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Biomedical subjects

M A Wasserman

Publications and source records attributed to M A Wasserman.

At least 19 recordsLinked to original sources
PubMed2006

Composted municipal waste effects on chemical properties of a Brazilian soil.

The spread of composted municipal waste (CMW) on land can be used for sustainable crop production. Nevertheless, heavy metals availability may be a problem. Therefore, the main objective of this study was to assess the impact of CMW disposal on heavy metal accumulation in soil and plants. The treatments consisted of an untreated plot (control) and four rates of CMW application. All plots were cultivated in succession of carrot, cauliflower, sweet corn, and radish. Cu and Pb significantly accumulated in the topsoil (0-5 cm) with a similar pattern in the depths of 5-10 cm and 10-20 cm. Cauliflower, for Fe and Cu, and radish, for Pb and Cu, had their tissue analysis significantly affected due to the increasing rates of application of CMW. Nevertheless, the levels of accumulation in both, soil and plant, are within permissible limits. The evidences provided by this experiment indicated that heavy metals are less likely to cause problems for the estimation of CMW loadings to Brazilian agricultural land.

Brazil↗
PubMed2002

Generic values for soil-to-plant transfer factors of radiocesium.

There is a need for soil-to-plant transfer factors of radionuclides that take into account all possible crops on all soil varieties to support dose assessment studies. Because only limited experimental data exist for worldwide soil systems, such values should necessarily have a generic character. This paper describes a generic system for 137Cs, mainly based on a reference soil-to-plant transfer factor which depends solely on soil properties such as nutrient status, exchangeable K-content, pH and moisture content. Crops are divided into crop groups, cereals serving as reference group. The transfer of other crop groups can be calculated by multiplying data for cereals by a conversion factor. Existing data present in the IUR (International Union of Radioecologists) databank and in large part the work of a FAO (Food and Agriculture Organisation)/IAEA(International Atomic Energy Agency)/IUR project on tropical systems provided the basis for the derivation of the conversion factors and reference values.

Cesium Radioisotopes↗
PubMed1996

Effects of Ro 47-0203 on endothelin-1 and sarafotoxin S6c-induced contractions of human bronchus and guinea-pig trachea.

Endothelin exerts a variety of biological effects in the lung which indicate that this peptide may have a role in the pathophysiology of a number of pulmonary diseases. In this study, the endothelin receptors on the human bronchus were compared with those on the guinea-pig trachea using the novel, non-peptide antagonist Ro 47-0203 (4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2,2' -bipyrimidin-4-yl]-benzenesulphonamide, non-selective for endothelin ETA over endothelin ETB receptor) and the peptide antagonist BQ123 (cyclo(-D-Val-Leu-D-Trp-D-Asp-Pro), endothelin ETA receptor selective). On the human bronchus and guinea-pig trachea, the concentration-effect curve for endothelin-1 was shifted to the right by Ro 47-0203 (100 microM) with concentration ratios of 28.2 +/- 6.8 and 39.5 +/- 13.9, respectively but lower concentrations of the antagonist had no effect. Although the concentration-effect curve for sarafotoxin S6c on the human bronchus was shifted to the right by Ro 47-0203 (30 and 100 microM, concentration ratio: 6.88 +/- 1.72 and 69.7 +/- 17.2, respectively), equivalent degrees of inhibition could be obtained on guinea-pig trachea with lower concentrations of antagonist (10 and 30 microM, concentration ratio: 6.90 +/- 1.58 and 75.8 +/- 14.1 respectively). The lack of effect of BQ123 (10 microM) and the high concentrations of Ro 47-0203 needed to show antagonism indicate that endothelin receptors on both tissues are probably the endothelin ETB subtype. Although the antagonism by Ro 47-0203 is not classically competitive, the greater effect of Ro 47-0203 against sarafotoxin S6c on the guinea-pig trachea may reflect a difference between the endothelin ETB receptors on these tissues.

Adult↗
PubMed1996

Suitability of enalapril as a probe of the dipeptide transporter system: in vitro and in vivo studies.

PURPOSE: Previous in situ and in vitro studies indicated that the intestinal absorption of enalapril is a saturable carrier-mediated process via the dipeptide transporter system (DTS); however, the oral absorption of enalapril has not been reported to be a saturable process in vivo. Our objectives were to: 1) evaluate the suitability of enalapril as a probe of the DTS, and 2) compare various experimental models as they pertain to studying the DTS. METHODS: The in vitro uptake of enalapril by rat intestinal rings and permeability across Caco-2 cells were studied as a function of concentration and in the presence of compounds that are known substrates of the DTS. The effect of enalapril on the uptake of [3H]-glycyl-L-proline (gly-L-pro) by Caco-2 cells was also examined. In vivo studies were conducted in rats (1 to 50 mg/kg) and dogs (0.06 to 6 mg/kg) to evaluate the oral absorption of enalapril over a wide dose range. RESULTS: In vitro intestinal uptake/permeability of enalapril was not saturable nor inhibited by beta-lactam antibiotics, gly-L-pro, or SQ-29852. Moreover, a 20,000-fold molar excess of enalapril did not inhibit the uptake of [3H]-gly-L-pro by Caco-2 cells. The in vivo studies in rats and dogs did not demonstrate saturable absorption. CONCLUSIONS: The present in vitro and in vivo results indicated that enalapril is primarily absorbed by a non-saturable, passive diffusion process and it is not a suitable model compound for studying the DTS.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1996

Inhibition of Sephadex-induced lung injury in the rat by Ro 45-2081, a tumor necrosis factor receptor fusion protein.

Tumor necrosis factor (TNF) is an inflammatory cytokine produced by many cell types which may contribute to the pathophysiology of a variety of lung diseases. In this study we have used Ro 45-2081 (a soluble receptor composed of the human p55 TNF receptor and human heavy-chain immunoglobulin G) to explore the role of TNF in the acute inflammatory response in the rat lung to intravenous injection of Sephadex beads. The effects of Ro 45-2081 have also been compared with those of dexamethasone. At 24 and 72 h after Sephadex, there was a significant increase in the total number of leukocytes in bronchoalveolar lavage fluid (BALF). At 24 h, the number of neutrophils comprised around 50% of the total leukocyte number, decreasing to around 10% of total by 72 h. The eosinophil count was maintained at around 10% of the total leukocyte number. Pretreatment with either Ro 45-2081 [1 and 3 mg kg-1, intraperitoneally (i.p.)] or dexamethasone (0.1 and 0.3 mg kg-1, i.p.) inhibited the neutrophilia at 24 h after Sephadex, although Ro 45-2081 had no significant effect on total cell number. At 72 h after Sephadex, Ro 45-2081 (1 and 3 mg kg-1, i.p., daily) significantly reduced the neutrophil influx into BALF but had no inhibitory effect on eosinophil number. In contrast, dexamethasone (0.1 and 0.3 mg kg-1, i.p., daily) virtually abolished the infiltration of neutrophils and eosinophils into BALF. The lack of effect of Ro 45-2081 on eosinophil infiltration into the rat lung and the inhibition caused by dexamethasone suggest that factors other than TNF are involved in this part of the inflammatory response induced by Sephadex. However, the inhibitory effects of Ro 45-2081 show that TNF may play an important role in the recruitment of neutrophils into the lungs of Sephadex-treated rats.

Animals↗
PubMed1996

Pharmacological evidence for tumor necrosis factor as a mediator of allergic inflammation in the airways.

Tumor necrosis factor (TNF) has been implicated in the pathophysiology of a number of inflammatory diseases of the lung. Using the TNF receptor fusion protein, Ro 45-2081, our study investigated the involvement of TNF in allergic inflammatory responses in the airways of sensitized guinea pigs and Brown-Norway rats. Sensitized guinea pigs exhibited an enhanced airway reactivity to substance P (1-10 micrograms/kg, i.v.) at 6 hr after antigen challenge which was inhibited (P < .05) by Ro 45-2081 (3 mg/kg, i.p.). Treatment with Ro 45-2081 (1-3 mg/kg, i.p.) dose-dependently inhibited (P < .05) the accumulation of neutrophils and total cells in bronchoalveolar lavage fluid in sensitized guinea pigs examined at 6 and 24 hr postchallenge. Ro 45-2081 (3 mg/kg, i.p.) also significantly (P < .05) reduced the number of eosinophils in bronchoalveolar lavage at both time points whereas a lower dose (1 mg/kg, i.p.) had no effect. Ro 45-2081 (1 or 3 mg/kg, i.p.) abolished antigen-induced microvascular leakage (quantified by tissue content of Evans blue dye) in the trachea and main bronchi in sensitized guinea pigs. In the Brown-Norway rat, Ro 45-2081 (1-3 mg/kg, i.p.) caused a dose-dependent inhibition of neutrophil and eosinophil infiltration into bronchoalveolar lavage fluid at 24 hr after antigen challenge. In both guinea pig and Brown-Norway rat models, treatment with dexamethasone (30 mg/kg, i.p., for guinea pig and 0.3 mg/kg, i.p., for Brown-Norway rat) produced virtually identical results to those obtained with Ro 45-2081. The ability of Ro 45-2081 to inhibit antigen-induced responses in sensitized animals suggests that TNF is a mediator of allergic inflammation in the lung.

Animals↗
PubMed1995

Design and development of a vasoactive intestinal peptide analog as a novel therapeutic for bronchial asthma.

Analogs of vasoactive intestinal peptide (VIP) were synthesized and screened as bronchodilators with the ultimate goal of enhancing the potency and extending the duration of action of the native peptide. Several design approaches were applied to the problem. First, the amino acid residues required for receptor binding and activation were identified. A model of the active pharmacophore was developed. With knowledge of the secondary structure (NMR) of the peptide, various analogs were synthesized to stabilize alpha-helical conformations. Having achieved a level of enhanced bronchodilator potency, our approach then concentrated on identification of the sites of proteolytic degradation and synthesis of metabolically-stable analogs. Two primary cleavage sites on the VIP molecule were identified as the amide bonds between Ser25-Ile26 and Thr7-Asp8. This information was used to synthesize cyclic peptides which incorporated disulfide and lactam ring structures. Analog work combined the best multiple-substitution sites with potent cyclic compounds which resulted in identification of a cyclic lead peptide. This compound, Ro 25-1553, exhibited exceptionally high potency, metabolic stability, and a long duration of action and may be an effective therapeutic for the treatment of bronchospastic diseases.

Amino Acid Sequence↗
PubMed1994

Ro 25-1553: a novel, long-acting vasoactive intestinal peptide agonist. Part I: In vitro and in vivo bronchodilator studies.

Ro 25-1553, a cyclic peptide analog of vasoactive intestinal peptide (VIP), was designed to overcome many of the deficiencies inherent in this natural neuropeptide. On isolated guinea pig tracheal smooth muscle, Ro 25-1553 produces concentration-dependent relaxation of contractile responses to a number of different spasmogens. Depending on the contractile stimulus, Ro 25-1553 is 24 to 89 times more potent than VIP as a relaxant of guinea pig trachea. The high potency of Ro 25-1553 extends to studies on isolated, histamine-contracted, human bronchial smooth muscle, where Ro 25-1553 exhibits a 390-fold enhancement over native VIP and is more potent than other bronchodilating drugs, such as the beta 2-adrenoceptor agonists isoproterenol and salbutamol. Ro 25-1553 was shown to displace the radioligand 125I-VIP from rat forebrain membranes with an IC50 value of 4.98 nM, thereby demonstrating that it acts at a VIP receptor. In addition, when tested in a battery of 40 other binding assays (e.g., muscarinic, histamine, LTs, Ca++, TxA2, endothelin, alpha and beta adrenergic, platelet-activating factor, neurokinins, etc.) at concentrations as high as 10 microM, Ro 25-1553 was found to be inactive; thus it appears to be specific for VIP receptors. The potent smooth muscle relaxant activity exhibited in vitro by Ro 25-1553 is also evident after in vivo intratracheal administration or aerosolization of the compound. Pulmonary responses evoked by histamine, leukotriene D4, platelet-activating factor and acetylcholine are inhibited dose-dependently by intratracheally instilled Ro 25-1553 with nearly identical potency (ED50 values ranging from 0.07 micrograms to 0.26 micrograms).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1994

Ro 25-1553: a novel, long-acting vasoactive intestinal peptide agonist. Part II: Effect on in vitro and in vivo models of pulmonary anaphylaxis.

Studies were conducted to compare the effect of native vasoactive intestinal peptide (VIP), Ro 25-1553 (a cyclic peptide analog of VIP) and salbutamol (a beta2-adrenoceptor agonist) on antigen-induced pathophysiological effects in the guinea pig. Ro 25-1553 and salbutamol (0.01-1.0 microM) prevented antigen-induced contractions of the guinea pig trachea in vitro with IC50 values of 0.07 and 0.05 microM, respectively. VIP (0.01-1.0 microM) had no effect on antigen-induced tracheal contractions. Aerosolized Ro 25-1553 and salbutamol were equipotent in preventing antigen-induced increases in guinea pig lung resistance (IC50 value = 0.0001%), whereas aerosolized VIP (0.1%) was ineffective. Ro 25-1553 (0.1-100 micrograms), instilled intratracheally 2 min before the antigen challenge of buffer-perfused lungs from sensitized guinea pigs, produced a dose-dependent inhibition of bronchoconstrictor, vasoconstrictor and edemagenic responses, whereas intratracheal VIP (100 micrograms) had no effect. Intratracheal salbutamol (0.1-100 micrograms) inhibited antigen-induced responses in a manner comparable to Ro 25-1553. Lung inflammation was assessed as leukocyte accumulation in bronchoalveolar lavage fluid after the antigen provocation. Aerosolized antigen-induced bronchoalveolar lavage eosinophilia (13-fold increase over saline controls) at 6 hr after challenge was prevented in a concentration-dependent manner by pretreatment with nebulized Ro 25-1553 and salbutamol, but not by pretreatment with native VIP. These results indicate that Ro 25-1553 suppresses various pathophysiological features associated with pulmonary anaphylaxis and asthma, including airway reactivity, edema formation and granulocyte accumulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Albuterol↗
PubMed1994

Differential antagonism of airway contractile responses to prostaglandin (PG)D2 and 9 alpha, 11 beta-PGF2 by atropine, SK&F 88046 and SQ 29,548 in the guinea pig.

PGD2, the predominant prostanoid released from activated human lung mast cells, is metabolized to 9 alpha, 11 beta-PGF2 by an 11-ketoreductase. Both prostanoids contract mammalian airway smooth muscle. In the present study, aerosol administration of PGD2 or 9 alpha, 11 beta-PGF2 (five puffs of 10-50 micrograms/ml) to anesthetized, spontaneously breathing guinea pigs produced significant increases in airway resistance and decreases in dynamic lung compliance. The changes in airway resistance and dynamic lung compliance induced by 50 micrograms/ml were reduced approximately 60% and 25%, respectively, by pretreatment with atropine (1 mg/kg, i.v., -10 min). Pretreatment with the TxA2 receptor antagonist SK&F 88046 (N,N'-bis[7-(3-chlorobenzene aminosulfonyl)-1,2,3,4- tetrahydroisoquinolyl]disulfonylimide) (5 mg/kg, i.v., -10 min), nearly abolished the changes in airway resistance and dynamic lung compliance that were elicited by both agonists. Pretreatment with a TxA2 synthase inhibitor, CGS 13080 (10 mg/kg, i.v., -10 min), had no effect on PGD2- or 9 alpha, 11 beta-PGF2-induced bronchoconstriction, suggesting that these prostanoids did not provoke the release of TxA2. In vitro, PGD2, 9 alpha, 11 beta-PGF2 and a TxA2 mimic, U-44069, produced concentration-dependent contractions of the guinea pig isolated trachea with pD2s of 6.4, 6.0 and 7.2, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1992

SK&F 104353, a selective leukotriene receptor antagonist, inhibits leukotriene D4- and antigen-induced bronchoconstriction in cynomolgus monkeys.

The ability of SK&F 104353 to prevent and reverse leukotriene (LT) D4- and antigen (Ag)-induced bronchoconstriction was examined in anesthetized, spontaneously breathing cynomolgus monkeys. Aerosol administration of LTD4 (10 micrograms/ml; 20 breaths) produced a sustained increase in pulmonary resistance and decrease in dynamic lung compliance. Aerosolized SK&F 104353 (150 breaths, 0.3 or 4.4 mg/ml) administered 15 min prior to LTD4 challenge antagonized these changes in a dose-dependent manner. When given intravenously 6 min after LTD4, SK&F 104353 (5 mg/kg) rapidly and completely reversed the ongoing bronchoconstriction. In mepyramine-pretreated (2 mg/kg i.v.) monkeys sensitive to aerosolized Ascaris suum Ag, intravenously administered SK&F 104353 (5 mg/kg) substantially reversed, but did not abolish, Ag-induced bronchoconstriction when administered 12 min after the Ag challenge. In contrast, SK&F 104353 (5 mg/kg i.v.) did not reverse Ag-induced bronchoconstriction in animals that had not been pretreated with mepyramine. Similar results were obtained when SK&F 104353 (20 mg/kg i.v.) was administered (as a pretreatment) 5 min prior to Ag under these conditions. Thus, SK&F 104353 reduced Ag-induced bronchoconstriction in mepyramine-pretreated monkeys, but had little effect in the absence of mepyramine. The data suggest that LTs, in addition to histamine, play a role in allergic bronchoconstriction in cynomolgus monkeys.

Administration, Inhalation↗
PubMed1989

Interactive effects of peptidoleukotrienes and histamine on microvascular permeability and their involvement in experimental cutaneous and conjunctival immediate hypersensitivity.

The involvement of peptidoleukotrienes (LTs) in mediating the increase in microvascular permeability associated with experimental cutaneous immediate hypersensitivity was studied by examining the effect of SK&F 104353, a potent and selective LT-antagonist, on the response evoked by graded, intradermal injections of antigen. SK&F 104353, employed at doses that profoundly blocked LTC4, LTD4 and LTE4 responses, significantly reduced the response produced by experimental cutaneous immediate hypersensitivity. The response to the lowest antigen dose (0.1 microgram) was, however, entirely insusceptible to SK&F 104353. The effect of SK&F 104353 was also examined in combination with a pyrilamine-cimetidine dosing regimen sufficient to remove the histaminergic component of cutaneous immediate hypersensitivity. The non-histaminergic component associated with higher antigen doses (10 and 100 micrograms) was significantly reduced but not abolished by SK&F 104353; the non-histaminergic component associated with low antigen doses (0.1 and 1 microgram) was not susceptible to SK&F 104353. Thus, the increase in cutaneous microvascular permeability evoked by immediate hypersensitivity appears to comprise three components: (1) A histaminergic response apparent for all antigen doses; (2) a LT-mediated component which is manifest in response to high antigen doses; (3) a third, unidentified component that is present for the entire antigen dose-range but contributes less to the overall response when high antigen doses are used. A distinct non-histaminergic, non-leukotriene mediated component was not a feature of conjunctival immediate hypersensitivity. SK&F 104353 administered in combinatio with pyrilamine-cimetidine virtually abolished the response with a small residual remaining only for the highest antigen dose. In further contrast to cutaneous immediate hypersensitivity, SK&F 104353 alone was comparatively ineffective in type 1 allergic conjunctivitis. This difference in susceptibility to SK&F 104353 appears to reflect the type of histamine-LTD4 interactive effect on microvascular permeability. Histamine and LTD4 were additive in terms of cutaneous microvascular permeability. In the conjunctiva, histamine and LTD4 appeared mutually exclusive in that the level of response produced by the combination tended not to exceed that of the single component which caused the greater effect.

Animals↗
PubMed1989

Inflammatory mediators of experimental colitis in rats.

Colonic inflammation was induced in rats by intracolonic administration of 0.25 ml of 50% ethanol containing 30 mg of trinitrobenzene sulfonic acid (TNB). Control rats were treated with 0.25 ml of 50% ethanol or with 30 mg of TNB in 0.25 ml of saline. After 24 h, mucosal ulceration and hemorrhage were observed in TNB/ethanol-, 50% ethanol-, and to a lesser extent, in TNB/saline-treated rats. After 1 wk, mucosal damage was completely resolved in the 50% ethanol and TNB/saline-treated rats but the lesions in the TNB/ethanol-treated rats persisted and progressed to a chronic active inflammatory process after 3 wk. Myeloperoxidase activity was significantly elevated in mucosal scrapings from all treatment groups at all time intervals when macroscopic and microscopic mucosal injury was evident. Interleukin-1 was found to be the most sensitive indicator of mucosal inflammation, and its mucosal values correlated with myeloperoxidase activity. Leukotriene B4 was increased in control rats at 1 wk and in TNB/ethanol-treated rats at all time intervals. The maximal increase in leukotriene B4 was observed at 1 wk. Thromboxane B2 generation was reduced while platelet activating factor generation was not increased in TNB/ethanol-treated rats. These results indicate that in this TNB/ethanol model of gut inflammation, myeloperoxidase activity and interleukin-1 are reliable and sensitive indicators of colonic inflammation, and that thromboxane B2 is not involved in the acute lesions, whereas leukotriene B4 appears in the chronic active inflammatory response.

Animals↗
PubMed1989

The bronchopulmonary pharmacology of SK&F 104353 in anesthetized guinea pigs: demonstration of potent and selective antagonism of responses to peptidoleukotrienes.

The bronchopulmonary pharmacology of SK&F 104353 [2(S)-hydroxy-3(R)-[2(2-carboxyethyl)thio]-3[2-(8- phenyloctyl)phenyl]-propanoic acid], a potent and selective leukotriene (LT) receptor antagonist in vitro, was assessed in anesthetized, spontaneously breathing guinea pigs. Aerosol administration of SK&F 104353 (5-2000 micrograms/ml x 100 breaths) reduced in a concentration-dependent manner the response to a standard LTD4 challenge (4.33 micrograms/ml x 5 breaths) given 30 min later. Inhalation of a 2000 micrograms/ml solution abolished LTD4-induced bronchoconstriction for at least 2 hr. The i.v. administration of SK&F 104353 10 min before challenge antagonized LTD4-induced bronchoconstriction with an ID50 of 0.55 mumol/kg (0.25 mg/kg). Substantial antagonism of LTD4-induced bronchospasm was observed for at least 60 min after i.v. administration of 5 mumol/kg of SK&F 104353. Infusion of SK&F 104353 at various rates revealed that a steady-state plasma concentration of 0.125 microM (0.06 micrograms/ml) reduced LTD4-induced bronchoconstriction by 60%. In addition to preventing the response to LTD4, i.v. administered SK&F 104353 (10 mumol/kg) rapidly and completely reversed ongoing LTD4-induced bronchoconstriction. SK&F 104353 also was effective when given intraduodenally 1 hr before LTD4 challenge, although the ID50 (32 mumol/kg) was 60-fold greater than the i.v. ID50. Given intragastrically, 100 mumol/kg of SK&F 104353 abolished the response to LTD4 for 1 hr, and reduced the response for 6 hr. SK&F 104353 (20 mumol/kg i.v.) had no effect on the bronchoconstriction induced by aerosolized acetylcholine, histamine or U-44069, but did antagonize the response to LTC4. SK&F 104353 alone did not produce bronchoconstriction when administered by any route or dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Aerosols↗
PubMed1988

Modulation of arachidonic acid metabolites as potential therapy of asthma.

Bronchial asthma is a multifactorial disease characterized by reversible bronchoconstriction, airway hyperreactivity, oedema and excessive mucus production. Present therapy directed against specific mediators has not been overwhelmingly successful. Even though there exists a multiplicity of purported mediators, perhaps the key to better therapy is a vigorous understanding of the arachidonic acid cascade and investigations to modulate specific products of these pathways. Within the cyclooxygenase pathway an interesting scenario might be to effectively antagonize the potent bronchoconstrictive effects of prostaglandin (PG)D2 and its recently identified predominant metabolite, an 11-hydroxyl epimer, 9 alpha,11 beta-PGF2. PGD2 is the major cyclooxygenase product released from sensitized human lung and bronchoalveolar lavage (BAL) mast cells; it possesses a myriad of biological actions relevant to the pathogenesis of asthma. While no specific antagonists of PGD2 or 9 alpha,11 beta-PGF2 have been identified, some preliminary studies have suggested that, perhaps, PGD2 may be interacting, at least in part, with thromboxane receptors. In addition, peroxidation of arachidonic acid catalyzed by 5-lipoxygenase produces the leukotrienes, which are extremely potent bronchoconstrictors as well as oedema and mucus secretagogues. Leukotrienes are primary mast cell mediators which may be the vital link to both early (acute) and late (chronic) asthmatic attacks. Research seeking leukotriene antagonists has been intensive. Leading clinical candidates have emerged from Smith Kline and French, Lilly, Merck-Frosst, ICI-Stuart and other groups. However, we must await the outcome of ongoing clinical trials in asthmatics to determine just how important the leukotrienes really are in the pathogenesis of asthma, allergy and inflammation. Thus, modulation of the effects of products of arachidonic acid metabolism may provide a new and more specific treatment for bronchial asthma.

Animals↗