NEUTRAL ENDOPEPTIDASE 3.4.24.11 INHIBITION POTENTIATES THE INHIBITORY EFFECTS OF TYPE-C NATRIURETIC PEPTIDE ON LEUKOTRIENE D4-INDUCED AIRWAY CHANGES

1. Microvascular leakage, a primary feature of inflammation, is well known for worsening the asthmatic condition. Gene expression of and a specific receptor for type-C natriuretic peptide (CNP), initially considered a neuropeptide, have been detected in the human vascular wall and secretion of CNP from vascular endothelial cells has recently been demonstrated. These facts suggest the presence of a vascular natriuretic peptide system and led us to expect that CNP may act beneficially on airway microvascular leakage in asthma. In the present study, we investigated the effects of CNP against leukotriene (LT) D4 -induced airway microvascular leakage and bronchocon-striction and how these effects were potentiated by thiorphan, a potent neutral endopeptidase 3.4.24.11 (NEP) inhibitor. 2. Anaesthetized male guinea-pigs, ventilated via a tracheal cannula, were placed into a plethysmograph for 10 min, in order to measure pulmonary mechanics and mean blood pressure, after challenge with 2 μg/kg LTD₄ and then the extravasation of 20 mg/kg Evans blue dye into airway tissue was investigated to indicate and evaluate microvascular leakage. 3. Intravenous administration of CNP (100, 300 and 1000 μg/kg) significantly inhibited the LTD₄-induced microvascular leakage and bronchoconstriction in a dose-dependent manner. These inhibitory effects were enhanced by pretreatment with 20 mg/kg thiorphan, suggesting the important role of NEP in the pulmonary metabolism of CNP. 4. We believe that these results are encouraging for the further investigation of the therapeutic applications of exogenous CNP in asthma.     

桑白皮醇提取物对白三烯拮抗活性的研究(2)

目的对本实验室自行制备的桑白皮醇提取物 (MA)进行了抗白三烯作用的研究。方法通过整体实验 ,研究样品对白三烯D4(LTD4)引起的微血管渗漏 ,LTD4、组胺引起支气管收缩的影响。结果该提取物对LTD4引起豚鼠呼吸道微血管渗漏有明显抑制作用 ,且与选择性白三烯受体拮抗剂普仑司特 (Pranlukast)对呼吸道的作用相类似。同时对白三烯及组胺引起支气管痉挛也具有一定的改善作用 ,显示出与普仑司特不同的作用特点。结论桑白皮醇提取物具有白三烯拮抗活性 ,提示其抗哮喘作用可能与此有关。     

The single and multiple dose pharmacokinetics of pranlukast in healthy volunteers

Objective: The pharmacokinetics of pranlukast, a leukotriene LTD₄ antagonist, were studied in 48 young, healthy subjects after single and repeated oral doses (given every 12 h) ranging from 112.5 to 675 mg. The doses were administered 30 minutes after a light breakfast. Results: Maximal drug concentrations generally occurred between 2 and 6 h after dosing, and there was some evidence of an absorption lag-time. Secondary peaks were observed in the plasma concentration vs. time profiles of many of the study subjects after both single and repeated doses, particularly during the period of maximum drug absorption. In general, after both single and repeated doses, there were related increases in the corresponding C_max and AUC with a rise in dose, although the increase was diminished at doses above 450 mg. With repeated dosing of pranlukast the mean AUC was generally higher (up to 1.6-fold), and the higher plasma concentrations allowed characterisation of a longer mean t_1/2 than after single dose administration. The mean steady-state trough plasma concentrations attained after evening doses were considerably higher (up to 14-fold) than those obtained after the morning dose. Conclusion: The data suggested that the pharmacokinetics of pranlukast are influenced by the time of dosing. Based on analysis of urinary 6β-hydroxycortisol excretion, there was no evidence that pranlukast modified the metabolic activity of cytochrome P-450 3A isoenzymes. Received: 6 November 1995/Accepted in revised form: 17 April 1996     

A New Powder Design Method to Improve Inhalation Efficiency of Pranlukast Hydrate Dry Powder Aerosols by Surface Modification with Hydroxypropylmethylcellulose Phthalate Nanospheres

Purpose. A new particle design method to improve the aerosolization properties of a dry powder inhalation system was developed using surface modification of hydrophobic drug powders (pranlukast hydrate) with ultrafine hydrophilic particles, hydroxypropylmethylcellulose phthalate (HPMCP) nanospheres. The mechanism of the improved inhalation properties of the surface-modified particles and their deposits on carrier particles (lactose) was clarified in vitro. Methods. Drug particles were introduced to aqueous colloidal HPMCP dispersions prepared by emulsion-solvent diffusion techniques followed by freeze- or spray-drying of the resultant aqueous dispersions. The surface-modified powders obtained with HPMCP nanospheres and their mixture with lactose powders were aerosolized by Spinhaler and their mode of deposition in lung was evaluated in vitro using a twin impinger. To elucidate the inhalation mechanism of these surface modified particles, we measured their modified micromeritic properties, such as surface topography, specific surface area, dissolution rate, and dispersibility in air. Results. Dramatically improved inhalation properties of the surface modified powder, i.e. a two-fold increase in emission and a three-fold increase in delivery to deep lung, were found in vitro compared with the original unmodified powder. Improved inhalation was also found with the surf ace-modified drug deposited on lactose particles. Those improvements were attributed to the increased surface roughness and hydrophilicity of the surface-modified particles, and the resultant increased dispersibility in air. Conclusions. Surface modification of hydrophobic drug particles with HPMCP nanospheres to improve hydrophilicity was extremely useful in increasing the inhalation efficiency of the drug itself and the drug deposited on carrier; this was attributed to increased dispersibility in air and emission from the device, for spray- and freeze-dried particles, respectively.     

Cocaine pharmacodynamics after intravenous and oral administration in rats: relation to pharmacokinetics

  Rationale: To design optimal dose regimes for oral cocaine, it is essential to characterize pharmacokinetics (PK) of cocaine after IV and PO administration. Objectives: To investigate the absolute bioavailability of oral cocaine, its effectiveness and the relation between PK and PD in a within-subject design. Methods: We used the effects of IV and PO cocaine on a contingency-controlled timing behavior, the differential reinforcement of low rate schedule (DRL 45-s) in 3-h sessions, as the PD measures [i.e., the shorter-response rate (srr) and the reinforcement rate (rr)]. Cocaine PK parameters were determined by simultaneous modeling of the concentration-time profiles (CTPs) after IV 2 mg/kg and PO 20 mg/kg cocaine administration. The absolute oral cocaine bioavailability was determined pharmacokinetically (F) and pharmacodynamically (F_srr and F_rr). Results: IV and PO cocaine increased the shorter response rate and decreased the reinforcement rate in a dose- and time-related fashion, which mirrored the respective prototypical serum cocaine CTPs. After the absorption phase, the serum cocaine CTP of PO cocaine paralleled that of IV cocaine. The duration of action for PO cocaine was longer than that for IV cocaine owing to its larger mean residence time. The active metabolite, norcocaine, was not detected after IV but after PO cocaine administration. The value of F was 4.66% which was significantly lower than the values of F_srr (13.67%) and F_rr (32.63%). Furthermore, the concentration-effect relations for the reinforcement rate revealed that PO cocaine was more potent than IV cocaine. Conclusions: Oral cocaine is more effective behaviorally than from predictions made in terms of its PK. The differences in active metabolite profiles as well as the rate and extent of acute tolerance for IV versus PO cocaine may account for the greater potency observed for oral cocaine. Received: 23 July 1998 / Final version: 2 February 1999     

Patent Evaluation: Carboxylic Acid Leukotriene Antagonists

Summary

Novelty: Novel phenoxyalkylcarboxylic acid derivatives, said to have strong and selective leukotriene (LT) antagonistic action, are disclosed. These compounds may be useful for the prevention and treatment of allergic diseases such as asthma. Processes for preparing these carboxylic acid derivatives are described.

Biology: The effects of the exemplified compound on leukotriene D₄-induced bronchoconstriction in guinea pigs was evaluated. Bronchoconstriction was inhibited by 71% at a dose of 1 mg/kg iv. The compounds also showed strong antagonistic action to leukotriene D₄ in the isolated guinea pig trachea.

Chemistry: Synthesis of the compounds is described in seven examples, including 4[3[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propxy]-6-1(-hydroxyethyl)-2-propylphenoxy]butanoic acid.

Structure:      

Effect of TYB-2285 on lung anaphylaxis in actively sensitized rats

• 1.1. We examined the effect of TYB-2285 on the acute phase and the late phase of lung anaphylaxis in rats.
• 2.2. TYB-2285 (3-30 mg/kg PO) inhibited antigen-induced bronchoconstriction and TxB₂ production during the acute phase of lung anaphylaxis in a dose-dependent manner.
• 3.3. Ketotifen fumarate (30 mg/kg PO) inhibted bronchoconstriction and TxB₂ production less potently than TYB-2285.
• 4.4. TYB-2285 (30 mg/kg PO) inhibited the accumulation of neutrophils during the late phase of lung anaphylaxis significantly without a significant change in total cells.
• 5.5. Hydrocortisone acetate (100 mg/kg PO) inhibited the accumulation of total cells as potent as neutrophils.

     

Protective effect of pranlukast,a cysteinyl-leukotriene receptor 1 antagonist,on indomethacin-induced small intestinal damage in rats

We examined the effect of pranlukast, the receptor antagonist of the cysteinyl leukotrienes (CysLTs; LTC₄, LTD₄ and LTE₄), on indomethacin-induced small intestinal lesions in rats. Animals non-fasted were given indomethacin (10 mg/kg) s.c., and killed 24 hr later. Pranlukast (1–10 mg/kg) was given p.o. twice, 30 min before and 6 hr after the administration of indomethacin. A single s.c. administration of indomethacin provoked multiple haemorrhagic lesions in the small intestine, mainly in the jejunum and ileum. This treatment also caused an increase in MPO activity, microvascular permeability, and enterobacterial counts in the mucosa. Pretreatment of the animals with pranlukast (1–10 mg/kg) dose-dependently reduced the severity of these lesions and improved the patho-physiological alterations occurred after indomethacin treatment. Although indomethacin increased intestinal motility and decreased mucus secretion, the events being responsible for bacterial invasion, these changes were not significantly affected by pranlukast. These results showed that pranlukast prevents indomethacin-induced small intestinal lesions, probably through its inhibitory action, primarily on bacterial invasion and secondly on neutrophil migration as well as vascular permeability, and suggest the importance of CysLTs in the pathogenic mechanism of this lesion model. Received 2 August 2006; revised and accepted 11 January 2007     

Montelukast, a cysteinyl leukotriene receptor-1 antagonist, attenuates chronic brain injury after focal cerebral ischaemia in mice and rats

Objectives Previously we demonstrated the neuroprotective effect of montelukast, a cysteinyl leukotriene receptor‐1 (CysLT₁) antagonist, on acute brain injury after focal cerebral ischaemia in mice. In this study, we have determined its effect on chronic brain injury after focal cerebral ischaemia in mice and rats. Methods After transient focal cerebral ischaemia was induced by middle cerebral artery occlusion, montelukast was intraperitoneally injected in mice or orally administered to rats for five days. Behavioural dysfunction, brain infarct volume, brain atrophy and neuron loss were determined to evaluate brain lesions. Key findings Montelukast (0.1 mg/kg) attenuated behavioural dysfunction, brain infarct volume, brain atrophy and neuron loss in mice, which was similar to pranlukast, another CysLT₁ receptor antagonist. Oral montelukast (0.5 mg/kg) was effective in rats and was more effective than edaravone, a free radical scavenger. Conclusion Montelukast protected mice and rats against chronic brain injury after focal cerebral ischaemia, supporting the therapeutic potential of CysLT₁ receptor antagonists.     

Patent Evaluation: Indole Derivatives which Inhibit Leukotriene Biosynthesis

Summary

Novelty: Substituted indolyl compounds are claimed. They are said to be potent inhibitors of the lipoxygenase enzymes. These compounds may be useful for the treatment or amelioration of inflammatory disease states, in which leukotrienes play a role.

Biology: Inhibition of leukotriene biosynthesis was evaluated in vitro. Calcium ionophore-induced LTB₄ biosynthesis which is expressed by human polymorphonuclear leukocytes (PMNL) or whole human blood was also assayed. Inhibition of in vivo leukotriene biosynthesis, after oral administration of the compound, was determined using a rat peritoneal anaphylaxis model. These compounds were found to be orally effective in preventing in vivo leukotriene biosynthesis.

Chemistry: The syntheses of the compounds are described in several reaction schemes. All compounds are prepared using conventional methods. Two-hundred and seventy-eight examples are given. Twenty-four compounds are specifically claimed, including N′-hydroxy-N′-methyl-N-2-[2-methyl-3-(1-(4-chlorophenylmethyl)-3-(1,1-dimethyl-ethylthio)-5-(1-methylethyl)indol-2-yl)]propyl urea.

Structure:      

Patent Evaluation: Novel Quinoline Leukotriene Receptor Antagonists

Summary

Novelty: Unsaturated hydroxyalkylquinoline acids, which are said to be leukotriene antagonists and inhibitors of leukotriene biosynthesis, are disclosed. Quinoline acids may be useful for treating conditions such as angina, cerebral spasm and hepatitis.

Biology: Leukotriene antagonism was evaluated in LTD₄ receptor binding studies undertaken on g.p. lung membranes (in vitro) and in vivo in guinea pigs. A PMN leukocyte LTB₄ assay was also performed. In vivo leukotriene antagonism and leukotriene biosynthesis inhibition were assessed using asthmatic rats and pulmonary mechanics tests. However, no data are provided.

Chemistry: The syntheses of the compounds are described in fifteen reaction schemes. Preparatory details are included for thirty-nine compounds. A further one hundred and sixty-seven examples are given. All compounds were prepared by conventional methods.

Structure:     

Bio‐distribution and in vivo antioxidant effects of cerium oxide nanoparticles in mice

Cerium oxide nanoparticles have oxygen defects in their lattice structure that enables them to act as a regenerative free radical scavenger in a physiological environment. We performed a comprehensive in vivo analysis of the biological distribution and antioxidant capabilities of nanoceria administered to mice perorally (PO), intravenously (IV), or intraperitoneally (IP) by dosing animals weekly for 2 or 5 weeks with 0.5 mg kg^?1 nanoceria. Next, we examined if nanoceria administration would decrease ROS production in mice treated with carbon tetrachloride (CCl₄). Our results showed that the most extensive and cumulative nano‐deposition was via IV and IP administered while PO administration showed mice excreted greater than 95% of their nanoceria within 24 h. Organ deposition for IV and IP mice was greatest in the spleen followed by the liver, lungs, and kidneys. Elimination for all administration routes was through feces. Nanoceria administration showed no overt toxicity, however, WBC counts were elevated with IV and IP administration. Our in vivo studies show that nanoceria administration to mice with induced liver toxicity (by CCl₄) showed similar findings to mice treated with N‐acetyl cystine (NAC), a common therapeutic to reduce oxidative stress. Taken together, our studies show that nanoceria remains deposited in tissues and may decrease ROS, thereby suggesting that cerium oxide nanoparticles may be a useful antioxidant treatment for oxidative stress. © 2011 Wiley Periodicals, Inc. Environ Toxicol 2013.     

Addressing Concerns about Changing the Route of Antimicrobial Administration from Intravenous to Oral in Adult Inpatients

Background:Many health care institutions are in the process of establishing antimicrobial stewardship programs. Changing the route of administration of antimicrobial agents from intravenous to oral (IV to PO) is a simple, well-recognized intervention that is often part of an antimicrobial stewardship program. However, the attending health care team may have concerns about making this switch.Objectives:To provide insights into common concerns related to IV to PO conversion, with the aim of helping antimicrobial stewardship teams to address them.Conclusions:When considering a change to oral therapy, it is important to have a thorough understanding of key aspects of the antimicrobial agent, the patient, and the disease being treated. The antimicrobial stewardship team has an important role in facilitating IV to PO conversion, educating prescribers, and addressing any concerns or reservations that may interfere with timely transition from IV to PO administration.     

Estimation of Oral Bioavailability of a Long Half-Life Drug in Healthy Subjects

Purpose. To estimate and compare the oral bioavailability of a drug (BMS-187745) administered as single doses of oral solution of either the parent drug or its prodrug (BMS-188494). Methods. A single-dose, two-period, three-treatment, control-balanced, residual-effect, incomplete block crossover study was completed in 16 healthy male subjects. All subjects received a 10 mg IV infusion of BMS-187745, and a single oral dose of either BMS-187745 (PO1) or BMS-188494 (PO2). A model is proposed to calculate the oral bioavailability of BMS-187745 which has a long half-life; incomplete data points were available to characterize its elimination phase. The plasma concentration-time data obtained following IV infusion of parent drug, and after administration of either PO1 or PO2 treatment were fitted simultaneously with systemic pharmacokinetic parameters shared by both the oral and IV routes of administration. Results. The best simultaneous fittings of the plasma concentration-time data were obtained by using a biexponential pharmacokinetic model with a first-order absorption rate constant. The mean bioavailability (F) values of BMS-187745 estimated by the proposed model were 26.5% and 2.6% when given as oral solution of its prodrug and as the parent drug. The coefficient of variation (CV) of these F values are reasonable, ranging from 38–40%. In contrast, F calculated by the model-independent AUC method exhibited high CV, ranging from 111–120%. Conclusions. The oral bioavailability values estimated by the proposed model were more reasonable compared to those calculated by the model-independent AUC method. The proposed approach may be useful for estimating bioavailability of long half-life drugs when incomplete data points are available to characterize their elimination phase.     

Pharmacokinetics and penetration of moxifloxacin into infected diabetic foot tissue in a large diabetic patient cohort

Objectives

Physiological changes occurring in patients with diabetes may affect the pharmacokinetics and penetration of antimicrobial agents into peripheral tissue. We examined the pharmacokinetics and the penetration of moxifloxacin into perinecrotic tissue of diabetic foot lesions in patients with diabetic foot infections (DFI).

Patients and methods

Adult patients suffering from type 2 diabetes mellitus and hospitalized for DFI (Texas classification of at least B2) were treated with 400?mg moxifloxacin intravenously (IV) or orally (PO) once daily. The pharmacokinetics of moxifloxacin and its concentration 3 h after administration in samples of perinecrotic tissue resected from infected diabetic foot wounds were determined at steady state (days 4?C8).

Results

A total of 53 patients with diabetes mellitus type 2 (mean age 69.4?±?10.8?years) were included in the study, of whom 28 received PO and 25 IV moxifloxacin therapy for a median of 8?days. In the PO and IV subgroups, the mean maximum observed plasma concentration (C _max) in plasma was 2.69 and 4.77?mg/l at a median of 2 [time to reach C _max (T _max) range 1.0?C8.0?h] and 1?h after administration, respectively. A mean area under the plasma concentration?Ctime curve from time 0 until the last quantifiable plasma concentration (AUC_0-24?h) of 29.36?mg h/l (PO) and 27.09?mg h/l (IV) was achieved. Mean moxifloxacin concentrations in perinecrotic tissue of infected diabetic foot wounds following PO or IV administration were 1.79?±?0.82?and 2.20?±?1.54???g/g, thus exceeding the MIC₉₀ (minimum inhibitory concentration required to inhibit growth of 90% of organisms) for Staphylococcus aureus (0.25?mg/l) by seven- and eightfold and the MIC₉₀ for Escherichia coli (0.06?mg/l) by 29-fold and 36-fold, respectively. The mean tissue-to-plasma ratios of moxifloxacin concentration 3?h after administration were 1.01?±?0.57 (PO) and 1.09?±?0.69 (IV). Significant differences between the routes of administration were observed for T _max and C _max (P?<?0.01), but not for other clinically relevant parameters (AUC_0-24; moxifloxacin DFI tissue concentration).

Conclusions

The plasma concentration?Ctime curve of moxifloxacin in diabetic patients is similar to that of healthy volunteers. We also observed a good penetration of moxifloxacin into inflamed DFI tissue which taken together with the possibility of sequential IV/PO therapy suggest that moxifloxacin 400?mg once daily is a therapeutic option in the treatment of DFI caused by susceptible organisms.     

Novel polyhydroxylated steroids from the East China Sea gorgonian Echinogorgia sassapo reticulata with suppressive activity of leukotriene C4 generation and degranulation in bone marrow-derived mast cells

The gorgonian Echinogorgia sassapo reticulata contains two new bioactive polyhydroxylated steroids, sassapols A (1), B (2), and five related known compounds (3–7). Compound 6 has been encountered for the first time in natural sources. The structures of these new compounds were defined by spectroscopic analysis. All the compounds (1–7) isolated from E. sassapo reticulata were tested for anti-inflammatory activity. Compounds 1, 3, 5, and 7 inhibited both the generation of leukotriene C₄ and the degranulation reaction in mouse bone marrow-derived mast cells.     

Effect of Polypodium leucotomos on acute, chronic and reactivated trinitrobenzene sulphonic acid colitis in rats

The effects were examined of a Polypodium leucotomos extract on trinitrobenzene sulphonic acid (TNBS) induced rat colitis. Pretreatment with the extract had a dose-dependent acute anti-inflammatory effect which was maximal at 100 mg/kg/day. This was characterized by preservation of glutathione levels at low doses (25-50 mg/kg) and inhibition of leukotriene B₄ synthesis at high doses (50-100 mg/kg). Treatment was also active in chronic colitis, induced by TNBS, as was evident by enhanced colonic fluid absorption and reducing myeloperoxidase levels, while glutathione levels and leukotriene B₄ synthesis were unaffected by treatment. Finally, treated animals were partially protected against colitis reactivation, showing lower myeloperoxidase and leukotriene B₄ synthesis than controls and normal fluid absorption, but no change in glutathione. In conclusion, Polypodium leucotomos is useful to control experimental colitis (acute, chronic and reactivated) but no common mechanism of action could be delineated, since neither an antioxidative mechanism nor inhibition of leukotriene B₄ synthesis can account for the overall effect.     

Relative systemic availability of budesonide in patients with asthma after inhalation from two dry powder inhalers

ABSTRACT

Background: To improve dosing consistency and product features, budesonide inhalation powder delivered via a dry powder inhaler (DPI) (DPI?A^* 200?μg) was redesigned to include lactose, a newly shaped mouthpiece, and a new dose indicator (DPI?B^*). Budesonide DPI?B is available in two strengths (90?μg, 180?μg).

Objective: To compare the relative rate and extent of the systemic availability of budesonide inhaled via DPI?A and DPI?B and test for systemic absorption bio­equivalence.

Methods: Adults (n?=37) with asthma as defined by the American Thoracic Society were randomized in an open-label, crossover, single-center, single-dose study to budesonide DPI?A 200?μg × 4 inhalations, budesonide DPI?B 180?μg × 4 inhalations, or budesonide DPI?B 90?μg × 8 inhalations, on 3 days, each separated by a washout period of?≥?5 days. Plasma samples were collected immediately before and up to 12?h after dosing. Primary pharmacokinetic variables were area under the drug plasma concentration–time curve from 0 to infinity (AUC_0–∞) and maximum plasma concentration (C_max); plasma concentration at 12?h (C_12h) and time to maximum plasma concentration (T_max) were secondary variables. Treatments were considered bioequivalent if the 90% confidence intervals (CIs) for their AUC_0–∞ and C_max ratios fell between 80 and 125%. Adverse events were collected.

Results: The 90% CIs for the ratios of AUC_0–∞ and C_max for budesonide DPI?A 200?μg and DPI?B 180?μg and for both budesonide DPI?B strengths fell between 80% and 125% (AUC_0–∞: budesonide DPI?B 180?μg × 4/DPI?A 200?μg × 4: 96.3% [90 % CI: 90.9, 102.1]; budesonide DPI?B 180?μg × 4/DPI?B 90?μg × 8: 92.2% [90 % CI: 87.0, 97.7]; C_max: (budesonide DPI?B 180?μg × 4/DPI?A 200?μg × 4: 100.4% [95 % CI: 92.1, 109.4]; budesonide DPI?B 180?μg × 4/DPI?B 90?μg × 8: 94.4% [90 % CI: 86.6, 102.9]). No differences in C_12h and T_max were found between treatments. All treatments were well tolerated.

Conclusions: Budesonide DPI?A 200?μg and DPI?B 180?μg have systemic absorption bioequivalence, and DPI?B 90?μg and 180?μg are dose-strength equivalent when administered at the same dose. These results may not be generalized to all patients with asthma, as this analysis included only patients with mild-to-moderate asthma aged?≥?19 years.     

Pharmacological profile of MEN91507, a new CysLT(1) receptor antagonist

MEN91507 (8-[2-(E)-[4-[4-(4-fluorophenyl)butyloxy]phenyl]vinyl]-4-oxo-2-(5-1H-tetrazolyl)-4H-1-benzopyran sodium salt)) potently displaced [3H]leukotriene D(4) binding from guinea-pig lung and dimethylsulphoxide-differentiated U937 (dU937) cell membranes (K(i) 0.50 +/- 0.16 and 0.65 +/- 0.29 nM, respectively). On the other hand, MEN91507 did not display significant binding affinity for a series of receptors or channels. In functional studies on dU937 cells, MEN91507 behaved as insurmountable antagonist of leukotriene D(4)-induced calcium transients, with an apparent pK(B) of 10.25 +/- 0.15. In anaesthetized guinea-pigs, MEN91507 antagonized in a dose-dependent manner leukotriene D(4)-induced bronchoconstriction following i.v. or oral administration: the ED(50s) were 3.0 +/- 0.3 and 140 +/- 90 nmol/kg, respectively. The inhibition of leukotriene D(4)-induced bronchoconstriction by MEN91507 was long-lasting, since a dose of 0.6 micromol/kg produced 74% reduction of the response after 8 h from administration. Likewise, leukotriene D(4)-induced microvascular leakage was antagonized by MEN91507 either following i.v. or oral administration: a significant inhibitory effect was still evident at 16 h from oral administration of a dose of 6 micromol/kg. It is concluded that MEN91507 is a potent and selective antagonist of both guinea-pig and human CysLT(1) receptors; in addition, in vivo studies on guinea-pigs indicate that MEN91507 is an orally available and long-lasting antagonist of the bronchomotor and pro-inflammatory effects induced by leukotriene D(4) through the stimulation of CysLT(1) receptors.     

Targeting leukotriene B4 in inflammation

Introduction: Leukotriene (LT) B₄ is a powerful proinflammatory lipid mediator and triggers adherence to the endothelium, activates and recruits leukocytes to the site of injury. When formed in excess, LTB₄ plays a pathogenic role and may sustain chronic inflammation in diseases such as asthma, rheumatoid arthritis, and inflammatory bowel disease. Recent investigations have also indicated that LTB₄ is involved in cardiovascular diseases.

Areas covered: As the 5-lipoxygenase pathway involves several discrete, tightly coupled, enzymes, which convert the substrate, ‘step by step', into bioactive products, several different strategies have been used to target LTB₄ as a means to treat inflammation. Here, we discuss recent findings regarding the development of selective enzyme inhibitors and antagonists for LTB₄ receptors, as well as their application in preclinical and clinical studies.

Expert opinion: Components of the 5-lipoxygenase pathway have received considerable attention as candidate drug targets resulting in one new class of medications against asthma, that is, the antileukotrienes. However, efforts to specifically target LTB₄ have not yet been fruitful in the clinical setting, in spite of very promising preclinical data. Recently, crystal structures along with hitherto unknown functions of key enzymes in the leukotriene cascade have emerged, offering new opportunities for drug development and, with time, pharmacological intervention in LTB₄-mediated pathologies.