Ngm Orie

Immediate and late bronchial obstructive reactions to inhalation of house dust and protective effects of disodium cromoglycate and prednisolone

Abstract The immediate and late obstructive reactions after house dust inhalation were studied in 10 patients with reversible obstructive lung disease. The immediate obstructive reactions were of the conventional type. The late obstructive reactions occurred 4 to 8 hours after the allergen challenge and in this respect followed the time table of the Arthus reaction but were otherwise clearly distinct from the conventional Arthus reaction: marked bronchial obstruction, no crepitations, no fever, and no leukocytosis. Disodium cromoglycate showed an evident protective effect on the immediate reactions in contrast to prednisolone, which produced no protection in this type of reaction. There was a marked inhibitory effect on the late obstructive reaction with prednisolone and with disodium cromoglycate.

Protection tests on bronchial allergen challenge with disodium cromoglycate and thiazinamium

Abstract The efficacy of the new antiallergic drug, disodium cromoglycate, has been studied with protection tests on bronchial allergen challenge in 17 patients with reversible obstructive lung disease. There was, in general, a markedly protective effect on the immediate allergic reaction without concomitant bronchodilitation. Thiazinamium also produced a very good protective effect, probably the result of the combination of bronchodilation and a specific antihistaminic activity.

Disposition and clinical pharmacokinetics of microcrystalline theophylline.

SummaryVariation in the systemic disposition of theophylline after ingestion of a new microcrystalline product (Theolair®) has been investigated in 7 hospitalized patients with generalized obstructive lung disease. Disposition (absolute bioavailability) was determined by comparing in the same patients the areas under the serum concentration-time curves after a single oral dose of microcrystalline theophylline and after an intravenous infusion of aminophylline. Oral absorption appeared to be fast. The half-life of absorption was 19±9 min (mean±SD). Maximal serum concentrations reached after 100±30 min were found to be in a rather narrow range: 9.8±2.5 mg · 1−1. The absolute bioavailability of the microcrystalline preparation was high and it showed only small variation: 102.7±10.2% of the dose. Relevant pharmacokinetic parameters (half-life of elimination, volume of distribution and total body clearance) were determined after both routes of administration. Individual dosage regimens required to obtain a therapeutic serum concentration were calculated for each individual patient on the basis of the observed pharmacokinetic parameters.

DETERMINATION OF LOW CONCENTRATIONS OF QUATERNARY AMMONIUM COMPOUND THIAZINAMIUM METHYLSULFATE IN PLASMA AND URINE

A sensitive and selective method for the quantitative determination of the quaternary ammonium antiacetylcholine‐compound thiazinamium methylsulphate (Multergan) in plasma and urine is described. The procedure is based on ion pair extraction of the compound with iodide as the counter ion. This is followed by gas chromatography using an alkali flame ionization detector. The detection limit is 2 ng ml−1 with a recovery of 88·0 ± 6·2% from plasma, 91·4 ± 4·6% from urine. The described method can also be applied to other quaternary ammonium compounds.

DETERMINATION OF OXYPHENONIUM BROMIDE IN PLASMA AND URINE BY MEANS OF ION-PAIR EXTRACTION, DERIVATIZATION AND GAS CHROMATOGRAPHY-ELECTRON-CAPTURE DETECTION

A sensitive and selective method for the determination of the quaternary ammonium compound oxyphenonium bromide (Antrenyl), a drug with strong anticholinergic properties, in human plasma and urine is described. The method is based on ion-pair extraction of the cation with perchlorate, a re-extraction according to ion-pair principles with tetrapentylammonium as the counter ion, hydrolysis to cyclohexylphenylglycolic acid, derivatization of this acid to its pentafluorobenzyl ester and determination of the ester by gas chromatography and electron-capture detection. Quantitation is possible down to 2 ng/ml of oxyphenonium bromide using 1 ml of plasma and down to 200 ng/ml using 0.1 ml of urine. The method described can also be applied to other anticholinergic drugs with an ester function.

Variations in the bioavailability of thiazinamium methylsulfate

Bioavailability after oral administration of the anticholinergic drug thiazinamium methylsulfate (Multergan), a phenothiazine derivative with a quaternary ammonium group in the moleeule, has been studied in patients and volunteers by measuring the drug concentrations in plasma or the excretion of the parent drug in urine. The relative bioavailability as compared to intramuscular injection seems to be of the order of 10%. Much more of the drug is absorbed, however, but is metabolized during the first liver passage. Moreover, there seems to be a substantial interindividual variation in the bioavailability of the drug. Studies in a group of eight volunteers showed that there is also a substantial intraindividual variation, but its magnitude is smalter than that of the interindividual variation.

ABSOLUTE BIOAVAILABILITY OF MICROCRYSTALLINE THEOPHYLLINE

SummaryA study was carried out to investigate the variation in the systemic availability of theophylline after ingestion of a new microcrystalline tablet (‘Theolair”). Serum concentrations obtained after oral administration of the drug were compared with those after intravenous infusion of aminophylline in the same patient. The absolute bioavailability was calculated and oral absorption appeared to be very fast, resulting in maximum serum concentrations after 100±30 min (mean ± S.D.J. Inter-patient variation of maximum serum concentrations was low: 9.8±2.5 μg/ml (mean ± S.D.). The fast absorption resulted in a complete absolute bioavailability with a very low variation: 102.7±10.2 (mean ± S.D.).

BRONCHIAL HYPERREACTIVITY AND BRONCHIAL OBSTRUCTION IN RESPIRATORY VIRAL-INFECTION - AN ATTEMPT TO EVALUATE THE RELATIONSHIP

The aim of this study was to investigate the relation of viral respiratory infection with bronchial hyperreactivity and bronchial obstruction. A viral infection using a live attenuated influenza virus was induced successfully in 10 of 30 patients with chronic obstructive pulmonary disease (COPD) and in 3 subjects without COPD (non-COPD). No significant change in bronchial reactivity and lung function could be found in comparison with the baseline values.

Multi-dose comparative study of microcrystalline theophylline and choline theophyllinate

SummaryPreliminary findings are reported of a double-blind trial carried out in patients with chronic obstructive lung disease to compare the plasma theophylline concentrations achieved after oral administration of 125 mg tablets of a microcrystalline theophylline and 200 mg tablets of choline theophyllinate. Measurements were also made of lung function parameters (FEY1 and PEFR). Seven patients were treated for 2 days each with the two theophylline preparations and with placebo. Treatment sequence was randomized and there was at least 1 day in between each period. Dosage levels, providing approximately the same amount of theophylline with both drugs, were 875 mg theophylline or 1400 mg choline theophyllinate on Day 1 and 500 mg theophylline or 800 mg choline theophyllinate on Day 2, given in divided administration. Although the plasma concentrations on the first day barely reached a therapeutic value {normally between 10 and 20 μg/ml) with either preparation, PEFR and FEV1 values were higher than those o...

BIOAVAILABILITY AFTER RECTAL ADMINISTRATION OF THIAZINAMIUM METHYLSULFATE IN DIFFERENT VEHICULES

Abstract The bioavailability in humans of the quaternary ammonium compound thiazinamium methylsulphate (Multergan) was studied using plasma concentration measurements after the application of the drug in a lipophilic (Witepsol H-15) and a hydrophilic (a polyethylene glycol mixture) suppository base. The best results were obtained with Witepsol H-15. The peak in the plasma concentration-time curve appeared about 60 min after administration, indicating that the rate of absorption is faster than that observed after oral administration. After the maximum, the curve declined rather rapidly, and usually dropped to zero or almost zero concentration in7h. The bioavailability obtained with Witepsol H-15 suppositories was about 6% of the dose, which is of the same order of magnitude as after oral administration. Interindividual variation was also similar to that obtained after oral administration. After the application of the drug in the polyethylene glycol base, very low plasma concentrations were found and the bioavailability was almost negligible.