Safety and tolerability of methacholine challenge in infants with recurrent wheeze.

Bronchial hyperreactivity (BHR) is a key feature of asthma, but measurement can usually not be achieved in infants with standard lung function tests. We investigated the safety and tolerability of methacholine challenge in infants with recurrent wheezing episodes. 78 methacholine challenges in 51 sedated infants aged 12-36 months with recurrent wheezing episodes were performed. Methacholine challenge was stopped when clinical signs (coughing, wheezing, or cyanosis) or a drop of oxygen saturation (SPO2) of at least 5% or a drop of transcutaneous oxygen tension (PtcO2) of at least 0.8 kPa or an increase of resistance (RrsSO), of 50% by single occlusion technique were observed. Prior to methacholine challenge, all children were symptom-free with a mean SPO2 of 97.4% (SD 1.80%). In 48 cases (61.5%), no clinical sign was observed, 17 (21.8%) coughed, and 13 (16.7%) wheezed. A mean reduction of SPO2 of 5.0% (SD 3.89%) for the entire population was observed. In 15 of 78 cases, a decrease of SPO2 <90% occurred. This SPO2 drop was short-lasting and resolved spontaneously or after bronchodilator inhalation. Infants whose SPO2 dropped <90% showed a greater increase of RrsSO compared to infants who did not drop <90% (133% vs. 65% RrsSO increase, p<0.001). Methacholine challenge, using a combination of clinical observation, monitoring of SPO2 and PtcO2, and airway resistance using the single-occlusion technique, is a safe and tolerable tool to measure the BHR in infants with recurrent wheezing episodes.

Structures of histamine H1-receptor antagonists derived from the cimetidine group of histamine H2-receptor antagonists.

The crystal and molecular structures of ten compounds with strong structural resemblances to the cimetidine group of histamine H2-receptor antagonists, but exhibiting selective H1-receptor antagonist activity, (1)-(7), or H1 and H2 activity (8)-(10), have been determined: (1) 2-[4-(5-Bromo-3-methyl-2-pyridyl)butylamino]-5- (6-methyl-3-pyridylmethyl)-4-pyrimidone trihydrobromide (temalastine), C21H27BrN5O3+.3Br-, M(r) = 685.09, triclinic, P1, a = 6.314 (2), b = 11.192 (2), c = 19.441 (5) A, alpha = 102.47 (2), beta = 92.77 (2), gamma = 103.28 (2) degrees, V = 1298.51 A3, Z = 2, Dx = 1.75 g cm-3, mu = 61.6 cm-1, F(000) = 672, R = 2.93% for 3208 independent reflexions. (2) 2-[4-(5-Bromo-3-methyl-2-pyridyl)butylamino]-4-pyrimidone, C14H19BrN4O2, M(r) = 355.23, monoclinic, I2/a, a = 16.359 (3), b = 10.469 (6), c = 18.339 (4) A, beta = 90.90 (2) degrees, V = 3140.49 A3, Z = 8, Dx = 1.503 g cm-3, mu = 26.0 cm-1, F(000) = 1176, R = 4.2% for 1872 independent reflexions. (3) 3-[4-(5-Bromo-3-methyl-2-pyridyl)butylamino]-4- amino-1,2,5-thiadiazole-1-oxide, C12H16BrN5OS, M(r) = 358.26, triclinic, P1, a = 14.295 (2), b = 12.447 (2), c = 9.917 (2) A, alpha = 95.77 (2), beta = 113.86 (2), gamma = 106.91 (1) degrees, V = 1495.18 A3, Z = 4, Dx = 1.59 g cm-3, mu = 50.96 cm-1, F(000) = 728, R = 5.98% for 5674 independent reflexions. (4) 3-[4-(5-Bromo-3-methyl-2-pyridyl)butylamino]-4- benzylamino-1,2,5-thiadiazole-1-oxide, C19H22BrN5OS, M(r) = 448.38, monoclinic, P2(1)/c, a = 36.293 (7), b = 4.826 (2), c = 11.528 (3) A, beta = 96.91 (2) degrees, V = 2004.27 A3, Z = 4, Dx = 1.49 g cm-3, mu = 39.2 cm-1, F(000) = 920, R = 12.1% for 1945 independent reflexions. (5) 2-[3-(N-Benzyl-N-2- pyridylamino)propylamino]-4-pyrimidone, C19H21N5O, M(r) = 335.4, orthorhombic, Pbna, a = 7.082 (1), b = 19.889 (3), c = 24.899 (3) A, V = 3507.16 A3, Z = 8, Dx = 1.27 g cm-3, mu = 6.24 cm-1, F(000) = 1424, R = 4.05% from 2470 independent reflexions. (6) 3-[3-(N-4-Fluorobenzyl-N-2- pyridylamino)propylamino]-4-ethylamino-1,2,5-thiadiazole-1-oxide, C19H23FN6OS, M(r) = 402.5, monoclinic, P2(1)/n, a = 6.686 (2), b = 14.717 (3), c = 20.850 (5) A, beta = 97.83 (2) degrees, V = 2032.47 A3, Z = 4, Dx = 1.32 g cm-3, mu = 16.41 cm-1, F(000) = 848, R = 8.5% from 2484 independent reflexions. (7) 5-(6-Methyl-3-pyridylmethyl)-2-[3-(5,6,7,8-tetrahydro-8- quinolyl)propylamino]-4-pyrimidone, C23H29N5O2, M(r) = 407.5, monoclinic, P2(1)/c, a = 14.966 (2), b = 16.075 (2), c = 9.1608 (9) A, beta = 99.158 (8) degrees, V = 2175.83 A3, Z = 4, Dx = 1.24 g cm-3, mu = 6.19 cm-1; F(000) = 872, R = 5.3% from 2784 independent reflexions. (8) 2-(4-Phenylbutylamino)-5-(3-pyridyl-methyl)-4-pyrimidone, C20H26N4O3, M(r) = 370.5, monoclinic, P2(1)/c, a = 8.040 (4), b = 21.279 (4), c = 11.404 (2) A, beta = 92.08 (5) degrees, V = 1949.68 A3, Z = 4, Dx = 1.26 g cm-3, mu = 0.93 cm-1, F(000) = 792, R = 4.05% from 3816 independent reflexions.(ABSTRACT TRUNCATED AT 400 WORDS)

Structure-activity studies of pyridinylalkyl-isocytosine H1-receptor antihistamines and identification of an active conformation.

For a series of 2-(pyridin-2-ylbutylamino)-5-(3-picolinylmethyl)pyrimidin- 4(1H)-ones (isocytosines) substituted in the pyridine 3-position, activity as H1- and H2-receptor histamine antagonists appears to correlate with the size of the 3-substituent. Steric interaction between the substituent and the butyl chain is explored by conformational analysis using Molecular Mechanics and Molecular Orbital calculations on 2-propyl- and 2-propyl-3-methyl-pyridines; it appears that the substituent may alter activity by changing the preferred conformation of the drug. This observation is extended by synthesis of a semirigid bicyclic analogue wherein 3-methylpyridinylbutyl is replaced by tetrahydroquinolinylpropyl. This compound is 2-3 times more potent as an H1-receptor antagonist confirming that a trans/trans conformation favours activity. Although derived from an H2-antagonist structure, the compound is not an antagonist at histamine H2 receptors thus proving that the conformational requirements are different at H1 and H2 receptors.