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At least 19 recordsLinked to original sources
PubMed1992

Indomethacin and methacholine tolerance in normal subjects. Role of prostaglandin synthesis in the attenuation of methacholine's effect during repeated inhalation challenges.

Within hours, tolerance occurs to repeated methacholine challenge in normal subjects, and this study examines whether prostaglandin synthesis produces this phenomenon. On two separate study days, ten nonasthmatic non-smoking subjects with measurable baseline responsiveness to methacholine performed five sequential methacholine challenge tests over 6 h. Pretreatment before each day consisted of either placebo tablets or 50-mg tablets of indomethacin given three times daily for 48 h prior to testing. Medications were administered in a single-blind crossover fashion, with study days assigned in random order and separated by at least 1 wk. Methacholine challenge tests were summarized by the PD20FEV1 (the provocative dose in cumulative breath units [cbu] required to produce a 20 percent fall in FEV1). Indomethacin pretreatment had no effect on baseline spirometry between the two study days; however, the baseline geometric mean PD20FEV1 fell from 145 +/- 2 cbu (+/- percent SD) after placebo pretreatment to 65 +/- 1 cbu (+/- percent SD) on the indomethacin day (p = 0.046). This effect of indomethacin on baseline airway responsiveness persisted when an additional ten subjects were studied to further investigate this finding. Significant tolerance to repeated methacholine challenges occurred on both study days, with geometric mean PD20FEV1 rising approximately 16-fold (p less than 0.0001) regardless of pretreatment received. This study demonstrates that the attenuation of methacholine's effect with repeated testing is not due solely to prostaglandin synthesis and must involve, in part, other mechanisms, such as changes in methacholine deposition, agonist-receptor interactions, or postreceptor responses. In addition, prostaglandin inhibitors may increase baseline methacholine responsiveness in healthy nonasthmatic subjects.

Adult↗
PubMed2003

Development of a methacholine challenge method to minimize methacholine waste.

BACKGROUND: The standard 2-min tidal breathing methacholine challenge utilizes 3 mL to produce an output of 0.26 mL per 2 min, resulting in a substantial amount of methacholine being discarded. OBJECTIVE: To develop a method with reduced methacholine waste and to compare it to the standard method. METHODS: Twelve subjects with mild, well-controlled asthma volunteered for this investigation. They underwent three methacholine challenges in random order. The first challenge was the conventional 2-min tidal breathing method using 3 mL of doubling concentrations inhaled for 2 min at 5-min intervals. The first modification utilized 1.5 mL of quadrupling concentrations inhaled for 1 min and then 2 min, keeping the time interval constant at 3 min between completion of one inhalation and commencement of the next inhalation. The second modification utilized 1.5 mL of eightfold concentration step-ups inhaled for 30 s, 60 s, and 120 s with a time interval of 3 min between completion of one inhalation and commencement of the next inhalation. For each method, the provocative concentration of methacholine causing a 20% fall in FEV(1) (PC(20)) was calculated based on a 2-min equivalent-dose inhalation. RESULTS: There was no significant difference in the geometric mean PC(20) (1.5 mg/mL, 1.6 mg/mL, and 1.6 mg/mL for the three methods, respectively; p = 0.47). The quadrupling concentration method was preferred because it was less subject to error than the other modification. CONCLUSION: The amount of methacholine discarded during a methacholine challenge can be reduced by two thirds by decreasing the volume from 3 to 1.5 mL, and by using quadrupling concentrations inhaled either with quadrupling-dose step-ups, or with doubling-dose step-ups by using sequential 1-min and 2-min inhalations.

Adult↗
PubMed1999

Methacholine challenge in preschool children: methacholine-induced wheeze versus transcutaneous oximetry.

Tracheal/chest auscultation for wheeze and transcutaneous oximetry have both been suggested as measures of outcome in bronchial provocation tests in young children. This study aimed to compare the sensitivity and safety of these two techniques as end-points for methacholine challenge in children aged <4 yrs. Seventy-two methacholine challenges were performed in 39 children aged <4 yrs with recurrent wheeze. Arterial oxygen saturation (Sa,O2) and transcutaneous oxygen pressure tcPO2 continuously, and the test was terminated when wheeze was heard or at Sa,O2 <91%. tcPO2 was not used as an end-point. Wheeze or desaturation occurred at < or =8 mg x mL(-1) methacholine in every test. One child had transient clinical cyanosis, but no other ill-effects were seen. Fifty-six tests (78%) were terminated for wheeze, seven (10%) for fall in Sa,O2 and nine (12%) showed simultaneous responses in both parameters. Twenty-eight tests (39%) contained a fall in tcPO2 >3 kPa but six of these also showed a significant rise. Fifty-three tests (75%) contained a fall in tcPO2 >15%, but 20 of these also showed a significant rise. Tracheal/chest auscultation with Sa,O2 monitoring is a sensitive and relatively safe end-point for bronchial challenges in preschool children. The erratic pattern of transcutaneous oxygen pressure response in some children casts doubt on its reliability as a proxy measure of bronchial obstruction.

Auscultation↗
PubMed1986

The use of methacholine inhalation, methacholine skin testing, distilled water inhalation challenge and eosinophil counts in the evaluation of patients presenting with cough and/or nonwheezing dyspnea.

Twenty-four patients presenting with cough and/or nonwheezing dyspnea were evaluated with methacholine inhalation challenge (MC), distilled water inhalation challenge (DC), intracutaneous tests to varying concentrations of methacholine, total eosinophil counts (TEC), sinus and chest x-rays. We found a statistically significant difference (P less than .005) in the mean TEC in those patients with a positive MC test and those with a negative test. Hyperreactivity of the airways to methacholine in asthmatics is not found in the skin. Distilled water inhalation did not serve to substitute for MC as a test of hyperreactive airways. The TEC is an excellent screening test as a predictor of patients with cough or dyspnea who have hyperreactive airways.

Adolescent↗
PubMed1983

Preparation and handling of methacholine chloride testing solutions. Effect of the hygroscopic properties of methacholine.

Persons with hyperreactive airways differ quantitatively from normal persons in their response to bronchial provocation testing with methacholine chloride (Mch). Methacholine chloride has strong hygroscopic properties that necessitate careful dessication, preparation, and handling if accurate results are to be achieved. The rate of hydration of Mch was determined by exposing the drug to various levels of relative humidity. The rate of water uptake was directly related to the availability of water in the atmosphere. At 49% relative humidity, a 0.125%/min gain in weight was noted, which increased to 0.489%/min at 80% relative humidity. Adequate dessication time and technique were determined by noting the time required to return the drug from a hydrated to a dry state. With proper technique, dessication was virtually complete by 4 to 6 h, and 20 to 24 h assured a return to the dry state. From these data, guidelines for preparation and handling of Mch test solutions can be formulated.

Bronchial Provocation Tests↗
PubMed1998

Methacholine-induced contraction of rabbit pulmonary artery: role of platelet-endothelial transcellular thromboxane synthesis.

Arachidonic acid- and methacholine-induced contractions of rabbit pulmonary arteries are mediated by thromboxane (TX) A2. Although removal of the endothelium abolishes the contractions, endothelial cells isolated from pulmonary arteries do not synthesize TXA2. Further studies described here showed that the expression of TX synthase was evident in platelets and intact pulmonary artery but not in endothelial cells. These studies examined the role of platelet TXA2 production in the vasoconstrictor response to methacholine. Endothelial cells were incubated with platelets in the presence or absence of methacholine. Methacholine caused an increase in TXB2 production. Pretreatment of endothelial cells with aspirin (100 micromol/L) before the addition of platelets did not impair the ability of methacholine to increase TXB2 synthesis. Conversely, if platelets were pretreated with aspirin, methacholine failed to stimulate TXB2. Using endothelial cells with their cellular lipids labeled with [3H]arachidonic acid, methacholine did not stimulate the production of [3H]TXB2. When the endothelial cells were incubated with methacholine and control platelets, [3H]TXB2 was detected. If aspirin-treated platelets were incubated with endothelial cells, methacholine did not increase the production of [3H]TXB2. However, pretreatment of the endothelial cells with aspirin did not affect the ability of methacholine to induce [3H]TXB2 release. This suggests that methacholine stimulated the endothelial cell to release arachidonic acid, which was transferred to the platelets and metabolized to TXA2. To test whether this cell-cell interaction is necessary for methacholine-induced contractions, rabbits were administered aspirin (20 mg/kg) for 2 days. On day 4, methacholine-induced contractions of pulmonary arteries were depressed in aspirin-treated compared with control subjects. Control arteries synthesized 6-keto-prostaglandin F1alpha and TXB2. Aspirin treatment inhibited both pulmonary artery and platelet TXB2 production but had no effect on vessel 6-keto-prostaglandin F1alpha. These studies implicate platelets as a vascular source of TXA2 and indicate that both endothelial cells and platelets may be required for methacholine-induced TXA2 synthesis and vasoconstriction.

6-Ketoprostaglandin F1 alpha↗
PubMed1997

Signal transduction pathways in modulation of ciliary beat frequency by methacholine.

The release of endogenous neurotransmitters plays an important role in the airway mucosal defense system. We studied the in vitro effect of methacholine, a beta-methyl ester of acetylcholine, on the ciliary beat frequency (CBF) of human adenoid explants and its mechanism of action. Tissue explants were cultured at 35 degrees C and covered with 1.0 mL of culture medium: minimum essential Eagle's medium (MEM) containing L-arginine (1.2 x 10(-3) mol/L). Methacholine was added to the cultured tissue at concentrations of 10(-10), 10(-8), and 10(-6) mol/L. The CBF was determined by phase contrast microscopy and microphotometry. Methacholine increased CBF in a dose-dependent manner with a maximum increase of 23.0% +/- 1.8% (p < .001). Atropine (10(-6) mol/L) significantly inhibited the ciliostimulatory effects of methacholine (p < .0007). The role of endogenous prostaglandins in methacholine-induced ciliostimulation was determined by treating specimens with a cyclooxygenase inhibitor (diclofenac sodium). Diclofenac (10(-6) mol/L) significantly inhibited the ciliostimulatory effects of methacholine (p < .0007). To determine if nitric oxide (NO) acts as an intermediary in ciliostimulation by methacholine, endogenous NO production was inhibited by treating specimens with an L-arginine analog, NG-nitro-L-arginine methyl ester (L-NAME), prior to addition of methacholine. L-NAME (10(-6) mol/L) inhibited the effects of methacholine in L-arginine-free MEM (p < .008), and this inhibition was reversed by L-arginine (10(-3) mol/L). To further examine the actions of NO in methacholine-induced ciliostimulation, a cyclic guanosine 3'5'-monophosphate (cGMP) kinase inhibitor (KT-5823) was used, prior to the addition of methacholine. KT-5823 (10(-6) mol/L) significantly inhibited the effects of methacholine (p < .0001). Ciliostimulation by methacholine in human upper airway mucosa involves both prostaglandin and NO second messengers and activation of a cGMP-dependent kinase.

Acetylcholine↗
PubMed1986

Methacholine sensitivity and cAMP protein kinase in tracheal smooth muscle.

We studied regional variation in canine trachealis smooth muscle sensitivity and responsiveness to methacholine as well as basal and methacholine-stimulated adenosine 3',5'-cyclic monophosphate (cAMP) and cAMP-dependent protein kinase activity. The trachea between the cricoid cartilage and the carina was divided into three segments of equal length (designated cervical, middle, and thoracic regions), each consisting of approximately 12-14 cartilage rings. Smooth muscle strips from each of the three regions were exposed to cumulative half-log increments of methacholine chloride. The sensitivity (-log EC50) and responsiveness (force per cross-sectional area and force per milligram protein) of the smooth muscle to methacholine in each region was determined from these data. Smooth muscle strips from cervical and thoracic regions were frozen before and after exposure to cumulative half-log increments of methacholine up to each region's previously determined EC50. Frozen samples were assayed for cAMP content or cAMP-dependent protein kinase activity. The relationship between resting tension and methacholine sensitivity and responsiveness were studied. For the size strips we used, 4 g resting tension set the average cervical and thoracic strips at 96 and 101% of their optimal length, respectively. The methacholine EC50 was not affected by a variation in resting tension. Sensitivity to methacholine was 7.1, 6.8, and 6.5 for cervical, middle, and thoracic regions, respectively. The responsiveness of the cervical and thoracic smooth muscle to methacholine was 16.4 and 16.3 g force/mm2, respectively, at an EC50 methacholine. Basal cAMP was lower in cervical smooth muscle than in thoracic. cAMP-dependent protein kinase activity ratios under both basal and EC50 methacholine-stimulated conditions were lower in cervical smooth muscle than in thoracic. We have observed in trachealis smooth muscle an inverse relationship between methacholine sensitivity and either cAMP or cAMP-dependent protein kinase activity. We suggest that cAMP and cAMP-dependent protein kinase play a role in the regulation of airway smooth muscle sensitivity to cholinergic agonists.

Animals↗
PubMed1990

Tachyphylaxis to inhaled methacholine in normal but not asthmatic subjects.

Methacholine inhalation tests measure airway responsiveness in asthmatic and normal subjects. Tachyphylaxis occurs with repeated methacholine inhalations in normal subjects. The purpose of this study was to examine the time course and mechanisms of methacholine tachyphylaxis in normal subjects and to determine whether this occurs in mildly asthmatic subjects. Fifteen normal and nine asthmatic subjects were studied on 2 study days, at least 48 h apart. Each day, two inhalation tests were carried out. On one day, subjects performed two methacholine inhalation tests 3 h later by a methacholine test. Results were expressed as the provocation concentration causing a 20% fall in forced expiratory volume in 1 s (FEV1), (PC20). All normal subjects developed methacholine tachyphylaxis. The mean PC20 increased from 47.3 mg/ml (%SE 1.34) to 115.6 (%SE 1.51) (P less than 0.0001) in a 3-h interval. This increase lasted for greater than or equal to 6 h (P = 0.012). Asthmatic subjects did not develop methacholine tachyphylaxis. Their mean methacholine PC20s were 1.6 mg/ml (%SE 1.4) and 1.5 (%SE 1.4) (P = 0.75) 3 h later. In two other series of experiments, normal subjects were pretreated with the cyclooxygenase inhibitors indomethacin (100 mg/day) or flurbiprofen (150 mg/day) or a placebo for 3 days before two methacholine tests 3 h apart. Both indomethacin and flurbiprofen significantly inhibited the development of methacholine tachyphylaxis. These results confirm that methacholine tachyphylaxis occurs in normal subjects, lasts greater than or equal to 6 h, and may occur through the release of inhibitory prostaglandins. By contrast, methacholine tachyphylaxis does not occur in asthmatic subjects.

Administration, Inhalation↗
PubMed2005

The effect of reducing the fine-particle mass of salmeterol from metered-dose inhalers on bronchodilatation and bronchoprotection against methacholine challenge: a randomized, placebo-controlled, double-blind, crossover study.

OBJECTIVE: This study examined the clinical relevance of fine-particle mass (FPM) delivered from metered dose inhalers (MDIs) to bronchodilatation and bronchoprotection against methacholine challenge by comparing a marketed chlorofluorocarbon (CFC) formulation of salmeterol with an investigational hydrofluoroalkane (HFA)formulation. METHODS: This was a randomized, double-blind, placebo-controlled, 3-way crossover study in patients with mild to moderate asthma who had a forced expiratory volume in 1 second (FEV (1)) of > or =60% predicted and a base-line provocation dose of inhaled methacholine required to produce a 20% decrease in FEV(1) (PD (20) [methacholine]) of < or =3.2 mg. On separate occasions, patients received 2 inhalations of salmeterol 25 microg from either the CFC MDI (FPM 14 microg), the investigational HFA MDI (FPM 7 microg), or placebo via CFC MDI. Serial measurements of FEV(1) were made over 90 minutes after dosing, followed by methacholine challenge. Efficacy end points were PD(20) (methacholine) and FEV(1) AUC (inc) (incremental area under the FEV(1) curve) over 15 to 90 minutes. The study was designed to demonstrate non-inferiority of the investigational HFA formulation to the CFC formulation in terms of protection against methacholine-induced bronchial hyperresponsiveness; for PD(20) (methacholine), noninferiority was predefined as 1.0 doubling dose of methacholine. RESULTS: The study enrolled 40 patients (65% men; mean age, 36.9 years). Both active treatments were significantly better than placebo in terms of PD(20) (methacholine) (P < 0.001). In the per-protocol population, the mean (SE) difference in bronchoprotection between the CFC MDI and placebo was 2.7888 (0.3432) doubling doses of methacholine (n = 32), and the difference between the investigational HFA MDI and placebo was 1.8268 (0.3418) doubling doses(n = 33). The adjusted mean (SE) treatment difference between the CFC MDI and HFA MDI was 0.9621 (0.3454) doubling doses. The upperlimit of the 95% CI (0.2714-1.6527) was greater than the predefined limit for noninferiority. There was no significant difference in FEV(1) AUC(inc) between formulations (mean treatment difference, 1.895 L . min; 95% CI, -4.893 to 8.684); however, both active treatments were significantly different from placebo (P < 0.001). CONCLUSIONS: FPM from different MDI formulations may affect the bronchoprotective properties of salmeterol. In this study, the formulation with the smaller FPM was associated with less-effective bronchoprotection, although there was no difference in bronchodilatation. This study did not demonstrate noninferiority of the investigational HFA formulation to the CFC formulation in terms of protection against methacholine-induced bronchial hyperresponsiveness.

Adult↗
PubMed1993

Importance of the time interval between FEV1 measurements in a methacholine provocation test.

We examined the hypothesis that a forced expiratory volume in one second (FEV1) manoeuvre (and the preceding deep inhalation) before inhalation of methacholine might influence FEV1 measured after methacholine, if the time between measurements was short. Six to nine healthy subjects inhaled a single dose of methacholine, known to cause about 20% decrease in FEV1, on different days in different test protocols. If an FEV1 manoeuvre was performed immediately before methacholine, the first FEV1 measured 3 min after provocation was higher (77% of basal FEV1) than if a pre-methacholine FEV1 manoeuvre was not performed (64%). This effect of a pre-methacholine FEV1 manoeuvre was also demonstrated at 2, 4 and 6, but not at 10 min after the start of methacholine inhalation. If an FEV1 manoeuvre was not performed before methacholine, the second and subsequent FEV1 measured in constricted airways was higher than the first, and of similar magnitude to the first FEV1 in tests where a pre-challenge FEV1 manoeuvre was performed. In another trial, 10 healthy subjects performed two stepwise methacholine tests, with either 6 or 3 min between dose steps. The percentage decrease in FEV1 per mg of inhaled methacholine decreased from 2.6 (1.9-5.2) to 1.7 (0.8-2.3) (median, interquartile-range) when the time interval was shortened. The results suggest that the deep inhalation associated with the FEV1 manoeuvre decreases the bronchial tone in airways constricted by methacholine for up to 6 min, possibly due to yielding of cross-links in airway smooth muscles.

Adult↗
PubMed2002

Bronchodilator response in asthmatic children is significantly reduced when measured immediately after methacholine challenge.

AIM: Airway responses to a bronchodilator (BDR) and to methacholine are frequently measured in the assessment of childhood asthma and in pulmonary research. For practical reasons, we wondered whether it would be possible to obtain a reliable BDR immediately after completion of a methacholine challenge test. To this end, we compared BDR with and without a preceding methacholine challenge. METHODS: The BDR was measured twice in random order on consecutive days in 24 asthmatic children with methacholine hyperresponsiveness. It was calculated as the change in forced expiratory volume in one second (FEV1) before and 20 min after inhaling 800 microg of salbutamol (metered dose inhaler with a spacer), expressed as a percentage of the predicted value (deltaFEV1%pred). On one day BDR was measured immediately after completing a methacholine challenge, on the other day without any preceding challenge. RESULTS: Mean(SD) baseline FEV1%pred was not significantly different between test days [98.6(14.2)% and 98.1(13.8)%, respectively, p=0.53]. The geometric mean provocative dose of methacholine producing a 20% fall in FEV1 (PD20) was 56.2 microg (range 10.3-306.2 microg). The mean (SEM) BDR without preceding methacholine challenge was 10.8(1.4)%, while after preceding methacholine challenge it was 5.2(1.5)% (mean difference 5.6%, 95% CI 3.0%-8.1%, p<0.001). Mean(SEM) postbronchodilator FEV1%pred was 109.4(3.0)% without and 103.4(2.7)% with preceding methacholine challenge (mean difference 6.0%, 95% CI 3.5%-8.6%, p<0.001). CONCLUSION: A preceding methacholine challenge significantly reduces BDR in asthmatic children. Therefore, a BDR, measured immediately after completing a methacholine challenge, cannot be used as a substitute for a separate bronchodilator test.

Administration, Inhalation↗
PubMed1992

Repeated methacholine challenge produces tolerance in normal but not in asthmatic subjects.

Repeated methacholine challenge in normal nonasthmatic subjects (who require higher doses of methacholine than do asthmatic subjects to produce a 20 percent decrease in FEV1) can produce progressively diminishing methacholine responsiveness (or tolerance) with serial challenges. To determine whether tolerance to methacholine occurs in asthmatic subjects as it does in nonasthmatic subjects, we studied eight young (mean age, 24 years) mild asthmatic patients (occasional but not regular use of bronchodilator medications, PC20 methacholine range 0.1 to 7.0 mg/ml) who underwent five sequential methacholine challenges at 1.5-h intervals. Serially increasing concentrations of methacholine were given until FEV1 fell by 20 percent. Results were compared with those in seven nonasthmatic control subjects who underwent an identical protocol. As seen in previous studies, the normal subjects demonstrated significant tolerance to methacholine when each of five challenges was compared to the first. By contrast, in the asthmatic group, the mean cumulative dose of methacholine producing a 20 percent fall in FEV1 in the fifth challenge was not significantly different from the dose required in the first challenge. These results indicate that marked tolerance to methacholine does not occur in mild asthmatic patients with multiple repeated challenges over 6 h. The lower cumulative dose of methacholine required by asthmatic patients may be insufficient to produce tolerance.

Adaptation, Physiological↗
PubMedDate not supplied

Standardization of methacholine inhalation challenge.

Methacholine inhalation challenge has been shown to be an extremely useful diagnostic test. The purpose of this study was to document the reproducibility of methacholine inhalation challenge used in our clinic. In addition, we also examined the output of the delivery system, the stability of four-month-old methacholine solution, and the cumulative effect of methacholine. To document reproducibility, two identical challenges were performed in each of 19 asthmatic children. The influence of the previous doses of methacholine on bronchial response was examined by performing a third challenge with a single dose of methacholine in ten of these children. The remaining nine children were also tested for the third time with four-month-old methacholine solution to examine the stability of that solution. The output of the delivery system was assessed by measuring the change in weight of the nebulizer. Responses to methacholine were highly reproducible within one doubling dose interval. There was a small but significant cumulative effect of methacholine. Comparable results were obtained with newly prepared methacholine solution and four-month-old solution. The variability of the output of the same nebuliser was less than that of different nebulisers of the same model. The major clinical implication of our results is that our methacholine inhalation challenge procedure is standardized. This encourages more widespread use of this important diagnostic test for demonstration of airway hyper-responsiveness.

Administration, Inhalation↗
PubMed1988

The combined effects of histamine and methacholine on the maximal degree of airway narrowing in normal humans in vivo.

In normal subjects in vivo the dose-response curve to inhaled nonsensitizing stimuli reaches a plateau at mild degrees of airway narrowing. We investigated whether the limitation of the response is due to non-optimal smooth muscle activation, by administering high doses of histamine and methacholine together. In fifteen normal subjects a complete dose-response curve to methacholine was recorded by a tidal breathing method on three randomized days. On a separate day a complete histamine inhalation test was carried out. Each methacholine test was directly followed by double blind inhalation of the highest dose of either histamine or methacholine, or a dose of saline. The response was measured by flows from partial flow-volume curves (V 40p), and was expressed in % fall from baseline. Twelve subjects reached a maximal response plateau to methacholine which was reproducible. The addition of saline or extra methacholine did not change the response from its methacholine plateau value. Histamine caused a small increase in the response on top of the methacholine plateau (+ 9.0% fall; p less than 0.001). However, the response to the combined histamine and methacholine was not significantly larger than the maximal response to histamine alone. We conclude that there is no interaction between histamine and methacholine on the maximal degree of airway narrowing. This suggests that the plateau of the dose-response curve in normal subjects in vivo is due to other factors than limited smooth muscle activation.

Adult↗
PubMed2001

Stability of stored methacholine solutions: study of hydrolysis kinetic by IP-LC.

Methacholine chloride is a powerful cholinergic bronchoconstrictor agent used during bronchial airway hyper-responsiveness diagnosis. Methacholine is susceptible to hydrolysis in aqueous solutions in acetic acid and beta-methylcholine. In the present work, kinetics of hydrolysis with different solvents (water and phosphate-buffered saline (PBS) pH 7.4) at different temperatures have been studied using a newly developed high-performance liquid chromatography. At 4 degrees C, kinetic determination of hydrolysis in methacholine chloride solutions (50 mg/ml) shows no hydrolysis in either aqueous or phosphate-buffered solutions over a 40-day period. At 30 degrees C, concentration of unbuffered methacholine chloride solutions remained unchanged, but buffered methacholine chloride solutions have degradation up to 5.5% over a 40-day period. At 40 degrees C, concentration of unbuffered methacholine chloride has degradation up to 5% and buffered methacholine chloride solutions have degradation up to 10% over a 40-day period. Methacholine chloride solutions are susceptibly to be used in hospital pharmacy at different concentrations. We have studied pH and osmolality for methacholine solutions prepared with different diluents potentially used in hospital pharmacies, i.e. deionized water, 0.9% NaCl and PBS pH 7.4. We have demonstrated that methacholine solutions prepared with deionized water at 50 mg/ml and diluted with PBS pH 7.4 from 5 to 40 mg/ml are isoosmotic and potentially available for inhalation tests to measure non-specific bronchial hyper-responsiveness.

Bronchoconstrictor Agents↗
PubMed2003

Dissimilarity between seasonal changes in airway responsiveness to adenosine-5'-monophosphate and methacholine in patients with grass pollen allergic rhinitis: relation to induced sputum.

BACKGROUND: In patients with allergic rhinitis, bronchial hyperresponsiveness (BHR) and airway inflammation may increase during pollen exposure. BHR can be assessed by adenosine-5'-monophosphate (AMP) or methacholine challenge. It has been suggested that BHR to AMP is more closely related to airway inflammation than BHR to methacholine. Seasonal allergic rhinitis offers a dynamic model to study changes in BHR and airway inflammation during natural allergen exposure. METHODS: We measured BHR [provocative concentration causing a 20% fall (PC(20)) in forced expiratory volume in 1 s (FEV(1))] to AMP and methacholine, and induced sputum cells in 16 rhinitis patients before and during the 2001 grass pollen season. RESULTS: There was a decrease in PC(20) methacholine during pollen exposure (geometric mean PC(20) from 3.22 to 1.73 mg/ml, p = 0.0023), whereas no reduction was observed for PC(20) AMP (p = 0.11). There was no increase in sputum eosinophils [pre: 0.69% (95% confidence interval 0.22-2.07); during: 1.85 (0.55- 5.6), p = 0.31]. Although the correlation of log PC(20) methacholine and log PC(20) AMP at baseline was good (r = 0.76, p = 0.001), individual seasonal changes (doubling concentrations) in PC(20) methacholine were not correlated with changes in PC(20) AMP (rho = 0.21, p = 0.44). There was no correlation between baseline log PC(20) methacholine or seasonal changes in PC(20) methacholine and sputum eosinophils (p > 0.12, all correlations). In contrast, there was a significant correlation between seasonal changes in PC(20) AMP and changes in sputum eosinophils (rho = -0.59, p = 0.025). CONCLUSIONS: These data show dissimilarity between seasonal changes in PC(20) AMP and methacholine in patients with seasonal allergic rhinitis. Moreover, PC(20) AMP seems to be more closely related to sputum eosinophils than PC(20) methacholine. The clinical significance of this discrepancy is unclear.

Adenosine Monophosphate↗