JP3121827B2 - Diagnostic agent for bronchoconstrictive lung disease containing adenosine or its phosphorylated derivative as active ingredient - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a diagnostic agent for bronchoconstrictive pulmonary disease containing adenosine or a phosphorylated derivative thereof as an active ingredient.

2. Description of the Prior Art Asthma is a syndrome characterized by acute or subacute seizures such as lack of breathing (dyspnea), gasping, and often coughing and sputum formation, resulting in airway narrowing (bronchospasm). , And as a result of increased secretion. Pathologies of asthma include increased airway resistance, increased functional residual volume and total lung volume, uneven ventilation, arterial hypoxia due to local ventilation or perfusion abnormalities, and arterial blood PCO. Hyperventilation of the alveoli may occur, with reduction of ₂ and respiratory acidosis.

In the case of an acute attack, the diagnosis is confirmed by using a pulmonary function test, although the typical symptoms do not appear well. Spirometry can be used to demonstrate a decrease in forced expiratory volume (FEV ₁ ) per second, and volume change recording can be used to demonstrate a decrease in specific airway conductance (SGaw) . During the asymptomatic period or if the lung function test is negative, bronchoconstriction can be induced by a pharmacological method (provocation test) to confirm the diagnosis.
In such a situation, the patient undergoes an aggressive test with methacholine, a type of parasympathetic stimulant that is aerosolized (sprayed) and inhaled in gradually increasing doses. It is. Pulmonary function tests are repeated at each dose step until abnormalities are detected or the maximum dose is reached. Although methacholine is the only pharmacological stimulant approved by the US Food and Drug Administration for the diagnosis of asthma, it is a very nonspecific bronchoconstrictor and its diagnostic value is relatively low. Low.

The pathogenesis of asthma has not been clearly elucidated. However, acute paroxysmal episodes are partially due to mast cell degranulation and bronchoconstrictor factors.
For example, it is presumed that the release of histamine, serotonin, and adenosine is mediated. The bronchoconstrictive activity of adenosine and its potential role in the pathophysiology of constrictive airway disease was first reported by Cushley and his colleagues [British Journal of Clinical Pharmacology ( Brit.J.Cli
n. Pharmacol.), Volume 15 (1983), pp. 161-165].

According to the researchers, inhalation of adenosine proves to significantly reduce specific airway conductance in both allergic asthmatics (n = 6) and non-allergic asthmatics (n = 7). Is done. The average dose of adenosine (PC ₄₀ ) required to lower SGaw by 40% from baseline is
0.86 mg / ml and 1.9 mg / ml in both groups, respectively. In normal volunteers, there was no change in specific airway conductance, even with inhalation of adenosine at amounts up to 6.7 mg / ml.

Subsequently, the same study group (South Hampton University, South Hampton, UK and General Hospital) published several papers on adenosine-induced bronchoconstriction in asthma [British Journal of Clinical. Pharmacology,
Volume 19 (1985) pp. 685-692; American Reviews in Respiratory Diseases (Am. Rev. Res.
pir. Disease, 132 (1985), pp. 1-6; Journal of Allergy and Clinical Immunology (J. Allergy Clin. Immunol.), Vol. 61 (1)
986) 1,667-1,676 pages]. In summary, such a research trajectory seeks to determine the role of adenosine in the pathophysiology of asthma. The researchers show that adenosine-induced bronchoconstriction can be inhibited by the direct acting adenosine antagonist, theophylline, as well as by the mast cell stabilizing compound, cromolyn sodium. . Furthermore,
Their data indicate that cholinergic reflexes in the airways, or reduced adrenergic β-ergic responsiveness, are not mediated by bronchoconstriction. An updated summary of these studies [STHolgate et al .: E. Gelrach and Becker (BFBecker), eds., "Topics and Perspectives
in Adenosine Research, Berlin and Heidelberg, Germany, Springer Verlag, 1987, pp. 614-624], they conclude:

"Adenosine is a selective antagonist of bronchoconstrictors in patients with asthma. This nucleoside transmits its action through amplification of ongoing degranulation, but is newly generated from activated bronchial mast cells. The authors have provided evidence that such activity is transmitted through stimulation of specific purine receptors, possibly belonging to the A-2 subtype. Further research is needed to determine whether the internal release of bronchial adenosine plays a role in the pathogenesis of the disease, and whether antagonism to it may provide some therapeutic potential. It is clear that this group, despite proving adenosine-induced bronchoconstriction in asthma, The use of properties as a diagnostic aid has never been proposed or studied. Therefore, the application of inhaled aerosolized adenosine as a provocation test in the diagnosis of asthma and its associated bronchoconstrictive lung disease is a novel application of this compound,
It forms the basis of the present invention.

[Problems to be Solved by the Invention] In view of the above, it is an object of the present invention to replace the methacholine test for confirming the diagnosis of asthmatics who show typical symptoms but whose lung function test results are normal. An object of the present invention is to provide a diagnostic agent used for a novel diagnostic method.

It is also an object of the present invention to provide a diagnostic agent used in a diagnostic test whose prediction accuracy is superior to a methacholine challenge test by using a pharmacological stimulant more directly related to the pathophysiology of the disease. is there.

Further, the present invention may be effected via adenosine,
Another object of the present invention is to provide a diagnostic agent used for a diagnostic test effective for testing other bronchoconstrictive pulmonary diseases in which a methacholine challenge test is completely ineffective, for example, sleep apnea.

[Means for Solving the Problems] Hereinafter, the above and other objects and advantages will be clarified by a more detailed description of the present invention.

The present invention provides a bronchoconstrictor effective amount of adenosine or a phosphorylated derivative thereof which is aerosolized and administered to a host human, which constitutes a diagnostic method for asthma and bronchoconstrictive pulmonary diseases related thereto.

Adenosine is chemically 9-β-D-ribofuranosyl-9H-purin-6-amine, 6-amino-9-β-D
-Ribofuranosyl-9H-purine, 9-β-D-ribofuranosidoadenine, adenine riboside and the like.

Adenosine is a kind of nucleoside widely distributed in nature, and yeast nucleic acid is used for its production. Adenosine is practically insoluble in alcohol,
Crystals form from the aqueous solution. Melting point: 234-235 ° C.

[Α] ¹¹ : 61.7 ゜ (c = 0.706, in water), [α] ⁹ : 58.2 ゜ (c = 658, in water), UVmax: 260 nm (∈15,100).

 The structural formula is as follows.

The empirical formula: C ₁₀ H ₁₃ N ₅ O ₄ , molecular weight: 267.24 The present invention is equally applicable to phosphorylated derivatives of adenosine, such as adenosine monophosphate, adenosine diphosphate, and adenosine triphosphate.

The description of the present invention is directed to adenosine administered aerosolized to symptomatic or asymptomatic patients suspected of having asthma (allergic or non-allergic) or associated bronchoconstrictive lung disease. I have. The present invention is intended to be used to confirm the diagnosis of bronchoconstrictive pulmonary disease in patients whose baseline pulmonary function test results are normal or near their limits despite the presence of typical symptoms. ing. The safety of nebulized (for inhalation) adenosine has already been confirmed and its bronchoconstrictive action has been described. However, the use of aerosolized adenosine as a provocation test in the diagnosis of bronchoconstrictive disease, and the use of its relatively high sensitivity and specificity to detect such conditions, has never been before. Not listed. The inventors now have
Clinical trials are underway to confirm the effectiveness (prediction accuracy) of the above diagnostic methods using aerosolized adenosine.

The practice of the present invention requires that a baseline lung function test be performed prior to the adenosine inhalation challenge test. Subjects were FE
V ₁ value must be at least 70% of the predicted value. The target level for a positive challenge test is a 20% reduction in FEV ₁ compared to the baseline value after inhalation of a control sodium chloride solution. To practice this method, adenosine is given to a subject in increasing concentrations of it. For each concentration, five inhalations are administered using a nebulizer that can be released at 0.6 second intervals either by a Y-tube or by a respiratory timing device (dose meter). The starting dose is about 0.5 μg total adenosine. Each time of inhalation,
The subject inhales the released volume gradually and completely, starting with the functional residual volume (FRC). 5 from the 5th inhalation
Measure FEV ₁ within minutes. If a positive response is not obtained (ie, the reduction in FEV ₁ is not more than 20% compared to baseline), the amount of adenosine released is increased by a factor of 10,
Repeat the operation. This procedure is repeated until a positive response is obtained or the cumulative total dose reaches 5.56 g.

Theophylline can also be administered by inhalation after an adenosine challenge test to facilitate FEV ₁ return to baseline and reduce patient discomfort. The majority of patients are expected to return to normal lung function within 5 minutes without a bronchodilator and 30-45 minutes without a bronchodilator.

The present invention is intended to distinguish asthmatics from non-asthmatics, and discrimination between the various subclasses of asthma (eg, allergic and non-allergic) is not expected. According to the adenosine challenge test,
It is also expected to identify other forms of bronchoconstrictive lung disease that can occur via adenosine, such as sleep apnea.

The adenosine or phosphorylated adenosine of the invention is typically administered in the form of a solution in water, saline, or an alcohol such as ethanol or isopropyl alcohol.

EXAMPLES A pilot clinical study was conducted to evaluate the safety, efficacy, and dose-response correlation of adenosine as a bronchial provocation test in the diagnosis of asthma.

Six subjects were studied, consisting of two healthy volunteers, two patients with chronic stable asthma, one patient with chronic bronchitis, and one patient with cystic fibrosis. The diagnosis of respiratory illness is already established by typical methods and conventional criteria. At the time of the study, each subject was clinically stable and had not received any medication. The setting used for the study was a cross-validation method in which a placebo was administered to a control group. Baseline measurements of lung function consisted of 1 second forced expiratory volume (FEV ₁ ) and airway resistance (AWR) and were obtained using standard procedures and commercially available equipment. Increased dose of adenosine (0.02
6, 0.077, 0.230, 0.689, 2.067, 6,200 mg / ml) and an equal volume of normal saline (placebo) using a hand-supported nebulizer at a rate of 0.2 ml / min for each dose. Administered in single inhalations. With each inhalation of each dose, measurements of lung function were repeated and respiratory parameters returned to baseline (typically 30 minutes) before the next dose. Bronchial challenge test shows FEV ₁ decreased by more than 15% or AW
An increase in R of more than 20% was defined as positive. Each study was terminated when a positive response was obtained or when the maximum dose was given without a positive response.

As expected, no subject tested positive with normal saline (placebo). Of the six subjects examined, only two asthmatics showed a positive response to adenosine induction. In each of these two cases, a positive reaction was observed after the fourth dose of adenosine (0.689 mg / ml), and no further dose was given. In the first case, AWR increased from baseline 4.75 to 10.49 and FEV ₁ decreased from baseline 2.80 to 2.43. In the second case, the AWR increases from the baseline of 2.11 to 7.24 and the FEV
₁ decreased from 2.95 at baseline to 2.58. During the study period, no subjects experienced systemic effects or side effects from adenosine or placebo.

These results indicate that adenosine administered by inhalation causes bronchoconstriction as well as respiratory confusion in asthmatics. Adenosine-induced bronchial induction appears to be specific for asthma, as two patients with other forms of chronic obstructive pulmonary disease (ie, bronchitis and cystic fibrosis) fail to respond positively .
In addition, adenosine appears to induce bronchoconstriction at low doses, with few, if any, side effects.

These data argue that adenosine administered nebulized by inhalation is effective in detecting hyperreactive airway disease and may provide a sensitive and specific method for the diagnosis of subclinical asthma. I support it.

Having described the invention, it is intended that the invention be limited only by the legal scope of the appended claims.

──────────────────────────────────────────────────続 き Continued on the front page (58) Field surveyed (Int. Cl. ⁷ , DB name) A61K 49/00 A61K 9/12 C07H 19/167 C07H 19/20 CAPPLUS (STN)

Claims (9)

(57) [Claims] A diagnostic agent for bronchoconstrictive pulmonary disease, comprising adenosine or a phosphorylated derivative thereof as an active ingredient, which is administered in the form of an aerosol for use in a lung function test. 2. A bronchus comprising adenosine or a phosphorylated derivative thereof as an active ingredient according to claim 1, wherein the phosphorylated adenosine is adenosine monophosphate, adenosine diphosphate or adenosine triphosphate. Diagnostic agent for contractile lung disease. 3. The method according to claim 1, wherein a spirometry or a volume change recording method is used as the pulmonary function test.
A diagnostic agent for bronchoconstrictive pulmonary disease, comprising the adenosine or a phosphorylated derivative thereof as an active ingredient. 4. The diagnosis of bronchoconstrictive pulmonary disease comprising adenosine or a phosphorylated derivative thereof as an active ingredient according to claim 1, wherein adenosine or adenosine derivative is solubilized by using a solubilizing vehicle. Agent. 5. The diagnostic agent for bronchoconstrictive pulmonary disease comprising adenosine or a phosphorylated derivative thereof as an active ingredient according to claim 4, wherein the vehicle is sodium chloride, water or alcohol. 6. A bronchoconstrictive pulmonary disease comprising adenosine or a phosphorylated derivative thereof as an active ingredient according to claim 1, wherein the solution of adenosine or adenosine derivative is aerosolized by a spraying method. Diagnostic agent. 7. The method according to claim 1, wherein the solution of aerosolized adenosine or adenosine derivative is administered by inhalation, nasal spray or sublingual administration. Diagnostic agent for bronchoconstrictive lung disease. 8. The adenosine or adenosine derivative thereof according to claim 1, wherein the solution of aerosolized adenosine or adenosine derivative can supply a local dose of adenosine or adenosine derivative sufficient to cause bronchoconstriction. A diagnostic agent for bronchoconstrictive pulmonary disease comprising an oxidized derivative as an active ingredient. 9. The adenosine or phosphorylated derivative thereof according to claim 8, wherein the effective dose sufficient to cause bronchoconstriction is about 0.5 to 5 mg as an inhaled dose. Diagnostic agent for bronchoconstrictive lung disease.