CA2060937A1 - Anti-reactive anti-asthmatic activity of non-steroidal anti-inflammatory drugs by inhalation - Google Patents
Anti-reactive anti-asthmatic activity of non-steroidal anti-inflammatory drugs by inhalationInfo
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Abstract
Abstract Anti-reactive anti-asthmatic activity of non-steroidal anti-inflammatory drugs by inhalation Non-steroidal anti-inflammatory drugs proved to be effective drugs for combatingand preventing asthma if administered by inhalation. Useful are for instance acetylsalicylic acid, and indomethacin, and ketoprofen, and tenoxicam.
Suitable pharmaceutical compositions for inhalation are aerosols with a particle size of from 0.5 µm to 7 µm which enter the compartments of the lungs. Aqueous or aqueous-organic solutions or suspensions can be nebulized in combination with propelling agents, or mixtures of powders with microfine drugs can be administered using inhalers. These pharmaceutical compositions may comprise appropriate additives, in order to improve their relevant pharmaceutical properties.
Suitable pharmaceutical compositions for inhalation are aerosols with a particle size of from 0.5 µm to 7 µm which enter the compartments of the lungs. Aqueous or aqueous-organic solutions or suspensions can be nebulized in combination with propelling agents, or mixtures of powders with microfine drugs can be administered using inhalers. These pharmaceutical compositions may comprise appropriate additives, in order to improve their relevant pharmaceutical properties.
Description
HC)ECHST AI~IENGESELLSCllAFr HOE 91/F 047 Dr. v.F./AL
Dascription:
5 Anti-reactive anti-asthmatic activity of non-steroidal anti-inflammatory drugs by inhalation Th0 invention relates to the use of non-steroidal anti-inflammatory drugs for thc production of an anti-rsactive anti-asthmatic drug to be administered by inhalation;
10 it relates also to non-steroidal anti-inflarnmatory drugs as meclicaments to be inhaled for combating and preventing asthma.
,' Bronchial inflammation plays a key role in the current views on the pathogeneticmechanisms of bronchial asthma (Am Rev Respir Dis 1987; 136:740-51~. Despite relatively large experimental evidence for the involvement of arachidonic acid metabolites in these mechanisms ( J Appl Physiol 1989, 66:578-583l, several previous attempts to influence the bronchial responses using anti-inflammatory drugs with cyclooxygenase inhibitory activity have failed to show a clinically significant and consistent effect of these drugs in asthma (J Aller~y Clin Immunol 1983, 71:245-249). One of the limiting factors of the effect of these drugs on bronchial responses might be a scarce availability of these drugs in the lung followin~ systemic administration. Indeed, a significant reduction of th~ bronchial response to ultrasonically nabulized water (UNW) in asthmatics a~ter oral administration of relatively high doses of aspirin was observed ( Progr~ss in Biochemical Pharmacology (Karger, Basel) 1985, 20:132-142.2, and Aller~ologie, deuxieme edition, J Charpin ed, Flammanion publ., Paris 1986, p 683-693, and Respiration 1988, 54(suppl 1):100-107).
Since a similar dose of the chemically related compound, sodium salicylate, which is devoid of inhibitory activity on cyclooxygenase, has no effect ( L~acetilsalicilato di lisina ma non il salicilato protegge dal broncospasmo da H20. Ill Conferenza .~ Italiana di Medicina Respiratoria, Milano 1990, Abstract book p 181), it can be concluded that cyclooxygenase inhibitors play a role in the therapeutic control of .. ~
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, asthma, but relatively high doses have to be administered to afford a significant protective effect. Unfortunately, chronic treatment with such oral doses of NSAlDs causes an unacceptable rate of side effects, as indicated by two controlled studies available on the effect of treatment with high doses (1.3 to ~.6 g daily) of aspirin in asthmatics ( J Allergy Clin Immunol 1984, 73:500-507; and J Allergy Clin Immunoi1990, 85:59-65).
.: :
The aim of ~his invention was to make a breakthrough in the treatment of asthma with acceptable doses of a non-steroidal medicament.
This was accomplish~d by inhaling a non-steroidal anti-inflammatory drug (NSAID), preferably acetylsalicylic acid ~ASA), but also indomethacin, ke~oprofsn and tenoxicam.
Part of this invention is also a non-steroidal anti-inflammatory drug for application by inhalation in combating asthma, non-steroidal anti-inflammatory drugs of particular interest are acetylsalicylic acid, indomethacin, ketoprofen and tenoxicam.
The studies of this invention clearly show that inhaled NSAlDs, particularly Iysine-acetylsalicylate (L-ASA), the soluble form of ASA, induce a remarkable attenuation of the bronchial responses to both non-specific (UNW) and specific (immediate and late reactions to allergen) stimuli in asthmatics in the absence of side-effects.
Suitable pharmaceutical compositions for inhalation are aerosols with a particle size of from 0.5 ~m to 7 llm which enter the compar~ments of the lungs. Aqueous or aqueous-organic solutions or suspensions which can be nebuli7ed in combination with propelling agents, such as fluoro chloro hydrocarbons, fluorinated hydrocarbons, dimethyl ether, propane, butane, nitrogen, carbon dioxide, N2O, ormixtures of powders with microfine drugs, which can be administered using inhalers are particularly suitable. These pharmaceutical compositions may comprise appropriate additives, such as surface active substances, for instance ,:
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.;~ ,.
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. .
phospholipids, sorbitane esters, polyoxy sorbitane esters, or oleic acids, alcohols and polyols such as ethanol, glycerol, poly ethylene glycol, gluc4ss, mannitoi, sorbitol, in order to improve their relevant pharmaceutical properties.
PATIENTS AND MErHODS
A) Studies on non-spaciflc bronchial hyperreactivity:
- Patients:
10 Clinically stable patients with either allergic or non-allergic asthma with a baseline forced expiratory volume at 1 second (FEVl) greater than 70 % of predicted, who were free of viral or bacterial respiratory infection for at Isast 4 wesks were studied.
None of the patients had a history of L-ASA induced asthma. All the patients were either treated with inhaled beta2-stimulants or with inhaled beta2-stimulants and topical steroids, that were withheld for 10 hours before administration of the test drug ( J Allergy Immunol 1975; 56:323-327).
Methods:
Bronchial reactivity to ultrasonically nebulized water (UNW~ was msasured as '~ ~ 20 previously described ( Eur J Respir Dis 1980 (suppl 106):~1-9; and Pulmonary Pharmacology 198~, 1:187-191). Each subject inhaled increasing doubling doses ofUNW produeed by an ultrasonic nebulizer (DeVilbiss Ultra-neb 99) set to an output of 2 ml/min. The subject~ were instructed to breath at tidal volume, keeping themouthpiece between their teeth with the mouth semi-opened. Doubling doses o~
UNW were administered by progressively increasin~ the time of exposure from 30"
(1 ml) to 240" (15 ml) and if necessary for further 240" setting the output to 4ml/min (31 ml3. Respiratory function was monitored after each dose, un~il a F~
decrease of 20 % or greater compared to baseline was observed. In the cases where specific airway resistance (sRaw) was measured, this was done during normal breathing using a constant-volume body plethysmograph with a closed bag system to condition air to body temperature pressure saturation (BTPS) (Fenyves &
Gut, Basel, Switzerland) before and after pretreatment, and immedia~ely after each .~
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. , ,,, ., ~ . , ,: .~ . ..
test. FEV, was measured usin~ a spirometer (Vitalograph). The best value of the nrst 3 technically satisfactory spirograms was chosen for analysis. The dose of UNW causing a 20 % FEV, decrease (PD20) was then calculated by interpolation on the curnulative doss-response curve.
Study design:
To test the effect of ~^ASA on UNW-induced bronchoconstriction, in a group of 7 subjects with a positive response to a preliminary UNW ehallenge, the test was repeated twice, with in~arvals of 3-7 days betwesn treatments which were either 5 ml of ~-ASA (18Q mg/ml in saline corresponding to 100 mg/ml of ASA) or placebo, according to a randomized protocol, by means of a nebulizer set to run to dryness in about 30'. The UNW challenge was repeated 3O' after treatment and once more the next day, 24 hours after ~reatment. The clinical characteristics of the patients in this group ara reported in table 1.
In a second group of 6 patients, whose clinical characteristics are reported in table ll, the effect of inhaled indomethacin was tested according to a protocol identical to the previous one, except that pre-treatment consisted of the inhalation 20 of either 5 ml of indomsthacin 5 mg/ml for 25' or the appropriate placebo and the fog challenge was not repeated 24 hours after treatment. The test was repeated athird time in three of these patients after pretreatment with a higher dose of indomethacin (5 ml at 10 mg/ml nebulized in 25'~.
25 In four separate patients, with comparable clinical characteristics to th0 previous group, ~he effect of the two NSAJDs, ketoprofen and tenoxicam, on the immediate bronchial response to UNW was investigated in a pilot study. This study protocolwas identical ~o the previous study, except that L-ASA was substituted by a solution of either ketoprofen 10 mg/ml or tenoxicam 2 mg/ml. The effect of tenoxicam was 30 tested in three, and ketoprofen in two subjects.
Additionally, in a third group of patients, whose clinical characteristics are reported ".
.. . . .
.
' :'. ; , 2~ 37 in Table lll, the effects of tenoxicam on the immediate bronchial response to IJNW
was investiga~ed in seven patients. The study protocol was identical to the previous ones except that 5 rnl of a 4 mg/ml solution was nebulized over a period of 30 minutes in this test.
In a fourth group of five patients, whose clinical characteristics are reported in Table IV, the effects of Ketoprofen was investigated on the imrnediate bronchialresponse to UNW. Again the same protocol was used as in the previous studies except that 7 ml of a 7.14 mg/ml solution was nebulized over a period of 40 10 minutes in this study. The test was performed 40 min~es after the end of nebulization.
B) Allergen specific bronchial challenge:
; 15 Patients:
~`: Volunteers with aller~ic asthma who had an early obstructive response after specific allergen bronchial challenge were recruited among patients attending an allergy clinic. All the patients had a clinical history of allergic asthma and/or rhinitis, showed a positive immediate skin reaction to the clinically relevant allergen, were 20 either asymptomatic or had very mild respiratory symptoms, had a baseline ~EV, over 70 % of predicted and had been free of respiratory infections for at least 4 weeks. All the patients were eithar untreated or under occasional topical therapy, ` that was withheld as described for UNW tes~. Patients allergic to pollen were investigated outside the pollen season. ` 25 Methods:
Specific bronchial challenge was performed as reported in N Engl J Med 1989, 321:
1 069-1 073.
In a preliminary bronchial challsnge, the allergen (Frazioni Alfa, Dome/Hollister-30 Stier, Bayropharm Italiana, Milano, Italy) was administered by a dosimeter (MEFAR,Boveza, Italy). The apparatus was manually operated by the investigator and was set to deliver 3.7 ~I/puff in 0.6 seconds, with a pause of 6 seconds between puffs.
, The allergen was dissolved in normal saline at a concentration of 40 Activity Unit (AU) per ml for doses up ~o 2.4 AU (corresponding to a delivered close of 0.15 - AU/puff), or 160 AU/ml for doses up to 9.6 AU (0.6 AU/puf~, or 320 AU/ml (1.2 AU/puf~ for highsr doses. AU wera determined by the manufacturer using the 5 Radio Allergy Sorbant Test (RAST) inhibition assay compared with a referance preparation characterized by skin bioreactivity. FEV, and Peak ~xpiratory Flow Ra~e (PEFR) were measured using a dry spirometer (\/italograph, Buckingham, England) and a mini-Wright Peak Flow Meter (Clement Clarke International Ltd., London, England) before and 10 minutes after administration of a first dose of 0.15 AU. The 10 procedure was then repeated by doubling the allergen dose until a 25 % or greater decrease of FEVl from baseline was observed, or a maximum allergen dose of 19.2 AU was reached. The provocative dose of allergen causing a 25 % FEV, decrease (PD25) was then calculated by interpolation from the cumulative dose-response curve, plotted on semilogarithmic paper.
Study design: -The effect of pre-treatment with inhaled NSAID on the bronchial responses to allergen challenge was investigated in three different studies.
20 In a first study, the effect of pre-treatment with L-ASA on the immediate bronchial aller~ic response was investigated in a double blind, cross-over study compared to placebo, using a random-number table for randomization.
Clinical characteristics of the patients selected for the study according to the above criteria are listed in Table 1.
; 25 Each patient performed two bronchial challenges within an interval of 4 to 14 days, using a single dose of allergen corresponding to the PD2~ determined in the preliminary challenge. Bafore each test, the patients either received an aerosol with - 4 ml of L-ASA 180 mg/ml in saline, corresponding to 100 mg/ml of acetyl salicylic 30 acid (FlectadolR, Maggioni-Winthrop S.p.A., Milan, Italy) or a placebo (normal saline) in 15 minutes, given by means of a jet nebulizer (Mod. Soffio, Markos, Mon~a, Italy) set to an output of 0.27 ml/min. Immediately thereafter, the selected dose of : ' ' ' 3~
allergen was delivered by a dosimeter. Specific ainNay resistance (sRaw) was measured during normal breathing using a constant-volume body plethysmograph with a close~ bag system to condition air to BTPS (Fenyves & Gut, Basel, Switzerland before and af~er pretreatment, and at 5, 10, 15, 20, 30, 45 and 80 5 minutes after the challenge. These measurements were made at least in quintuplicate and the mean was computed. FEVl was obtained by intagration of flows rneasured with a No. 3 Fleisch pneumotachograph connected to the body plethysmogr~ph. The best value of the firs~ 3 technically sa~isfac~ory spirograms ; was chosen for analysis.
In four separate patients, with comparable clinical characteristics to tha previous group, the effect of the tvvo NSAlDs, indomethacin and ~enoxicam, on the immediate bronchial response to allergen was investigated. The stucly protocol was identical to the previous study, except that L-ASA was substituted by a solution of 15 either indomethacin 5 mg/ml or tenoxicam 2 mg/ml. The effect of indomethacin was tested in three, and tenoxicam in one subject.
To investigate the effect of pre-treatment with inhaled L-ASA on the late phase of the asthmatic reaction, two more patients presenting a dual asthmatic response to 20 the preliminary challenge and characterized by the occurrence of a second obstructive response after the resolution of the immediate response, between thefourth and the eighth hour after challenge were studied. The study was conducted- according to the previous protocol, except that respiratory function was rnonitored every 60 minutes up to eight hours after challenge.
Data analysis:
Data were expressed as absolute values or as a percentage of baseline values at time zero, i. e. after treatment with the active drug or placebo and immediatelybefore challenge.
Changes of UNW reactivity were measured as doubling doses of lJNW PD20 compared to placebo, and calculated as 1092 (PD20 after drug) - log2 (PD20 after placebo).
An increase of the PD20 by one doubling dose then corresponds to a 100 %
increase of the cumulative dose of nebulized water causing a 20 % FEV1 decrease.
The percentage protective effects on the specific asthmatic response for FEV1 and for sRaw were calculated for each patient according to the formula:
((AUC placebo - AUC treatment) / AUC placebo) x 100, where AUC is the area under the time-response curve of the absolute differences from baseline. All data were calculated without knowledge of the randomized treatment.
15 A two-way analysis of variance and a paired Student's test were used for statistical comparison of normally distributed variables, and the method of the least-significant j~ difference was used for multiple comparisons ( see Snedecor and Cochran, Statistical methods. 7th ed. Arnes, lowa University Press, 1980).
A level of p of less than 0.05 (two-tailed) was considsred significant.
RESULTS
Studies on non-specific bronchial reactivity:
The effect of pre-treatment with L~ASA on UNW-induced bronchoconstriction is shown in figure 1. The treatment was well tolerated, and no signiflcant changes of baseline respiratory function parameters were observed on tha different study days.
The bronchial response to UNW after trsatrnent with placebo was similar to the preliminary day. By contrast th~ UNW PD20 after inhaled L-ASA was markedly increased by 2.42 + 0.20 doub7ing doses (M + SE), and continued to be signHicantly increased compared to placebo even after 24 hours (1.33 ~ 0.16 doubling doses).
'~:
Indomethacin was also generally well tolerated when given by inhalation, and wasalso found to afford a si~nificant protection against UNW in asthmatics. In the group of 6 patients shown in figure 2, UNW PD20 rose by 1.2 0.23 doubling doses after treatment with indomethacin 5 mg/rnl. In three patients trçated withindomethacin 10 mg/ml th0 UNW PD20 rose ~ven higher reaching 3.14 + û.23 doubling doses (not shown).
In the pilot study both NSAIDS tenoxicam and katoprofen were also found ~o be suitable for administration by inhalstion to patients with asthma.
The effect of tenoxicam in two patients is shown in figures 3 and 4 in which theUNW test was conducted 20 minutes and 3 hours, respectively, after the inhalation of the drug. Similar results were obtained in a third patient. The effect of ketoprofen in one patient is also shown in figure 5.
In the group of 7 patients tenoxicam was also well tolerated when given by inhalation. The protective effects of tenoxicam are shown in Table V. The UNW
PD20 rose by less than 1 doubling dose resulting in a modest protection.
In ~he group of five patients ketoprofen was also generally well tolerated when given by inhalation. The protective effects are shown in Table Vl. The UNW PD20 rose by approximately 4 doubling doses. The taste of the solution was rath~r unpleasant. There was also a slight irritating effec~ of upper airways (larynx -trachea) after the inhalation of the aerosol. The protection on the average is good although highly variable among subjects.
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, 10 ~g ~ r?f~7 Studies on allergen chalienge:
In a first study the efFect of pr~-treatment with inhaled L-ASA on the bronchialresponses to allergen challenge was investigated in 6 patients. Baseline FEV, onthe study days rerrlained similar to those recorded during the preliminary challenge test. Values of FEV, and sRaw bsfor~ and immediately ~ftPr treatment on the study days were also not signiflcantly different. Af~er treatment with placebo, all the patients showed an immediate r~sponse which was characteriz~d by a maximum decrease in FE\J, of 24.5 + 2.3 % and a rnaximum increase in sRaw of 291 + 35 %
of baseline values ffig 6 and 7). A~er treatment with inhalad L-ASA, th~ bronchial response was markedly reduced, and the mean post-challenge FEV1 changes were significantly lower at every time point when compared with placebo ffigure 6). The effect on sRaw was somewhat less remarkable, probably due to the greater variability of the response. However, a remarkable difference was seen at 5 and 10 minutes compared to placebo (figurs 7). The maximum percentage decrease in FEV, and increase in sRaw (8.6 + 1.0 and 1~5 + 31 % of baseline, respectively) were also significantly smaller when as compared with placebo.
The protective activity of L-ASA on the immediate phase of the dual bronchial reaction, between 0 and 60 minutes, was 68 + 6 % when calculated from FEV1 changes, and 56 + 18 % when calculated from the changes of sRaw. None of ~he patients had clinical manifestations of a late asthmatic response after any of the :~ treatments.
The effect of pre-treatment with inhaled indomethacin on the early asthmatic response to allergen in a group of 3 patients is reported in figure 8. The drug provided a remarkable reduction of the intensity and the duration of the broncho-obstructive reaction. Maximum FEV, deerease in this group was 43 + 11 % aFter placebo and 17 + 5 % after indomethacin. The protection afforded by indomethacin, computed on FEV1 differences from baseline was 51 + 14 %. Also tenoxicam was effective in reclucing the early asthmatic reaction in one patient as shown in figure 9.
3~3~
None of the subjects included in the studies above had a late asthmatic reaction to allergen challenge. To evaluate the effect of inhaled NSAlDs on this phenomenon,two other patients showing a dual asthmatic reaction after the preliminary challenge were selected. The effect of pre-trea~ment with L-ASA or placebo on the allergen-induced reaction in these subjects is shown in figures 10 and 11. In both subjects the late phase of the reaction was markedly attenuated after treatment with inhaled L-ASA.
:
Discussion These data clearly show that these problems of high oral doses, resulting in systemic side-effeots, can be overcome by adminis~ration of NSAlDs by inhalation.
In fact, they indica~e that the inhalation of a variety of NSAlDs is able to inhibit the bronchial response to non-specific and specific bronchial stimuli in asthmatics. The inhalatory route is effective not only in reducing the side-effects in other organs which are bypassed by the topical treatment, but also in increasin~ th~ local activity of the drugs. The inhalatory route also takes advantage of a delayed drug metabolism, revealing the surprisingly long-lasting effect of inhaled L-ASA on UNW-induced bronchospasm ~figure 1).
; 20 It is also interesting to remark that the antireactive effect is not limited to ASA, but is also exerted by others NSAlDs, such as indomethacin, which affect cycloo~ygenasemetabolism by different mechanisms. It is particularly noteworthy that a significant inhibition of UNW- and allergen-induced responses was observed after inhalation of indomethacin, which in controlled studies has previously been shuwn to be ineffective on the bronchial response to lJNW (J Allergy Clin Immunol 1987, 79:503;
and J Allergy Clin Immunol 1987, 79:678-683) and to allergen challenge (J Appl Physiol 1989, 66:578-583; and Flev Respir Dis 1990, 141:1441-1445) after oral administration. Similarly, it is known that another anti-reactive drug, furosemide, is only effective on bronchial responses when given by inhalation and no~ systemically (Pulmonary Pharmacology 1989, 1:187-191). These data thus stress the importance of the inhalatory route in revealing the therapeutic success of these drugs.
`
~2 Finally, it is of particular interest that we have observed a good protec~ive effect of inhaled L-ASA also on the late phase of the asthrnatic response to allergen (figures 10 and 11).
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FIGURE LEGENDS
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Figure 1. Effect of inhaled L-ASA (100 mg/ml) on bronchial reactivity to UNW at 30' and 24 hrs after treatment. Data are expressed as M ~ SE of UNW PD20. (::linical : characteristics of the study ~roup are reported in table 1.
Figure 2. Effect of inhaled indomethacin (5 mg/ml) on bronchial reactivity to UNW, Clinical charactaristics of the study group are reported in table ll.
Figure 3. Effect of inhaled tenoxicam (2 mg/ml) on bronchial reactivity to UNW
15 maasured 20' after treatment in a patient with non-allergic asthma.
.~ Figure 4. Effect of inhaled tenoxicam (2 mglml) on bronchial reactivity to UNW
~` measured 3 hours after treatment in a patient with non-allergic asthrna.
' Figure 5. Effect of inhaled ketoprofen (10 mg/ml) on bronchial reactivity to UNWmeasured immediately after treatment in a patient with non-allergic asthma (Predieted FEV1 4.001).
' Figure 6. Time course of FEV, changes, expressed as percenta~e of post-treatmentvalue (tims 0), after specific allergen challenge. Bars represent mean and SE after inhalation of placebo (unfilled circles) and kASA (filled circles). Baseline valu~s (arrow) were 3.90 + 0.21 (M ~ SE) before placebo and 3.95 + 0.20 before L-ASA.
p < 0.05 compared to placebo at the same time point, paired t test.
.;
Figure 7. Time course of sRaw chan~es, expressed as percentage of post-;~ treatment value (time 0). Baselin~ sRaw were 0.32 + 0.32 kPa.s (M + SE) before placebo and û.35 ~ 0.01 befor~ L-ASA, respectively. Symbols as for flgure 6.
'' . , ~
., ;~r ~
Figure 8. Effect of the inhalation of indomethacin on the early asthmatic reaction to allergen challenge in a group of three allergic patients, measured as changes ofFEV,. Baseline F~V, in this group was 88 ~ 3 % of predicted.
5 Figure 9. Effect of the inhalation of tenoxicam on the early asthmatic reaction to allergen chalienge in a patient sensitive to grass pollen (FEV, predicted 4.01) measured as changes of FEV, (left) and ~Raw (right).
' Figure 10. Effect of inhaled L-ASA on the late asthmatic reaction to allergen challen0e in a patient sensitive to pol!en (predicted FEV, 3.491), measured as changes of FEV, (left) and sRaw (right).
,:
Figure 11. Eflect of inhaled L-ASA on the late asthmatic reaction to allergen challenge in an allerglc patient (predicted FEV, 3.371), measured as changes of 15 FEV, (left) and sRaw (right).
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'' Table 1. Effect of inhaled L-ASA on UNW-induced bronchial reactions.
(Patients' charactaristics) N. Sex Age FEV, ALLERGr Tl IERAPYb :. 5 litre %pred M 34 3.85 94 DP B2 + CS
2 M 24 3.18 78 - B2 3 F 39 2.47 98 - B2 + CS
Dascription:
5 Anti-reactive anti-asthmatic activity of non-steroidal anti-inflammatory drugs by inhalation Th0 invention relates to the use of non-steroidal anti-inflammatory drugs for thc production of an anti-rsactive anti-asthmatic drug to be administered by inhalation;
10 it relates also to non-steroidal anti-inflarnmatory drugs as meclicaments to be inhaled for combating and preventing asthma.
,' Bronchial inflammation plays a key role in the current views on the pathogeneticmechanisms of bronchial asthma (Am Rev Respir Dis 1987; 136:740-51~. Despite relatively large experimental evidence for the involvement of arachidonic acid metabolites in these mechanisms ( J Appl Physiol 1989, 66:578-583l, several previous attempts to influence the bronchial responses using anti-inflammatory drugs with cyclooxygenase inhibitory activity have failed to show a clinically significant and consistent effect of these drugs in asthma (J Aller~y Clin Immunol 1983, 71:245-249). One of the limiting factors of the effect of these drugs on bronchial responses might be a scarce availability of these drugs in the lung followin~ systemic administration. Indeed, a significant reduction of th~ bronchial response to ultrasonically nabulized water (UNW) in asthmatics a~ter oral administration of relatively high doses of aspirin was observed ( Progr~ss in Biochemical Pharmacology (Karger, Basel) 1985, 20:132-142.2, and Aller~ologie, deuxieme edition, J Charpin ed, Flammanion publ., Paris 1986, p 683-693, and Respiration 1988, 54(suppl 1):100-107).
Since a similar dose of the chemically related compound, sodium salicylate, which is devoid of inhibitory activity on cyclooxygenase, has no effect ( L~acetilsalicilato di lisina ma non il salicilato protegge dal broncospasmo da H20. Ill Conferenza .~ Italiana di Medicina Respiratoria, Milano 1990, Abstract book p 181), it can be concluded that cyclooxygenase inhibitors play a role in the therapeutic control of .. ~
'., ~ ' ' .
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, asthma, but relatively high doses have to be administered to afford a significant protective effect. Unfortunately, chronic treatment with such oral doses of NSAlDs causes an unacceptable rate of side effects, as indicated by two controlled studies available on the effect of treatment with high doses (1.3 to ~.6 g daily) of aspirin in asthmatics ( J Allergy Clin Immunol 1984, 73:500-507; and J Allergy Clin Immunoi1990, 85:59-65).
.: :
The aim of ~his invention was to make a breakthrough in the treatment of asthma with acceptable doses of a non-steroidal medicament.
This was accomplish~d by inhaling a non-steroidal anti-inflammatory drug (NSAID), preferably acetylsalicylic acid ~ASA), but also indomethacin, ke~oprofsn and tenoxicam.
Part of this invention is also a non-steroidal anti-inflammatory drug for application by inhalation in combating asthma, non-steroidal anti-inflammatory drugs of particular interest are acetylsalicylic acid, indomethacin, ketoprofen and tenoxicam.
The studies of this invention clearly show that inhaled NSAlDs, particularly Iysine-acetylsalicylate (L-ASA), the soluble form of ASA, induce a remarkable attenuation of the bronchial responses to both non-specific (UNW) and specific (immediate and late reactions to allergen) stimuli in asthmatics in the absence of side-effects.
Suitable pharmaceutical compositions for inhalation are aerosols with a particle size of from 0.5 ~m to 7 llm which enter the compar~ments of the lungs. Aqueous or aqueous-organic solutions or suspensions which can be nebuli7ed in combination with propelling agents, such as fluoro chloro hydrocarbons, fluorinated hydrocarbons, dimethyl ether, propane, butane, nitrogen, carbon dioxide, N2O, ormixtures of powders with microfine drugs, which can be administered using inhalers are particularly suitable. These pharmaceutical compositions may comprise appropriate additives, such as surface active substances, for instance ,:
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.;~ ,.
;' '." '' . ' . .
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phospholipids, sorbitane esters, polyoxy sorbitane esters, or oleic acids, alcohols and polyols such as ethanol, glycerol, poly ethylene glycol, gluc4ss, mannitoi, sorbitol, in order to improve their relevant pharmaceutical properties.
PATIENTS AND MErHODS
A) Studies on non-spaciflc bronchial hyperreactivity:
- Patients:
10 Clinically stable patients with either allergic or non-allergic asthma with a baseline forced expiratory volume at 1 second (FEVl) greater than 70 % of predicted, who were free of viral or bacterial respiratory infection for at Isast 4 wesks were studied.
None of the patients had a history of L-ASA induced asthma. All the patients were either treated with inhaled beta2-stimulants or with inhaled beta2-stimulants and topical steroids, that were withheld for 10 hours before administration of the test drug ( J Allergy Immunol 1975; 56:323-327).
Methods:
Bronchial reactivity to ultrasonically nebulized water (UNW~ was msasured as '~ ~ 20 previously described ( Eur J Respir Dis 1980 (suppl 106):~1-9; and Pulmonary Pharmacology 198~, 1:187-191). Each subject inhaled increasing doubling doses ofUNW produeed by an ultrasonic nebulizer (DeVilbiss Ultra-neb 99) set to an output of 2 ml/min. The subject~ were instructed to breath at tidal volume, keeping themouthpiece between their teeth with the mouth semi-opened. Doubling doses o~
UNW were administered by progressively increasin~ the time of exposure from 30"
(1 ml) to 240" (15 ml) and if necessary for further 240" setting the output to 4ml/min (31 ml3. Respiratory function was monitored after each dose, un~il a F~
decrease of 20 % or greater compared to baseline was observed. In the cases where specific airway resistance (sRaw) was measured, this was done during normal breathing using a constant-volume body plethysmograph with a closed bag system to condition air to body temperature pressure saturation (BTPS) (Fenyves &
Gut, Basel, Switzerland) before and after pretreatment, and immedia~ely after each .~
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. , ,,, ., ~ . , ,: .~ . ..
test. FEV, was measured usin~ a spirometer (Vitalograph). The best value of the nrst 3 technically satisfactory spirograms was chosen for analysis. The dose of UNW causing a 20 % FEV, decrease (PD20) was then calculated by interpolation on the curnulative doss-response curve.
Study design:
To test the effect of ~^ASA on UNW-induced bronchoconstriction, in a group of 7 subjects with a positive response to a preliminary UNW ehallenge, the test was repeated twice, with in~arvals of 3-7 days betwesn treatments which were either 5 ml of ~-ASA (18Q mg/ml in saline corresponding to 100 mg/ml of ASA) or placebo, according to a randomized protocol, by means of a nebulizer set to run to dryness in about 30'. The UNW challenge was repeated 3O' after treatment and once more the next day, 24 hours after ~reatment. The clinical characteristics of the patients in this group ara reported in table 1.
In a second group of 6 patients, whose clinical characteristics are reported in table ll, the effect of inhaled indomethacin was tested according to a protocol identical to the previous one, except that pre-treatment consisted of the inhalation 20 of either 5 ml of indomsthacin 5 mg/ml for 25' or the appropriate placebo and the fog challenge was not repeated 24 hours after treatment. The test was repeated athird time in three of these patients after pretreatment with a higher dose of indomethacin (5 ml at 10 mg/ml nebulized in 25'~.
25 In four separate patients, with comparable clinical characteristics to th0 previous group, ~he effect of the two NSAJDs, ketoprofen and tenoxicam, on the immediate bronchial response to UNW was investigated in a pilot study. This study protocolwas identical ~o the previous study, except that L-ASA was substituted by a solution of either ketoprofen 10 mg/ml or tenoxicam 2 mg/ml. The effect of tenoxicam was 30 tested in three, and ketoprofen in two subjects.
Additionally, in a third group of patients, whose clinical characteristics are reported ".
.. . . .
.
' :'. ; , 2~ 37 in Table lll, the effects of tenoxicam on the immediate bronchial response to IJNW
was investiga~ed in seven patients. The study protocol was identical to the previous ones except that 5 rnl of a 4 mg/ml solution was nebulized over a period of 30 minutes in this test.
In a fourth group of five patients, whose clinical characteristics are reported in Table IV, the effects of Ketoprofen was investigated on the imrnediate bronchialresponse to UNW. Again the same protocol was used as in the previous studies except that 7 ml of a 7.14 mg/ml solution was nebulized over a period of 40 10 minutes in this study. The test was performed 40 min~es after the end of nebulization.
B) Allergen specific bronchial challenge:
; 15 Patients:
~`: Volunteers with aller~ic asthma who had an early obstructive response after specific allergen bronchial challenge were recruited among patients attending an allergy clinic. All the patients had a clinical history of allergic asthma and/or rhinitis, showed a positive immediate skin reaction to the clinically relevant allergen, were 20 either asymptomatic or had very mild respiratory symptoms, had a baseline ~EV, over 70 % of predicted and had been free of respiratory infections for at least 4 weeks. All the patients were eithar untreated or under occasional topical therapy, ` that was withheld as described for UNW tes~. Patients allergic to pollen were investigated outside the pollen season. ` 25 Methods:
Specific bronchial challenge was performed as reported in N Engl J Med 1989, 321:
1 069-1 073.
In a preliminary bronchial challsnge, the allergen (Frazioni Alfa, Dome/Hollister-30 Stier, Bayropharm Italiana, Milano, Italy) was administered by a dosimeter (MEFAR,Boveza, Italy). The apparatus was manually operated by the investigator and was set to deliver 3.7 ~I/puff in 0.6 seconds, with a pause of 6 seconds between puffs.
, The allergen was dissolved in normal saline at a concentration of 40 Activity Unit (AU) per ml for doses up ~o 2.4 AU (corresponding to a delivered close of 0.15 - AU/puff), or 160 AU/ml for doses up to 9.6 AU (0.6 AU/puf~, or 320 AU/ml (1.2 AU/puf~ for highsr doses. AU wera determined by the manufacturer using the 5 Radio Allergy Sorbant Test (RAST) inhibition assay compared with a referance preparation characterized by skin bioreactivity. FEV, and Peak ~xpiratory Flow Ra~e (PEFR) were measured using a dry spirometer (\/italograph, Buckingham, England) and a mini-Wright Peak Flow Meter (Clement Clarke International Ltd., London, England) before and 10 minutes after administration of a first dose of 0.15 AU. The 10 procedure was then repeated by doubling the allergen dose until a 25 % or greater decrease of FEVl from baseline was observed, or a maximum allergen dose of 19.2 AU was reached. The provocative dose of allergen causing a 25 % FEV, decrease (PD25) was then calculated by interpolation from the cumulative dose-response curve, plotted on semilogarithmic paper.
Study design: -The effect of pre-treatment with inhaled NSAID on the bronchial responses to allergen challenge was investigated in three different studies.
20 In a first study, the effect of pre-treatment with L-ASA on the immediate bronchial aller~ic response was investigated in a double blind, cross-over study compared to placebo, using a random-number table for randomization.
Clinical characteristics of the patients selected for the study according to the above criteria are listed in Table 1.
; 25 Each patient performed two bronchial challenges within an interval of 4 to 14 days, using a single dose of allergen corresponding to the PD2~ determined in the preliminary challenge. Bafore each test, the patients either received an aerosol with - 4 ml of L-ASA 180 mg/ml in saline, corresponding to 100 mg/ml of acetyl salicylic 30 acid (FlectadolR, Maggioni-Winthrop S.p.A., Milan, Italy) or a placebo (normal saline) in 15 minutes, given by means of a jet nebulizer (Mod. Soffio, Markos, Mon~a, Italy) set to an output of 0.27 ml/min. Immediately thereafter, the selected dose of : ' ' ' 3~
allergen was delivered by a dosimeter. Specific ainNay resistance (sRaw) was measured during normal breathing using a constant-volume body plethysmograph with a close~ bag system to condition air to BTPS (Fenyves & Gut, Basel, Switzerland before and af~er pretreatment, and at 5, 10, 15, 20, 30, 45 and 80 5 minutes after the challenge. These measurements were made at least in quintuplicate and the mean was computed. FEVl was obtained by intagration of flows rneasured with a No. 3 Fleisch pneumotachograph connected to the body plethysmogr~ph. The best value of the firs~ 3 technically sa~isfac~ory spirograms ; was chosen for analysis.
In four separate patients, with comparable clinical characteristics to tha previous group, the effect of the tvvo NSAlDs, indomethacin and ~enoxicam, on the immediate bronchial response to allergen was investigated. The stucly protocol was identical to the previous study, except that L-ASA was substituted by a solution of 15 either indomethacin 5 mg/ml or tenoxicam 2 mg/ml. The effect of indomethacin was tested in three, and tenoxicam in one subject.
To investigate the effect of pre-treatment with inhaled L-ASA on the late phase of the asthmatic reaction, two more patients presenting a dual asthmatic response to 20 the preliminary challenge and characterized by the occurrence of a second obstructive response after the resolution of the immediate response, between thefourth and the eighth hour after challenge were studied. The study was conducted- according to the previous protocol, except that respiratory function was rnonitored every 60 minutes up to eight hours after challenge.
Data analysis:
Data were expressed as absolute values or as a percentage of baseline values at time zero, i. e. after treatment with the active drug or placebo and immediatelybefore challenge.
Changes of UNW reactivity were measured as doubling doses of lJNW PD20 compared to placebo, and calculated as 1092 (PD20 after drug) - log2 (PD20 after placebo).
An increase of the PD20 by one doubling dose then corresponds to a 100 %
increase of the cumulative dose of nebulized water causing a 20 % FEV1 decrease.
The percentage protective effects on the specific asthmatic response for FEV1 and for sRaw were calculated for each patient according to the formula:
((AUC placebo - AUC treatment) / AUC placebo) x 100, where AUC is the area under the time-response curve of the absolute differences from baseline. All data were calculated without knowledge of the randomized treatment.
15 A two-way analysis of variance and a paired Student's test were used for statistical comparison of normally distributed variables, and the method of the least-significant j~ difference was used for multiple comparisons ( see Snedecor and Cochran, Statistical methods. 7th ed. Arnes, lowa University Press, 1980).
A level of p of less than 0.05 (two-tailed) was considsred significant.
RESULTS
Studies on non-specific bronchial reactivity:
The effect of pre-treatment with L~ASA on UNW-induced bronchoconstriction is shown in figure 1. The treatment was well tolerated, and no signiflcant changes of baseline respiratory function parameters were observed on tha different study days.
The bronchial response to UNW after trsatrnent with placebo was similar to the preliminary day. By contrast th~ UNW PD20 after inhaled L-ASA was markedly increased by 2.42 + 0.20 doub7ing doses (M + SE), and continued to be signHicantly increased compared to placebo even after 24 hours (1.33 ~ 0.16 doubling doses).
'~:
Indomethacin was also generally well tolerated when given by inhalation, and wasalso found to afford a si~nificant protection against UNW in asthmatics. In the group of 6 patients shown in figure 2, UNW PD20 rose by 1.2 0.23 doubling doses after treatment with indomethacin 5 mg/rnl. In three patients trçated withindomethacin 10 mg/ml th0 UNW PD20 rose ~ven higher reaching 3.14 + û.23 doubling doses (not shown).
In the pilot study both NSAIDS tenoxicam and katoprofen were also found ~o be suitable for administration by inhalstion to patients with asthma.
The effect of tenoxicam in two patients is shown in figures 3 and 4 in which theUNW test was conducted 20 minutes and 3 hours, respectively, after the inhalation of the drug. Similar results were obtained in a third patient. The effect of ketoprofen in one patient is also shown in figure 5.
In the group of 7 patients tenoxicam was also well tolerated when given by inhalation. The protective effects of tenoxicam are shown in Table V. The UNW
PD20 rose by less than 1 doubling dose resulting in a modest protection.
In ~he group of five patients ketoprofen was also generally well tolerated when given by inhalation. The protective effects are shown in Table Vl. The UNW PD20 rose by approximately 4 doubling doses. The taste of the solution was rath~r unpleasant. There was also a slight irritating effec~ of upper airways (larynx -trachea) after the inhalation of the aerosol. The protection on the average is good although highly variable among subjects.
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, 10 ~g ~ r?f~7 Studies on allergen chalienge:
In a first study the efFect of pr~-treatment with inhaled L-ASA on the bronchialresponses to allergen challenge was investigated in 6 patients. Baseline FEV, onthe study days rerrlained similar to those recorded during the preliminary challenge test. Values of FEV, and sRaw bsfor~ and immediately ~ftPr treatment on the study days were also not signiflcantly different. Af~er treatment with placebo, all the patients showed an immediate r~sponse which was characteriz~d by a maximum decrease in FE\J, of 24.5 + 2.3 % and a rnaximum increase in sRaw of 291 + 35 %
of baseline values ffig 6 and 7). A~er treatment with inhalad L-ASA, th~ bronchial response was markedly reduced, and the mean post-challenge FEV1 changes were significantly lower at every time point when compared with placebo ffigure 6). The effect on sRaw was somewhat less remarkable, probably due to the greater variability of the response. However, a remarkable difference was seen at 5 and 10 minutes compared to placebo (figurs 7). The maximum percentage decrease in FEV, and increase in sRaw (8.6 + 1.0 and 1~5 + 31 % of baseline, respectively) were also significantly smaller when as compared with placebo.
The protective activity of L-ASA on the immediate phase of the dual bronchial reaction, between 0 and 60 minutes, was 68 + 6 % when calculated from FEV1 changes, and 56 + 18 % when calculated from the changes of sRaw. None of ~he patients had clinical manifestations of a late asthmatic response after any of the :~ treatments.
The effect of pre-treatment with inhaled indomethacin on the early asthmatic response to allergen in a group of 3 patients is reported in figure 8. The drug provided a remarkable reduction of the intensity and the duration of the broncho-obstructive reaction. Maximum FEV, deerease in this group was 43 + 11 % aFter placebo and 17 + 5 % after indomethacin. The protection afforded by indomethacin, computed on FEV1 differences from baseline was 51 + 14 %. Also tenoxicam was effective in reclucing the early asthmatic reaction in one patient as shown in figure 9.
3~3~
None of the subjects included in the studies above had a late asthmatic reaction to allergen challenge. To evaluate the effect of inhaled NSAlDs on this phenomenon,two other patients showing a dual asthmatic reaction after the preliminary challenge were selected. The effect of pre-trea~ment with L-ASA or placebo on the allergen-induced reaction in these subjects is shown in figures 10 and 11. In both subjects the late phase of the reaction was markedly attenuated after treatment with inhaled L-ASA.
:
Discussion These data clearly show that these problems of high oral doses, resulting in systemic side-effeots, can be overcome by adminis~ration of NSAlDs by inhalation.
In fact, they indica~e that the inhalation of a variety of NSAlDs is able to inhibit the bronchial response to non-specific and specific bronchial stimuli in asthmatics. The inhalatory route is effective not only in reducing the side-effects in other organs which are bypassed by the topical treatment, but also in increasin~ th~ local activity of the drugs. The inhalatory route also takes advantage of a delayed drug metabolism, revealing the surprisingly long-lasting effect of inhaled L-ASA on UNW-induced bronchospasm ~figure 1).
; 20 It is also interesting to remark that the antireactive effect is not limited to ASA, but is also exerted by others NSAlDs, such as indomethacin, which affect cycloo~ygenasemetabolism by different mechanisms. It is particularly noteworthy that a significant inhibition of UNW- and allergen-induced responses was observed after inhalation of indomethacin, which in controlled studies has previously been shuwn to be ineffective on the bronchial response to lJNW (J Allergy Clin Immunol 1987, 79:503;
and J Allergy Clin Immunol 1987, 79:678-683) and to allergen challenge (J Appl Physiol 1989, 66:578-583; and Flev Respir Dis 1990, 141:1441-1445) after oral administration. Similarly, it is known that another anti-reactive drug, furosemide, is only effective on bronchial responses when given by inhalation and no~ systemically (Pulmonary Pharmacology 1989, 1:187-191). These data thus stress the importance of the inhalatory route in revealing the therapeutic success of these drugs.
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~2 Finally, it is of particular interest that we have observed a good protec~ive effect of inhaled L-ASA also on the late phase of the asthrnatic response to allergen (figures 10 and 11).
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FIGURE LEGENDS
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Figure 1. Effect of inhaled L-ASA (100 mg/ml) on bronchial reactivity to UNW at 30' and 24 hrs after treatment. Data are expressed as M ~ SE of UNW PD20. (::linical : characteristics of the study ~roup are reported in table 1.
Figure 2. Effect of inhaled indomethacin (5 mg/ml) on bronchial reactivity to UNW, Clinical charactaristics of the study group are reported in table ll.
Figure 3. Effect of inhaled tenoxicam (2 mg/ml) on bronchial reactivity to UNW
15 maasured 20' after treatment in a patient with non-allergic asthma.
.~ Figure 4. Effect of inhaled tenoxicam (2 mglml) on bronchial reactivity to UNW
~` measured 3 hours after treatment in a patient with non-allergic asthrna.
' Figure 5. Effect of inhaled ketoprofen (10 mg/ml) on bronchial reactivity to UNWmeasured immediately after treatment in a patient with non-allergic asthma (Predieted FEV1 4.001).
' Figure 6. Time course of FEV, changes, expressed as percenta~e of post-treatmentvalue (tims 0), after specific allergen challenge. Bars represent mean and SE after inhalation of placebo (unfilled circles) and kASA (filled circles). Baseline valu~s (arrow) were 3.90 + 0.21 (M ~ SE) before placebo and 3.95 + 0.20 before L-ASA.
p < 0.05 compared to placebo at the same time point, paired t test.
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Figure 7. Time course of sRaw chan~es, expressed as percentage of post-;~ treatment value (time 0). Baselin~ sRaw were 0.32 + 0.32 kPa.s (M + SE) before placebo and û.35 ~ 0.01 befor~ L-ASA, respectively. Symbols as for flgure 6.
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Figure 8. Effect of the inhalation of indomethacin on the early asthmatic reaction to allergen challenge in a group of three allergic patients, measured as changes ofFEV,. Baseline F~V, in this group was 88 ~ 3 % of predicted.
5 Figure 9. Effect of the inhalation of tenoxicam on the early asthmatic reaction to allergen chalienge in a patient sensitive to grass pollen (FEV, predicted 4.01) measured as changes of FEV, (left) and ~Raw (right).
' Figure 10. Effect of inhaled L-ASA on the late asthmatic reaction to allergen challen0e in a patient sensitive to pol!en (predicted FEV, 3.491), measured as changes of FEV, (left) and sRaw (right).
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Figure 11. Eflect of inhaled L-ASA on the late asthmatic reaction to allergen challenge in an allerglc patient (predicted FEV, 3.371), measured as changes of 15 FEV, (left) and sRaw (right).
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'' Table 1. Effect of inhaled L-ASA on UNW-induced bronchial reactions.
(Patients' charactaristics) N. Sex Age FEV, ALLERGr Tl IERAPYb :. 5 litre %pred M 34 3.85 94 DP B2 + CS
2 M 24 3.18 78 - B2 3 F 39 2.47 98 - B2 + CS
4 F 19 3.08 100 GR B2 ;~ 10 5 F 35 2.10 . 75 - B2 + C;S :
6 F 40 2.32 90 GR B2 7 M 18 3.29 81 - B2 a) DP: Dermatophagoides, GP~: Grass pollen 15 b) B2: inhaled beta2-agonist, CS: inhaled steroids ., , ~ Tabl~ ll. Effect of inhaled indomethacin on UNW-induced bronchial raactions.
(Patients' characteristics) N. Sex Age FEV, ALLERGY~ THERAPYb iitre %pred .~ 1 F 60 2.12 87 - B2 + CS
. .
2 M 20 3.95 101 DP B2 - 25 3 F 40 2.15 84 - B2 ~ 4 M 25 3.33 85 - B2 + CS
M 20 4.04 98 - B2 ~ CS
6 F 18 2.55 B8 GR B2 ~ CS
~' 30 a~ DP: Dermatophagoides, GR: Grass pollen ~:: b) B2: inhaled beta2-agonist, CS: inhaled steroids Table lll. Effect of inhaled tenoxicam cn UNW-induced bronchiai reactions (Patients characteristics) N. Sex Age FEV, ATOPY THERAPYb litre %pred M 25 3.32 83.5 - B2 + CS
2 M 43 3.50 110 GR B2 + CS
3 M 18 5.0 111 GR B2 ~ CS
4 M 35 3.66 88.5 - B2 + CS
F 42 2.60 101 - B2 + CS
B M 19 4.13 101 GR B2 ~ CS
.: 7 F 60 3.20 92 - B2 + CS
.
~ a) DP: Dermatophagoides, GR: Grass pollen 15 b) B2: inhaled beta2-agonist, CS: inhaled steroids ., Table IV. Effect of inhaled ketopro~en on UNW-induced bronchial reactions 20 (Patients characteristics~
N. Sex Age FEV1 ATOPY THERAPY~
litre %pred 1 M 25 83.5 - B2 + CS
2 M 20 90 GR B2 ~ CS
3 M 45 98 B2 ~ CS
4 F 61 90.6 - B2 + CS
:~ 5 M 42 114 GR B2 + CS
`' .l 30 a) DP: Dermatophagoides, GR: Grass pollen b) B2: inhaled beta2-agonist, CS: inhaled steroids .
' ... ; ' `
Table V Tenoxicarn UNW PD20 ~ml) , ~ . ~ -- _ Preliminary Placebo Tenoxicam ¦ . _ . 5 ml - 4 mg/ml ¦ 1 3.7 3.5 6 2 8.2 8.0 15 ¦ ~ 1.5 _ 4 25 _ -- 40 0 16 3.0 6.75 6.25 7 --- -- . . .. 4.8 6.0 7.7 _ _ x 4.9 4.75 7.85 SD Z.4 2.25 3.4 , , . . .
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17 ~ 7 Table Vl Ketoprofen UNW PD2û (ml) :~' _ . . _ _--Preliminary Placebo Ketoprofen . ~ ml - 7.14 _ ~ _ mg/ml . ¦ 1 2.5 59 (PD 15) 2 4.5 7.5 23 I . _ _ 3 ~.2 6.2 59 , ~ - ~
4 4.0 ~.8 1 0 1 5 _ 2.8 . 2.5 6 ¦ . 4.0 4.9 31.4 I . _ 1.48 2.0 . --.:
:' ,~" '.
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6 F 40 2.32 90 GR B2 7 M 18 3.29 81 - B2 a) DP: Dermatophagoides, GP~: Grass pollen 15 b) B2: inhaled beta2-agonist, CS: inhaled steroids ., , ~ Tabl~ ll. Effect of inhaled indomethacin on UNW-induced bronchial raactions.
(Patients' characteristics) N. Sex Age FEV, ALLERGY~ THERAPYb iitre %pred .~ 1 F 60 2.12 87 - B2 + CS
. .
2 M 20 3.95 101 DP B2 - 25 3 F 40 2.15 84 - B2 ~ 4 M 25 3.33 85 - B2 + CS
M 20 4.04 98 - B2 ~ CS
6 F 18 2.55 B8 GR B2 ~ CS
~' 30 a~ DP: Dermatophagoides, GR: Grass pollen ~:: b) B2: inhaled beta2-agonist, CS: inhaled steroids Table lll. Effect of inhaled tenoxicam cn UNW-induced bronchiai reactions (Patients characteristics) N. Sex Age FEV, ATOPY THERAPYb litre %pred M 25 3.32 83.5 - B2 + CS
2 M 43 3.50 110 GR B2 + CS
3 M 18 5.0 111 GR B2 ~ CS
4 M 35 3.66 88.5 - B2 + CS
F 42 2.60 101 - B2 + CS
B M 19 4.13 101 GR B2 ~ CS
.: 7 F 60 3.20 92 - B2 + CS
.
~ a) DP: Dermatophagoides, GR: Grass pollen 15 b) B2: inhaled beta2-agonist, CS: inhaled steroids ., Table IV. Effect of inhaled ketopro~en on UNW-induced bronchial reactions 20 (Patients characteristics~
N. Sex Age FEV1 ATOPY THERAPY~
litre %pred 1 M 25 83.5 - B2 + CS
2 M 20 90 GR B2 ~ CS
3 M 45 98 B2 ~ CS
4 F 61 90.6 - B2 + CS
:~ 5 M 42 114 GR B2 + CS
`' .l 30 a) DP: Dermatophagoides, GR: Grass pollen b) B2: inhaled beta2-agonist, CS: inhaled steroids .
' ... ; ' `
Table V Tenoxicarn UNW PD20 ~ml) , ~ . ~ -- _ Preliminary Placebo Tenoxicam ¦ . _ . 5 ml - 4 mg/ml ¦ 1 3.7 3.5 6 2 8.2 8.0 15 ¦ ~ 1.5 _ 4 25 _ -- 40 0 16 3.0 6.75 6.25 7 --- -- . . .. 4.8 6.0 7.7 _ _ x 4.9 4.75 7.85 SD Z.4 2.25 3.4 , , . . .
` ' .
17 ~ 7 Table Vl Ketoprofen UNW PD2û (ml) :~' _ . . _ _--Preliminary Placebo Ketoprofen . ~ ml - 7.14 _ ~ _ mg/ml . ¦ 1 2.5 59 (PD 15) 2 4.5 7.5 23 I . _ _ 3 ~.2 6.2 59 , ~ - ~
4 4.0 ~.8 1 0 1 5 _ 2.8 . 2.5 6 ¦ . 4.0 4.9 31.4 I . _ 1.48 2.0 . --.:
:' ,~" '.
. , . ,
Claims (10)
1. Use of a non-steroidal anti-inflammatory drug for the preparation of a medicament to be inhaled for the treatment of asthma.
2. Use according to claim 1 wherein the non-steroidal anti-inflammatory drug is acetylsalicylic acid.
3. Use according to claim 1 wherein the non-steroidal anti-inflammatory drug is indomethacin.
4. Use according to claim 1 wherein the non-steroidal anti-inflammatory drug is ketoprofen.
5. Use according to claim 1 wherein the non-steroidal anti-inflammatory drug is tenoxicam.
6. A non-steroidal anti-inflammatory drug for application by inhalation in combating asthma.
7. A non-steroidal anti-inflammatory drug as claimed in claim 6 which is acetylsalicylic acid.
8. A non-steroidal anti-inflammatory drug as claimed in claim 6 which is indomethacin.
9. A non-steroidal anti-inflammatory drug as claimed in claim 6 which is ketoprofen.
10. A non-steroidal anti-inflammatory drug as claimed in claim 6 which is tenoxicam.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP91101818.2 | 1991-02-09 | ||
| EP91101818 | 1991-02-09 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2060937A1 true CA2060937A1 (en) | 1992-08-10 |
Family
ID=8206393
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002060937A Abandoned CA2060937A1 (en) | 1991-02-09 | 1992-02-10 | Anti-reactive anti-asthmatic activity of non-steroidal anti-inflammatory drugs by inhalation |
Country Status (16)
| Country | Link |
|---|---|
| US (1) | US6051566A (en) |
| JP (1) | JPH0648958A (en) |
| KR (1) | KR920016086A (en) |
| AT (1) | ATE179605T1 (en) |
| AU (1) | AU662509B2 (en) |
| BR (1) | BR9200429A (en) |
| CA (1) | CA2060937A1 (en) |
| CZ (1) | CZ281970B6 (en) |
| DE (1) | DE69229070T2 (en) |
| HU (1) | HUT60917A (en) |
| IE (1) | IE920427A1 (en) |
| IL (1) | IL100896A (en) |
| MX (1) | MX9200571A (en) |
| NO (1) | NO179893C (en) |
| NZ (1) | NZ241542A (en) |
| ZA (1) | ZA92890B (en) |
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| US6759029B2 (en) * | 2001-05-24 | 2004-07-06 | Alexza Molecular Delivery Corporation | Delivery of rizatriptan and zolmitriptan through an inhalation route |
| US7458374B2 (en) | 2002-05-13 | 2008-12-02 | Alexza Pharmaceuticals, Inc. | Method and apparatus for vaporizing a compound |
| DE60230609D1 (en) * | 2001-05-24 | 2009-02-12 | Alexza Pharmaceuticals Inc | ADMINISTRATION OF NON-TEROIDAL INFLAMMATION OF INHALATION OF ACTIVE SUBSTANCES |
| US20070122353A1 (en) | 2001-05-24 | 2007-05-31 | Hale Ron L | Drug condensation aerosols and kits |
| JP2005503425A (en) | 2001-05-24 | 2005-02-03 | アレックザ モレキュラー デリヴァリー コーポレイション | Delivery of drug ester by the prescribed inhalation route |
| EP1392258B1 (en) * | 2001-05-24 | 2008-11-26 | Alexza Pharmaceuticals, Inc. | Delivery of alprazolam, estazolam, midazolam or triazolam through an inhalation route |
| US7645442B2 (en) | 2001-05-24 | 2010-01-12 | Alexza Pharmaceuticals, Inc. | Rapid-heating drug delivery article and method of use |
| US6805853B2 (en) * | 2001-11-09 | 2004-10-19 | Alexza Molecular Delivery Corporation | Delivery of diazepam through an inhalation route |
| US20030051728A1 (en) | 2001-06-05 | 2003-03-20 | Lloyd Peter M. | Method and device for delivering a physiologically active compound |
| US7498019B2 (en) | 2001-05-24 | 2009-03-03 | Alexza Pharmaceuticals, Inc. | Delivery of compounds for the treatment of headache through an inhalation route |
| WO2003043570A2 (en) | 2001-11-15 | 2003-05-30 | Galileo Laboratories, Inc. | Formulations and methods for treatment or amelioration of inflammatory conditions |
| AU2002363947A1 (en) * | 2001-11-21 | 2003-07-24 | Alexza Molecular Delivery Corporation | Delivery of caffeine through an inhalation route |
| JP2005514393A (en) | 2001-12-19 | 2005-05-19 | ネクター セラピューティクス | Supplying aminoglycosides to the lung |
| WO2003094900A1 (en) | 2002-05-13 | 2003-11-20 | Alexza Molecular Delivery Corporation | Delivery of drug amines through an inhalation route |
| US20060193788A1 (en) * | 2002-11-26 | 2006-08-31 | Hale Ron L | Acute treatment of headache with phenothiazine antipsychotics |
| US7550133B2 (en) * | 2002-11-26 | 2009-06-23 | Alexza Pharmaceuticals, Inc. | Respiratory drug condensation aerosols and methods of making and using them |
| JP2006514633A (en) * | 2002-11-26 | 2006-05-11 | アレックザ ファーマシューティカルズ， インコーポレイテッド | Treatment of headache with antipsychotics delivered by inhalation |
| US20040105818A1 (en) | 2002-11-26 | 2004-06-03 | Alexza Molecular Delivery Corporation | Diuretic aerosols and methods of making and using them |
| AU2003294470B2 (en) * | 2002-11-26 | 2009-09-17 | Alexza Pharmaceuticals, Inc. | Use of loxapine and amoxapine for the manufacture of a medicament for the treatment of pain |
| US7913688B2 (en) | 2002-11-27 | 2011-03-29 | Alexza Pharmaceuticals, Inc. | Inhalation device for producing a drug aerosol |
| WO2004104490A1 (en) | 2003-05-21 | 2004-12-02 | Alexza Pharmaceuticals, Inc. | Self-contained heating unit and drug-supply unit employing same |
| US7540286B2 (en) | 2004-06-03 | 2009-06-02 | Alexza Pharmaceuticals, Inc. | Multiple dose condensation aerosol devices and methods of forming condensation aerosols |
| US8455437B2 (en) * | 2005-02-04 | 2013-06-04 | The United States Of America, As Represented By The Secretary Of The Department Of Health And Human Services | Method to predict and prevent oxygen-induced inflammatory tissue injury |
| ITMI20050417A1 (en) * | 2005-03-15 | 2006-09-16 | Medestea Res & Production S R L | USE OF NON-STEROID ANTI-INFLAMMATORY DRUGS BY INHALATION IN THE THERAPY OF ACUTE AND CHRONIC BRONCHITIS |
| CA2641616A1 (en) * | 2006-02-09 | 2007-08-23 | Schering Corporation | Pharmaceutical formulations |
| JP5094197B2 (en) * | 2006-04-27 | 2012-12-12 | 第一三共ヘルスケア株式会社 | Pharmaceutical composition containing antihistamine for suppressing goblet cell hyperplasia |
| EP2121088B1 (en) | 2007-03-09 | 2016-07-13 | Alexza Pharmaceuticals, Inc. | Heating unit for use in a drug delivery device |
| DE102008004386A1 (en) * | 2008-01-14 | 2009-07-23 | Activaero Gmbh | Use of an acetylsalicylic acid salt for the treatment of viral infections |
| WO2009134917A2 (en) * | 2008-04-29 | 2009-11-05 | Wyeth | Methods for treating inflammation |
| KR101704815B1 (en) * | 2009-08-21 | 2017-02-09 | 포항공과대학교 산학협력단 | Combination preparation for treating IL-17 mediated inflammatory diseases and the treatment method using the same |
| US20130281405A1 (en) * | 2012-04-02 | 2013-10-24 | Lenard M. Lichtenberger | Use of pc-nsaids to treat and/or prevent pulmonary inflammation |
| US9757395B2 (en) | 2012-12-20 | 2017-09-12 | Otitopic Inc. | Dry powder inhaler and methods of use |
| CN105473133A (en) | 2013-04-30 | 2016-04-06 | 欧缇托匹克公司 | Dry powder formulations and methods of use |
| TWI586383B (en) * | 2014-04-18 | 2017-06-11 | 林信湧 | Inhalation-type pharmaceutical composition for arthritis and preparation method thereof |
| EP3191091B1 (en) | 2014-09-12 | 2020-08-26 | Children's Medical Center Corporation | Dietary emulsion formulations and methods for using the same |
| WO2016196401A1 (en) * | 2015-05-29 | 2016-12-08 | The Texas A&M University System | Antimicrobial and anti-inflammatory compositions |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US5244899A (en) * | 1985-02-04 | 1993-09-14 | G. D. Searle And Co. | Azabicycloalkyl and azatricycloalkyl amides used to treat inflammation, allergy, asthma and skin disorders |
| US4885287A (en) * | 1988-08-09 | 1989-12-05 | University Of Kentucky Research Foundation | Novel method of administering aspirin and dosage forms containing same |
-
1992
- 1992-02-06 AT AT92101977T patent/ATE179605T1/en not_active IP Right Cessation
- 1992-02-06 DE DE69229070T patent/DE69229070T2/en not_active Expired - Lifetime
- 1992-02-07 IE IE042792A patent/IE920427A1/en unknown
- 1992-02-07 HU HU9200389A patent/HUT60917A/en unknown
- 1992-02-07 NZ NZ241542A patent/NZ241542A/en unknown
- 1992-02-07 CZ CS92352A patent/CZ281970B6/en unknown
- 1992-02-07 KR KR1019920001737A patent/KR920016086A/en not_active Application Discontinuation
- 1992-02-07 IL IL100896A patent/IL100896A/en not_active IP Right Cessation
- 1992-02-07 NO NO920504A patent/NO179893C/en unknown
- 1992-02-07 AU AU10772/92A patent/AU662509B2/en not_active Ceased
- 1992-02-07 ZA ZA92890A patent/ZA92890B/en unknown
- 1992-02-07 BR BR929200429A patent/BR9200429A/en not_active Application Discontinuation
- 1992-02-07 JP JP4056158A patent/JPH0648958A/en active Pending
- 1992-02-10 CA CA002060937A patent/CA2060937A1/en not_active Abandoned
- 1992-02-10 MX MX9200571A patent/MX9200571A/en unknown
-
1998
- 1998-03-02 US US09/032,973 patent/US6051566A/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| ATE179605T1 (en) | 1999-05-15 |
| IE920427A1 (en) | 1992-08-12 |
| NO179893B (en) | 1996-09-30 |
| HU9200389D0 (en) | 1992-04-28 |
| NO920504D0 (en) | 1992-02-07 |
| IL100896A (en) | 1998-02-22 |
| BR9200429A (en) | 1992-10-13 |
| DE69229070T2 (en) | 1999-11-18 |
| CZ281970B6 (en) | 1997-04-16 |
| NZ241542A (en) | 1996-05-28 |
| DE69229070D1 (en) | 1999-06-10 |
| AU1077292A (en) | 1992-08-13 |
| JPH0648958A (en) | 1994-02-22 |
| AU662509B2 (en) | 1995-09-07 |
| CS35292A3 (en) | 1992-08-12 |
| US6051566A (en) | 2000-04-18 |
| KR920016086A (en) | 1992-09-24 |
| ZA92890B (en) | 1992-12-30 |
| IL100896A0 (en) | 1992-11-15 |
| NO920504L (en) | 1992-08-10 |
| NO179893C (en) | 1997-01-08 |
| HUT60917A (en) | 1992-11-30 |
| MX9200571A (en) | 1992-12-01 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |