Bronchial allergen challenge: dose versus concentration

This study was designed to investigate if two equivalent doses of allergen administered by different dosing regimes--two breaths and 10 breaths of each concentration--would result in the same magnitude of the early and late asthmatic response. Fifteen patients with extrinsic allergic asthma were challenged twice with either two or 10 breaths of twofold increasing allergen concentrations. The challenge was continued until a 20% decrease in FEV1 had been achieved. A non-cumulative PC20FEV1 allergen was derived, and the cumulative dose of allergen given was similarly derived. In order to assess the reproducibility of the challenge, seven patients were challenged twice with two-breath regime. The mean value of allergen PC20 obtained by the two-breath regime was 4.1 fold (95% CI: 2.3-7.1 fold) greater than those obtained by the 10-breath regime (P less than 0.05), whereas the difference was 1.4 fold (95% CI: -3.3-0.5 fold) for the cumulative dose (P greater than 0.05). A statistically significant larger magnitude of the early asthmatic response, as determined by the maximum per cent fall in FEV1, and late asthmatic response determined by the maximum per cent fall in peak expiratory flow domiciliary recorded during the following 24 hr after challenge, was observed in favour of the 10-breath regime compared to the two-breath regime (mean difference 6%, 95% CI: 0.6-11%). The reproducibility of the provocation test was acceptable (+/- 1.8 two-fold concentration difference). These results confirm the 'equivalent dose hypothesis', and demonstrates that dosage rather than concentration appears to determine the early and late asthmatic response after bronchial allergen challenge.     

Reproducibility of responsiveness to a standardized bronchial allergen provocation—Rt compared to FEV1 as measurement of response to provocation

Standardized bronchial allergen provocation was performed twice in nineteen extrinsic, well defined, stable asthmatic patients, with an interval of median 15 days (range 14–19) to study the reproducibility of the bronchial response. Smoking and medications were withheld prior to the provocation after a rigid scheme. Ten-fold increasing concentrations of allergen solution 0.9 ml were inhaled by tidal volume breathing for 5 min with intervals of 10 min. The bronchial response to inhaled allergen was determined by forced expiratory volume in the first sec (FEV₁) and by total resistance to breathing (R_t) determined by an opening interrupter method. The provocation was continued until an allergen concentration causing at least 20% decrease of the postsaline FEV₁ or a 40% increase in R_t was reached. A PC₂₀-FEV₁ and a PC₄₀-R_t was calculated by interpolation on the log-dose-response curve. The reproducibility of PC₂₀-FEV₁ allergen was high with a 95% confidence interval (CI) for a single determination being the observed value ±0.83, ten-fold concentration difference, the intraclass correlation (IC) was 0.99 and the coefficient of variation 8.46%. Concerning PC₄₀-R_t a 95% CI for a single determination was calculated being the observed value ±0.58, ten-fold concentration difference, IC was 0.99 and the coefficient of variation was 5.79%. No significant correlation was found between differences in pre-challenge FEV₁ and R_t values and the corresponding PC₂₀-FEV₁ and PC₄₀-R_t values. Least square regression between PC₂₀-FEV₁ and PC₄₀-R₁ was performed for the first and the second provocation (P < 0.05). We conclude that bronchial allergen challenge performed in stable asthmatics is highly reproducible and as such a valuable test in the diagnosis of allergic asthma when connected with anamnesis, skin-prick test and the level of specific immunoglobulin E in peripheral blood.     

The Effects of Perfluorodecanoic Acid on Hepatic Stearoyl-Coenzyme A 1 Desaturase and Mixed Function Oxidase Activities in Rats

The Effects of Perfluorodecanoic Acid on Hepatic Stearoyl-CoenzymeA Desaturase and Mixed Function Oxidase Activities in Rats.VANRAFELGHAM, M. J., AND ANDERSON, M. E. (1988). Fundam. Appl.Toxicol. 11, 503-510. Perfluorodecanoic acid (PFDA) causes adioxin-lilce toxic syndrome and alters the hepatic oleate/stearateratio in rats. The acute toxic effects of a single ip dose (50mg/kg) of PFDA on hepatic stearoyl-CoA desaturase and mixedfunction oxidases were studied in male Fischer-344 rats, 14days after dosing. PFDA causes a marked decrease in food intakein rats, resulting in severe body weight loss with delayed lethality(2-3 weeks after dosing). To distinguish the effects of hypophagiafrom those caused by PFDA, pair-fed control rats were used inaddition to ad libitum-fed controls. Stearoyl-CoA desaturaseactivity, responsible for the conversion of stearoyl-CoA tooleoyl-CoA, was absent in both PFDA dosed rats and their pair-fedcontrols at Day 14. Electron transfer through the desaturasesystem was significantly reduced in PFDA-treated rats only,and in these rats there was a significant reduction in microsomalcytochrome an important component of this electron transfersystem. Pentobarbital sleeping times were significantly prolongedin both the PFDA-dosed and pairfed rats, as compared with thead libitumfed controls. This effect was more pronounced in PFDA-dosedrats. Waking plasma pentobarbital concentration was similarin all treatment groups. Hepatic microsomal cytochrome PASOcontent was unaffected. Aminopyrine N-de-methylase activitywas greatly reduced in PFDA-dosed rats. Although pairfed controlsalso had reduced demethylase activity, it was not as pronouncedas in PFDA-dosed rats, and was probably due to the fasted conditionof these animals. Although the mechanism of action of PFDA isnot known, it is possible that PFDA affects microsomal enzymesby altering the structure and/or function of the membranes inwhich they are located, through effects on lipid metabolism.     

The prognostic value of maximal exercise testing soon after first myocardial infarction

The prognostic value of ST-segment depression during maximalexercise test performed in the third to fourth week after acutemyocardial infarction (AMI), was studied in 126 consecutivepatients with no evidence of previous myocardial infarction,unstable angina pectoris or severe heart failure. All patientson average increased their pressure-rate product by 2.6 andno complications occurred. Within the first year of follow-up,major cardiac events occurred in 9 patients (20%), and werefatal in 6 (13%), of the 46 patients who developed ST-segmentdepression during exercise. Only 3 major cardiac events (4%)occurred in the 80 patients without exercise induced ST-segmentdepression. Depression of the ST-segment on maximal exercisewas a significant predictor of subsequent cardiac events inthese survivors of first AMI.     

Polychlorotrifluoroethylene (PCTFE) Oligomer Pharmacokinetics in Fischer 344 Rats: Development of a Physiologically Based Model

The hydraulic fluid oil polychiorotrifluoroethylene (PCTFE)is hepato- and nephrotoxic in the rat. Male Fischer 344 ratswere exposed to PCTFE either for a single 6-hr exposure (0.5or 0.25 mg/liter) or daily 5 days/week, 6 hr/day, for 13 weeks(0.5, 0.25, or 0.01 mg/liter). Blood, tissue, and urinary PCTFEconcentrations measured postexposure were used to develop aphysiologically based pharmacokinetic (PB-PK) model. The PCTFEhydraulic fluid used was a mixture of trimeric and tetramericoligomers with minor amounts of other chain lengths. The PB-PKmodel was designed to describe the behavior, not of individualoligomers, but of total mass for the trimer and tetramer ineach tissue. Partition coefficients were estimated using themodel to optimize tissue/blood concentration ratios measuredat the end of the 13-week exposure. First-order metabolic rateconstants for both trimeric (2.0 ^hr–1) and tetrameric(1.0 ^hr–1) portions were estimated by optimization againsturinary fluoride data assuming release of 0.77 mole fluorideper mole trimer and 0.844 mole fluoride per mole tetramer metabolized.To obtain accurate simulation of pharmacokinetic data it wasnecessary to hypothesize two fat compartments with diffusion-limitedexchange of PCTFE oligomer with the blood. Relative concentrationsof trimer and tetramer in venous blood, liver, and fat aftera single 6-hr exposure were proportional to inhaled concentrations.Tetramer accumulated preferentially with multiple exposure.Components of PCTFE were metabolized to carboxylic acids withrelease of fluoride. Due to their persistence tetrameric oligomersappear to be more important than trimeric oligomers as causativeagents of PCTFE hepato and nephrotoxicity in the rat.     

Catecholaminergic Polymorphic Ventricular Tachycardia with QT Prolongation

The QT interval in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) is typically normal. However, CPVT patients are sometimes misdiagnosed as concealed long QT syndrome (LQTS), because patients with LQTS also manifest with syncope or sudden death following periods of exertion or extreme emotion. We report a CPVT patient with a pathogenic RyR2 mutation associated with a marked QT prolongation, which normalized after flecainide therapy.