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Ro 22-3747 was orally active in two animal models of immediate hypersensitivity diseases mediated by immunoglobulin E: the rat passive cutaneous anaphylaxis test (ID50 of 0.65 mg/kg) and a model in which anaphylactic bronchospasm was studied in passively sensitized rats (ID50 of 0.022 mg/kg). In the latter model system Ro 22-3747 was also found efficacious by the aerosol route (Ro 22-3747 was 23-fold more potent than disodium cromoglycate by this route of administration). Like disodium cromoglycate (cromoglycate), Ro 22-3747 appears to act in these in vivo models by inhibition of allergic mediator release because it was a potent inhibitor of antigen-induced 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 did not exhibit end organ antagonism to histamine, serotonin or slow reacting substance of anaphylaxis. The mechanism by which Ro 22-3747 inhibits mediator release does not appear to involve inhibition of delta 5-lipoxygenase, phospholipase A2 or thromboxane synthase. Cromoglycate and Ro 22-3747 appear to have some similarities with regard to their mechanism of action, as they both exhibit a time-dependent loss of inhibitory activity when preincubated with peritoneal cells in vitro before antigen challenge. In addition, pretreatment with one prevented the subsequent inhibition of histamine release by the other. Unlike cromoglycate, however, Ro 22-3747 (10(-5) to 10(-3) M) also inhibited the release of histamine (3-59%), slow reacting substance of anaphylaxis (12-49%) and thromboxane (0-55%) from antigen-challenged (immunoglobulin G1-mediated) guinea-pig lung fragments.(ABSTRACT TRUNCATED AT 250 WORDS)

Pulmonary surfactant is thought to be internalized and processed for reuse by alveolar Type II cells. In the present study we followed the internalization and intracellular trafficking of purified surfactant protein A (SP-A) by primary cultures of alveolar Type II cells. Internalization of native rat SP-A was compared with that of recombinant rat and human SP-A isolated from a patient with alveolar proteinosis. All SP-A species were conjugated with colloidal gold for visualization by electron microscopy. The gold conjugates were biologically active, as demonstrated by inhibition of phospholipid secretion from alveolar Type II cells. The SP-A-gold conjugates were internalized to lamellar bodies (LB) via the endosomal system, which included both electron-lucent and -dense multivesicular bodies. Labeling of LB was time dependent, and after 7 hr 30-40% of these organelles were labeled. Alkylation of SP-A greatly reduced internalization, as did an excess of non-conjugated SP-A. No qualitative differences in uptake were observed with the three forms of SP-A. The percent of labeled LB was similar (30-40%) after 7 hr of internalization with the three species of SP-A. The recombinant SP-A produced using a baculovirus vector lacked hydroxyproline and had an altered oligosaccharide, but these features did not affect its internalization or the rate of LB labeling. Internalization of the gold-conjugated SP-A and endocytosis of the fluid-phase marker Lucifer Yellow were related to the shape of Type II cells. Both uptake of SP-A, which is receptor mediated, and fluid-phase endocytosis were found to be less active in the flattened than in the rounded cells. Therefore, cell shape and hence cytoskeletal organization may play an important role in SP-A recycling. However, it is possible that both morphology and decreased endocytosis are independent manifestations related to the loss of differentiated function of cultured Type II cells.

A quick and simple method for the radioimmunoassay of plasma cortisol is described. The mean morning plasma cortisol concentration in 43 normal subjects was 9.8 ± 3.1 (S.D.) μg/100 ml with a range of 5.0–19.5 μg/100 ml. Mean midnight concentration in 24 normal subjects was 4.3 ± 2.3 (S.D.) μg/100 ml with a range of 1.4–9.6 μg/100 ml. When compared with the fluorimetric method the mean results by radioimmunoassay of 154 routine specimens were 23% lower. In samples from unstimulated patients, regression analysis of results obtained by the two methods gave a correlation coefficient (r) of 0.93, regression line slope of 1.1, and intercept of 1.4 μg. Mean radioimmunoassay results were 15% lower. When plasma cortisol concentration was above the normal range (>30 μg/100 ml) the regression line slope was 0.87, the intercept 17.9 μg, r = 0.87 and mean radioimmunoassay results were 37% lower. Plasma cortisol concentration in patients after insulin or Synacthen stimulation exhibited similar responses when measured by either method. Plasma cortisol concentration in normal subjects given metyrapone was lower when measured by radioimmunoassay (mean ± S.D. = 8.7 ± 2.7 μg/100 ml) than when measured by fluorimetry (18.5 ± 10.8 μg/100 ml). The diagnostic usefulness of the two methods, ease of assay, and costs are compared.

Antechinus spp. respond to a snow-covered environment by increasing their metabolic rate and by occupying an insulated nest while not active. However, the two species occurring in the Snowy Mountains have different behavioural adaptations: Antechinus swainsonii is diurnal (allowing the benefits of basking in the sun), whereas A. stuartii is nocturnal and makes frequent visits to a communal nest. Antechinus stuartii is able to survive the winter with a lower ratio of field metabolic rate to basal metabolic rate, indicating that it is energetically less stressed and better adapted to existence in the cold per se than is A. swainsonii. However, A. swainsonii appears to forgo the energetic benefits of communal nesting in favour of the lesser competition for food afforded by solitary nesting.

Ro 24-5913, (E)-4-[3-[2-(4-cyclobutyl-2- thiazolyl)ethenyl]phenylamino]-2,2-diethyl-4-oxobutanoic acid, has been identified as a chemically unique, potent and selective LTD4 antagonist. In vitro, Ro 24-5913 competes with [3H]LTD4 for its binding site on guinea pig lung membranes with an IC50 of 6.4 +/- 2.2 nM. In isolated guinea pig tracheal smooth muscle, Ro 24-5913 produces concentration-dependent rightward shifts of LTD4-induced contraction curves (pA2 value of 9.6 +/- 0.2). The slope of the Schild plot is not significantly different from 1, indicating that the antagonism is of a competitive nature. In the human bronchus, Ro 24-5913 is an effective antagonist of LTD4-induced contractions (pKB of 9.3 +/- 0.1). In vivo, Ro 24-5913 dose-dependently inhibits LTD4-induced bronchoconstriction in guinea pigs by the i.v. (ID50 0.13 mg/kg), oral (ID50 0.12 mg/kg) and aerosol (IC50 0.008%) routes of administration. This in vivo activity is specific as evidenced by the inability of Ro 24-5913 to inhibit bronchoconstriction induced by LTB4, PAF or histamine. In comparison with other LTD4 antagonists evaluated in this guinea pig model, Ro 24-5913 is markedly superior in terms of oral potency, bioavailability and oral duration of action. Ro 24-5913 also blocks allergic bronchospasm mediated by endogenously generated leukotrienes in guinea pigs; the potency and duration of action is nearly equivalent to that seen as an antagonist of bronchoconstrictions produced by exogenous LTD4. In summary, Ro 24-5913 is representative of a novel chemical class of LTD4 receptor antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Ro 24-4736, (5-(3-[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl]-2-propynyl)phenanthri din- 6(5H)-one), has been identified as a potent, selective, p.o.-active platelet-activating factor (PAF) antagonist with a long duration of action. In vitro, Ro 24-4736 competes with [3H]PAF for its receptor site on dog platelets with an IC50 of 9.8 +/- 1.0 nM and selectively inhibits PAF-induced aggregation of guinea pig, dog and human platelets with concentration dependence. Ro 24-4736 dose-dependently inhibits in vivo bronchoconstriction (ID50 of 0.006-mg/kg p.o.) and ex vivo platelet aggregation (ID50 of 0.004 mg/kg p.o.) induced by PAF in guinea pigs. Time course studies show complete blockade of PAF-induced platelet aggregation (ex vivo) up to 8 hr after a single p.o. dose of 0.03 mg/kg as well as a long duration of action in vivo (30 hr). The in vivo PAF antagonistic activity is specific because, even at high p.o. doses (up to 10 mg/kg), Ro 24-4736 shows no inhibitory activity toward the bronchoconstrictor effects of leukotriene D4 or histamine. In comparison with other PAF antagonists evaluated in this guinea pig model, Ro 24-4736 is markedly superior in terms of p.o. potency, bioavailability and p.o. duration of action. Studies were also performed with Ro 24-4736 in additional in vivo models. When administered p.o. to sensitized guinea pigs, the drug attenuates inhaled antigen-induced airway hyper-reactivity without effect on bronchoalveolar lavage leukocyte accumulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Reaction of the dihydroxyacetophenone (I) with the bromoalkanoic acid esters (II) and subsequently with the dibromo compounds (III) yields the bromides (IV), which are coupled with (I) to give the esters (Va).

The esterification of the acid (I) with chloroacetonitrile (II) and subsequent reaction with the primary amines (III) yield the carboxamides (IVa) and (IVb).

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