cartilage explants. The proteoglycan- and collagen-degrading proteases required Ca2+ for activity. Latent proteoglycanase and collagenase had molecular weights of 44,000-56,500 and 34,000-44,000, respectively. The activated proteases had molecular weights of 30,000-40,000 and 22,000-36,000, respectively. Heparin-Sepharose affinity chromatography yielded two latent proteoglycanase-degrading protease activities and a collagen-degrading peak. The two proteoglycanase peaks also degraded fibronectin, laminin, gelatin, and azocoll but not type I collagen. The collagenase peak also degraded proteoglycan, gelatin, fibronectin, laminin, and azocoll. The activity of the proteoglycan- and collagen-degrading peaks was inhibited by phenanthroline and alpha 2-macroglobulin but not by phenylmethylsulfonylfluoride (PMSF), tosyllysylchloromethylketone (TLCK), pepstatin, or alpha 1-antitrypsin. The control of factors which augment protease production may offer a novel therapeutic approach to arthritis.

Exposure of hippocampal slices to quisqualate sensitizes synaptic responses to phosphonate-containing analogues of glutamate.

Exposure of transverse slices of rat hippocampus to quisqualate (Quis) resulted in a marked increase in the potency of D- and L-2-amino-4-phosphonobutanoate (APB) and D- and L-2-amino-5-phosphonopentanoate (APV) for depression of extracellular synaptic field potentials recorded from CA1 pyramidal cells. L-APB depressed the amplitude of CA1 field potentials with an IC50 = 1800 microM before exposure to Quis. After a brief (4 min) exposure to sufficient Quis (16 microM) to depress the response by 50%, L-APB depressed these responses with an IC50 = 54 microM. These phosphonate-containing glutamate analogues transiently induced population-spiking after the tissue was pretreated with Quis. This suggests that APB and APV can act as agonists at micromolar concentrations.

Effect of antirheumatic agents on the mitogen response of arthritic rat spleen cells.

Splenic lymphoid cells from rats with adjuvant induced polyarthritis show a diminished response to the T-cell mitogens Con A and PHA. This report describes the in vitro effects of various antirheumatic agents on the mitogen induced proliferative response of normal (NSC) and arthritic (ASC) rat spleen cells. Indomethacin enhanced only the arthritic responses. Other PG synthesis inhibitors such as ibuprofen and naproxen enhanced the arthritic as well as the normal spleen cell proliferative responses. Gold sodium thiomalate augmented arthritic but not normal blastogenesis. Penicillamine significantly enhanced only the Con A response of arthritic cells at 10(7)M. Levamisole produced a significant increase in the PHA response of arthritic cells and the Con A NSC response. Chloroquine diphosphate enhanced the Con A response of normal cells at 10(-5)M and 10(-6)M; both chloroquine and tilorone suppressed blastogenesis of arthritic spleen cells at 10(-4)M and 10(-5)M. When classifying antirheumatic agents as stimulator or suppressors of immune function, one must account for their effects on arthritic as well as normal lymphoid cells at the predicted pharmacologic plasma levels.