Antiasthmatic Agents Research Articles

Antiasthma Agents: Cromolyn Sodium and Nedocromil Sodium

Antiasthma Agents: Cromolyn Sodium and Nedocromil Sodium

High-affinity binding of mequitamium iodide (LG 30435) to muscarinic and histamine H 1 receptors

Mequitamium iodide (LG 30435) is a novel quaternary ammonium phenothiazine with potential as an anti-asthmatic agent. In vitro binding experiments were performed in order to clarify the molecular mechanisms underlying its biological activity. Mequitamium iodide was found to bind with high affinity only to histamine H 1 receptors in rat brain membranes (K i = 9 nM) and to muscarinic acetylcholine receptors in various tissues homogenates (K i = 12–77 nM) with no clearcut selectivity for any of the known subtypes. The interaction with muscarinic receptors in rat cerebral cortex and lung parenchyma was competitive, as showed by saturation studies. Lower affinity values (K i = 1–10 μM) were found for serotonin 5-HT 2, platelet-activating factor (PAF), verapamil and β-adrenergic agents. These results indicate that both the potent antimuscarinic and antihistamine and the relatively weak anti-PAF pharmacological effects of mequitamium iodide may be explained by the direct interaction of the substance with the respective receptors.

Development of a novel series of (2-quinolinylmethoxy)phenyl-containing compounds as high-affinity leukotriene receptor antagonists. 1. Initial structure-activity relationships

This series of reports describes the development of orally active, highly potent, specific antagonists of the peptidoleukotrienes containing a (2-quinolinylmethoxy)phenyl moiety. Described in this first report are the structure-activity relationships that led to a more than a 20-fold improvement of the potency and selectivity of the initial chemical lead (RG 5901). From this series of compounds, RG 7152 (16) was identified and selected for further evaluation in the clinic as an antiasthmatic agent. Compound 16 competitively inhibits [3H]LTD4 binding to membranes from guinea pig lung (Ki = 38 +/- 6 nM) and the spasmogenic activity of LTC4, LTD4, and LTE4 in parenchymal lung strips from guinea pigs. Unlike the original lead (RG 5901), compound 16 does not inhibit 5-lipoxygenase from guinea pig PMNs. Following oral administration to guinea pigs, 16 blocks LTD4-induced dermal permeability (ED50 = 6.9 mg/kg), LTD4-induced bronchoconstriction (ED50 = 1.1 mg/kg), antigen-induced bronchoconstriction (ED50 = 2.5 mg/kg), and anaphylactic-induced mortality (ED50 = 16 mg/kg). These studies on structure-activity relationships indicate that there is a requirement for an acidic function and the presence of the (2-quinolinylmethoxy)phenyl moiety in a specific geometric arrangement.

Preparation of triazolo[1,5-c]pyrimidines as potential antiasthma agents

With the use of the human basophil histamine release assay, 5-aryl-2-amino[1,2,4]triazolo[1,5-c]pyrimidines were found to be active as mediator release inhibitors. These compounds were prepared by reacting arylamidines with sodium ethyl formylacetate or with ethyl propiolate to give pyrimidinones. Treatment with phosphorus oxychloride gave a chloropyrimidine, which was converted to a hydrazinopyrimidine with hydrazine. Cyclization, using cyanogen bromide, gave the triazolo[1,5-c]pyrimidines, after a Dimroth rearrangement. Following a structure-activity evaluation, the 5-[3-(trifluoromethyl)phenyl]-2-amino (8-10), 5-(3-bromophenyl)-2-amino (8-13), 5-[3-(difluoromethoxy)-phenyl]-2-amino (8-11), and 5-(4-pyridinyl)-2-amino (6-7) compounds were found to have the best activity. They were chosen for further pharmacological and toxicological study.

Eosinophilic Polymyositis Induced by Tranilast

A 38-year-old man with asthma developed eosinophilic polymyositis following the administration of Tranilast, an antiasthmatic agent. Low grade fever, erythematous rashes on the entire body, dysphagia, blood eosinophilia, elevations of serum creatine phosphokinase and myoglobin levels, and inverted T waves in the electrocardiogram were noted. A muscle biopsy showed focal degeneration of muscle fibers with an infiltrate of eosinophils and lymphocytes. A rechallenge with Tranilast resulted in erythema formation, blood eosinophilia, and elevations of some serum muscle enzymes and myoglobin levels. Tranilast was considered to be the causative agent. This is the first reported case of Tranilast-induced eosinophilic polymyositis.

PAF-induced airway responses in sheep: Effects of a PAF antagonist and nedocromil sodium

Platelet-activating factor (PAF) is a potent inflammatory mediator that can cause bronchoconstriction and airway hyperresponsiveness in selected human subjects and animals. The mechanism by which PAF induces these changes is not clearly understood. We therefore studied the effects of intratracheal instillation of PAF (30 μg/kg) on airway resistance and airway responsiveness in allergic sheep (n = 7) and attempted to modulate these effects with the specific PAF antagonist, WEB-2086, and the antiasthmatic agent, nedocromil sodium (NED). Specific lung resistance (SR L) was measured to assess bronchial responses to PAF, and airway responsiveness was determined by deriving a provocative dose of carbachol in breath units causing an increase in SR L to 4 L times centimeters of H 2O per liters per second (PD 4) from carbachol dose-response curves. PAF instillation increased mean ± SD SR L to 228 ± 134% above baseline. Two to 4 hours after PAF instillation, PD 4 decreased by 55 ± 9% from a baseline of 39 ± 9 breath units ( p < 0.05). Airway responsiveness remained increased at 24 hours but returned to baseline by 48 hours. Pretreatment with WEB-2086 (3 mg/kg, intravenously) or NED (1 mg/kg, nebulized) blocked ( p < 0.05) PAF-induced bronchoconstriction and PAF-induced airway hyperresponsiveness. Instillation of lyso-PAF (30 μg/kg) did not cause bronchoconstriction or airway hyperresponsiveness. Thus, instilled PAF causes bronchoconstriction and airway hyperresponsiveness in allergic sheep by a receptor-mediated mechanism that likely involves the release of secondary mediators, the latter process being sensitive to NED.

Evaluation of the Safety and Efficacy of Multiple Doses of Azelastine to Adult Patients with Bronchial Asthma over Time

Azelastine is a new oral antiasthma agent with bronchodilating and antiallergic properties. This 12-wk study compared azelastine (2, 4, 6, and 8 mg) and placebo given twice a day in asthmatics 12 to 60 yr of age requiring daily bronchodilator therapy. Patients were allowed albuterol aerosol, short-acting theophylline, and pseudoephedrine only as needed. The study was completed by 221 asthmatic subjects. No significant differences in symptoms, medication, or pulmonary function existed between groups at baseline. Analysis of the zero hour FEV1 before azelastine administration on eight occasions during the 12 wk of therapy indicated an increasing slope for azelastine 6 mg that was statistically different from that of placebo; similarly, the slope for azelastine 4 mg showed the same trend, but it did not reach statistical significance. All azelastine groups had significant reductions of as-needed medication after 1 wk; only in the 4-mg and 6-mg groups was this reduction sustained for 12 wk. Asthma symptom scores and peak expiratory flow measurements remained stable in the azelastine groups despite significant reductions in concomitant medication administration. Side effects were minor and included: altered taste (30.1 to 51.9%), drowsiness (6.0 to 16.9%), and dry mouth (3.8 to 6.1%). The occurrence of these adverse events decreased with time throughout the study.(ABSTRACT TRUNCATED AT 250 WORDS)

A Refractory Type Asthmatic Whose Symptoms Markedly Improved by Midaglizole

We present a patient with refractory intrinsic asthma who showed a good response to both a single oral dose and a 4-week period of administration of the selective alpha-2 adrenoceptor antagonist, midaglizole. After the single dose, bronchodilation was immediately observed. With continuous administration, the peak expiratory flow rate (PEFR) was increased and the total daily intake of aerosol was decreased in a dose-dependent fashion. These results suggest that the addition of midaglizole to the usual antiasthmatic agents can be of value in the management of refractory asthma.

Azelastine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential.

Azelastine is an antiallergic agent which demonstrates histamine H1-receptor antagonist activity and also inhibits histamine release from mast cells following antigen and non-antigen stimuli. Azelastine antagonises histamine- and leukotriene-induced bronchospasm in animal studies and reduces airway responsiveness to inhaled antigen or distilled water, and exercise challenge. In comparative studies, orally administered azelastine in doses up to 4 mg/day consistently relieved symptoms in patients with seasonal or perennial rhinitis - comparable to inhaled sodium cromoglycate (cromolyn sodium) 80 mg/day, oral chlorpheniramine (chlorphenamine) and oral terfenadine 120 mg/day. In addition, azelastine administered as an intranasal spray was as effective as oral terfenadine 120 mg/day and intranasal budesonide 0.4 mg/day in alleviating symptoms of rhinitis. Azelastine is also a potent antiasthmatic agent which produces significant and long lasting bronchodilation in patients with bronchial asthma. The drug is superior to placebo and comparable to oral ketotifen 2 mg/day and sustained release theophylline 700 mg/day when administered as a twice daily oral 4 mg dose. Azelastine is generally well tolerated: the most common adverse effects are altered taste perception and drowsiness. Adverse effects are mild and transient and result in withdrawal of treatment in less than 2% of patients. In a comparative study oral azelastine 2 or 4 mg/day produced no more sedation than terfenadine 120 mg/day. Thus, barring unexpected findings with wider clinical use, azelastine offers an effective and well tolerated choice of treatment for patients with allergic rhinitis and/or bronchial asthma, which may be particularly beneficial in patients in whom inhaled drug treatment is contraindicated.

Psychological problems associated with drug therapy in childhood asthma

Ten studies designed to evaluate the psychological and behavioral effects of the antiasthma agent theophylline in children have been carried out to date. In this review, we evaluate the strengths and weaknesses of those investigations and discuss whether theophylline is responsible for learning disabilities or behavioral disorders such as hyperactivity. We also discuss the similarities between studies of theophylline and those of other xanthines, such as caffeine, to suggest that some persons appear to have a heightened response to these substances and would benefit from closer monitoring, not only of serum drug levels but also of their consumption of food and beverages that contain caffeine. In addition, we describe strategies for examining whether a functional relationship exists between theophylline use and behavioral and psychological changes in children.

The prescribing of antiasthmatic agents in Hong Kong is suboptimal

The prescribing of antiasthmatic agents in Hong Kong is suboptimal

Pattern of anti-asthmatic drug utilization in Hong Kong compared to other parts of the world

Inhaled drugs are now considered first line agents for the treatment of asthma, whereas oral beta-agonists, theophylline and its derivatives have been relegated to a secondary role. To determine whether current prescribing in Hong Kong conforms to these recommendations, we have evaluated anti-asthmatic drug utilization in the territory as reflected by 1984-86 drug sales (courtesy Medical and Health Department, Hong Kong). Sales/prescription statistics were also obtained from corresponding agencies of other governments and from published literature. If appropriate, data for comparison was expressed as defined daily doses (DDDs) per 1000 inhabitants per day. In contrast to the pattern of utilization in several developed nations, in Hong Kong (a) oral anti-asthmatic agents (particularly beta agonists) were more commonly utilized than inhaled drugs, and (b) inhaled therapy mainly consisted of non-selective beta-agonists, steroids being very rare. Further education is required to improve anti-asthmatic drug utilization patterns in the community.

Pharmacological profile of MDL 26,024GO: a novel antiasthmatic agent.

MDL 26,024GO was shown to be an orally absorbed mediator release inhibitor in the rat PCA and PPA tests. In addition, the compound was shown to both elicit and inhibit elicitation of the Bezold-Jarisch reflex in the dog. MDL 26,024GO also significantly reduced Ascaris-induced changes in pulmonary mechanics in cynomolgus monkeys. The compound inhibited both early and late phase antigen induced-changes in Ascaris-sensitive sheep, as well as the increased airway hyperreactivity which normally follows antigen challenge. These results suggest the compound may have therapeutic potential in the treatment of asthma.

Theophylline does not inhibit allergen-induced increase in airway responsiveness to methacholine

Allergen-induced increase in airway hyperresponsiveness can be used as a model of airway inflammation for assessing antiasthma pharmacologic agents. Steroids and cromolyn, but not βn-agonists, inhibit this increase; theophylline, recently suggested as having anti-inflammatory effects, has not been evaluated in this model. Six atopic subjects with asthma and with late asthmatic responses (N = 5) and postallergen reduction in a provocative concentration of methacholine causing a 20% fall in FEV 1 (PC 20) (N = 6) were studied. Sustained-release theophylline (Theo-Dur; Astra Pharmaceuticals Canada, Ltd., Mississauga, Canada), 300 mg, and placebo were administered single-blind twice daily for eight doses up to 1 hour before allergen inhalation; cromolyn sodium, 10 mg, was administered in a single dose 10 minutes before allergen inhalation on another day as a “positive control.” Mean theophylline levels were in the low therapeutic range, 57 ± 17 and 58 ± 13 μmol/L 1 and 8 hours after the last tablet. The FEV 1 was 7% and 9% greater after the seventh and eighth doses of theophylline versus placebo ( p < 0.05). Theophylline also produced a significant ( p < 0.05) twofold increase in methacholine PC 20. There was a 40% ( p = 0.06) reduction in early asthmatic fall in FEV 1 and a 25% (not significant) reduction in late FEV 1 fall when theophylline was compared to placebo. Theophylline did not influence the geometric mean allergen-induced fall in methacholine PC 20 Δ log PC 20; this was true individually in five of the six subjects. By contrast, cromolyn sodium inhibited all aspects of the allergen response completely. When FEV 1 had returned to baseline, the cromolyn sodium Δ log PC 20 (−0.02 ± 0.06) was significantly less than the theophylline Δ log PC 20 (0.42 ± 0.27) ( p = 0.016). These data fail to provide evidence for an anti-inflammtory effect of theophylline in this in vivo human model. Theophylline appears to have primarily a bronchodilator effect.

Ketotifen does not inhibit asthmatic reactions induced by toluene di‐isocyanate in sensitized subjects

In order to determine whether treatment with ketotifen inhibits asthmatic reactions induced by toluene di-isocyanate (TDI), we studied six sensitized subjects with previously demonstrated dual or late asthmatic reaction after inhalation challenge with TDI. Ketotifen (1 mg b.i.d., orally) or placebo was administered for 7 days to the examined subjects, according to a double-blind, cross-over, placebo-controlled study design. When the subjects were treated with either ketotifen or placebo, FEV1 markedly decreased after exposure to TDI. These results suggest that the anti-asthmatic agent ketotifen is not effective in TDI-induced asthma and suggest that it should not be used in the prophylaxis of asthmatic reactions induced by TDI in sensitized subjects.

Development of Preclinical Models for Testing Antiasthma Drugs

The antiasthmatic agent, sodium cromoglycate, owes its discovery to a series of antigen challenge tests carried out during the 1960s by an asthmatic, Roger Altounyan, on himself. Until recently, research efforts to identify new antiasthma drugs have relied heavily on screening methods which involved passively-sensitised mast cells. In theory these tests, such as rat passive cutaneous anaphylaxis, appeared relevant and showed sodium cromoglycate to have a stabilising effect on the mast cell membrane. In practice no new drugs were discovered, since this type of activity in animal models was not predictive of antiasthmatic potential. A more relevant research programme has subsequently evolved, which attempts to approach more closely the conditions prevailing in the asthmatic lung. The use of a model of immune lung inflammation in macaque monkeys in conjunction with a model of bronchial hyper-reactivity in the dog has been successful in producing the new compound, nedocromil sodium, which is proving to be an effective addition to the drugs available for the treatment of inflammatory diseases of the airways.

Immunopharmacological studies on TBX, a new antiallergic drug. (3). Inhibitory effects on histamine release from lung fragments and bronchoconstriction in guinea pigs.

The effects of 9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one potassium salt (TBX), a new antiallergic drug, on histamine release from lung fragments, experimental asthma and isolated tracheal muscle were investigated in guinea pigs. TBX (10(-7) to 10(-4) g/ml) dose-dependently inhibited antigen-induced histamine release from lung fragments of guinea pigs passively sensitized with homologous IgE serum. Antigen inhalation-induced experimental asthma in passively sensitized animals was inhibited in a dose-dependent fashion by i.v. (1 to 5 mg/kg) and p.o. (10 to 100 mg/kg) administrations of TBX. In vivo bronchoconstriction by platelet-activating factor (PAF, i.v.) was also inhibited by TBX (0.3 to 10 mg/kg, i.v.). However, high concentrations of TBX (more than 3 x 10(-4) g/ml) were needed to inhibit PAF-induced platelet aggregation in vitro. With regard to the effect on isolated tracheal muscle, TBX itself at concentrations higher than 10(-5) g/ml induced dose-dependent reduction in the resting tonus, which was not affected by pretreatment with propranolol. Neither the leukotriene D4-induced contraction nor the prostaglandin F2 alpha-induced one was specifically antagonized by TBX. The results obtained indicate that TBX is an antiasthmatic agent effective in inhibiting both IgE- and PAF-induced bronchoconstriction, possibly by interfering with mediator release.

Immunopharmacological Studies on TBX, a New Antiallergic Drug (3) Inhibitory Effects on Histamine Release from Lung Fragments and Bronchoconstriction in Guinea Pigs

The effects of 9-methyl-3-(1 H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidm-4-one potassium salt (TBX), a new antiallergic drug, on histamine release from lung fragments, experimental asthma and isolated tracheal muscle were investigated in guinea pigs. TBX (10-7 to 10-4 g/ml) dose-dependently inhibited antigen-induced histamine release from lung fragments of guinea pigs passively sensitized with homologous IgE serum Antigen inhalation-induced experimental asthma in passively sensitized animals was inhibited in a dose-dependent fashion by i.v. (1 to 5 mg/kg) and p.o. (10 to 100 mg/kg) administrations of TBX. In vivo bronchoconstriction by platelet-activating factor (PAF. i.v.) was also inhibited by TBX (0.3 to 10 mg/kg, i.v). However, high concentrations of TBX (more than 3×10-4 g/ml) were needed to inhibit PAF-induced platelet aggregation in vitro. With regard to the effect on isolated tracheal muscle, TBX itself at concentrations higher than 10-5 g/ml induced dose-dependent reduction in the resting tonus, which was not affected by pretreatment with propranolol. Neither the leukotriene D4-induced contraction nor the prostaglandin F2α-induced one was specifically antagonized by TBX. The results obtained indicate that TBX is an antiasthmatic agent effective in inhibiting both IgE- and PAF-induced bronchoconstriction. possibly by interfering with mediator release.

Inhibition of Allergic and Nonallergic Leukotriene C&lt;sub&gt;4&lt;/sub&gt; Formation and Histamine Secretion by Azelastine: Implication for Its Mechanism of Action

Azelastine, an orally effective antiasthmatic agent, has been reported to inhibit antihistamine-resistant, leukotriene-mediated allergic bronchoconstriction in guinea pigs. This suggests that azelastine might act through inhibition of leukotriene (LT) C4/D4 synthesis. We have examined the effect of azelastine on allergic and nonallergic histamine secretion and LTC4 formation. Azelastine and the known 5-lipoxygenase inhibitors, nordihydroguaiaretic acid and AA-861, exerted concentration-dependent inhibition of allergic LTC4 formation in chopped lung tissue from actively sensitized guinea pigs and calcium ionophore A23187-stimulated LTC4 synthesis in mixed peritoneal cells from rats. Azelastine also produced concentration-dependent inhibition of allergic and nonallergic histamine secretion from rat peritoneal mast cells. The ability of azelastine to inhibit allergic and nonallergic histamine secretion and LTC4 generation may contribute to its mode of action and its therapeutic efficacy.

Receptor binding studies of LG 30435, a new potential antiasthmatic agent

Receptor binding studies of LG 30435, a new potential antiasthmatic agent