Pharmacokinetic/pharmacodynamic modelling of the eosinopenic and hypokalemic effects of formoterol and theophylline combination in healthy men.

Interactions of formoterol and theophylline were evaluated with the use of pharmacokinetic-pharmacodynamic (PK/PD) modelling. Oral doses of 144 microg of formoterol and 375 mg of theophylline were given separately or combined to healthy subjects. As effect parameters, plasma eosinophil and potassium concentrations were used. Kinetic interactions between formoterol and theophylline were not found. Plasma drug concentrations were linked to the observed effects via an effect compartment model with a sigmoid E max model. The E max values+/-SD for the hypokalemic effects were 2.29+/-0.78 mmol/l for formoterol and 1.64+/-1.16 mmol/l for theophylline (P>0.05). The E max values for the eosinopenic effects were fixed at zero. The EC 50 values of the eosinopenic and hypokalemic effects were respectively 91.4+/-38.2 pg/ml and 128.4+/-52.9 pg/ml for formoterol, and 11. 9+/-4.6 microg/ml and 15.5+/-4.8 microg/ml for theophylline. Effects of both drugs combined were described with a non-competitive interaction model. The correlation coefficients of the fits of the eosinopenic and hypokalemic effects were respectively 0.9520+/-0. 0311 and 0.9371+/-0.0227, supporting our hypothesis of non-competitive interaction.

Pharmacokinetics and effects of formoterol fumarate in healthy human subjects after oral dosing.

OBJECTIVE: To evaluate the effects of formoterol after oral administration on plasma eosinophils and plasma potassium in healthy subjects. METHODS: Plasma concentrations of formoterol, peripheral eosinophil count and plasma potassium were determined during 7 h after oral administration of 168 microg of formoterol to eight healthy subjects. Descriptions of the concentration-time course of formoterol are given using a one-compartment pharmacokinetic model with first-order absorption in four subjects and a two-compartment model in the other four subjects. Effects on potassium and eosinophils are described using pharmacokinetic/pharmacodynamic (PK/PD) modelling with the 'effect-compartment' approach. RESULTS: The values of the kinetic parameters were: Ka: 6.9 (h(-1)), t1/2, 8.5 (h), AUC: 741 (pg x h(-1) x l(-1), V(area/f): 1470 (l). Formoterol concentrations were related to dynamic data using a sigmoid Emax model. CONCLUSION: Plasma concentrations of formoterol can be measured in plasma of healthy subjects after oral administration. These data can be used for describing concentration-effect relations with respect to plasma potassium and eosinophils. With comparable EC50 values for the two effects, remarkable differences were found for k(e0) and n values.

Biphasic effect-time courses in man after formoterol inhalation: eosinopenic and hypokalemic effects and inhibition of allergic skin reactions.

The kinetics of inhaled racemic formoterol and its effects on the size of the early cutaneous reaction to intradermal injection of an allergen, eosinopenia and hypokalemia were assessed by pharmacokinetic-pharmacodynamic modeling. After inhalation of either 120 microg of formoterol or placebo, blood samples were taken and skin tests were performed in seven healthy subjects. A two-compartment model was needed to describe the observed formoterol plasma concentration-time curves. To describe the observed biphasic concentration, two absorption routes with different absorption rate constants were incorporated in the model. These two phases were explained by rapid absorption via the respiratory tract together with a slower and delayed oral absorption. For the description of the concentration-effect relations, an Emax (the maximum obtainable effect) formula for competitive agonism, with an effect compartment, had to be used. Fitting the wheal and flare, an apparent diurnal variation had to be taken into account by incorporating in the model rising base-line values. For the flare responses, influence of the location on the forearm appeared to be operative. Systemic formoterol absorbed via the oral route behaved differently from the fraction absorbed via the lungs, with EC50 (steady state concentration that gives 50% of maximum effect) values for all three systemic effects being three times lower after oral absorption than after absorption via the respiratory tract. Pharmacodynamic parameters can probably only be estimated quantitatively when the kinetics of the separate enantiomers of formoterol can be taken into account.

Pharmacodynamic modelling of the drug-induced downregulation of a beta 2-adrenoceptor mediated response and lack of restoration of receptor function after a single high dose of prednisone.

Changes in beta 2-adrenoceptor function by chronic dosing of beta 2-mimetics and the possible influence of a single dose of prednisone have been studied as changes over time in the concentration-effect relationship of the beta 2-adrenoceptor agonist terbutaline. Hypokalaemia was used as the specific beta 2-adrenoceptor mediated effect. 8 healthy volunteers were given subcutaneous terbutaline 0.01 mg.kg-1 BW on 3 occasions over a 10-day experimental protocol: 1 Control experiment on Day 1; 2 After 7 days of oral terbutaline 5 mg t.i.d. (Day 8); and 3 After 8 days on oral terbutaline and 12 h after prednisone 100 mg orally (Day 10). The time course of the terbutaline concentrations and hypokalaemia was related using a pharmacokinetic-pharmacodynamic model. A sigmoid and a threshold Emax model were used to relate drug concentrations to effects. The oral terbutaline treatment caused a 35% increase in the distribution volume of SC terbutaline. After one week on oral terbutaline the concentration-effect relationship was shifted to the right and was steeper, with a higher EC50 of terbutaline and higher values for the apparent threshold concentration. These observations are compatible with a decrease in receptor numbers after 7 days of terbutaline in a system characterised by the presence of spare receptors. The data after prednisone pretreatment showed an apparent decline in the baseline plasma potassium concentrations that could be included in the Emax model. There was no change in the concentration-effect relationship 12 hours after prednisone.

First high-performance liquid chromatography assay of formoterol concentrations in the low-picogram-per-milliliter range.

A method for the assay of plasma concentrations of the long-acting beta 2-adrenoceptor agonist, formoterol is described. This method, in which high-performance liquid chromotography is used with electrochemical detection, enables, for the first time, pharmacokinetic and pharmacodynamic research with this drug. After column extraction of plasma samples, the eluent is injected on the chromatographic system. Retention times of formoterol and the internal standard, bromo-formoterol, were 5.6 and 10 min, respectively. Our results show that this is a sensitive and reproducible method with a very low limit of detection (20 pg/ml), which creates the possibility of measuring concentrations in a range achievable in humans.

Time-dependent effects of dexamethasone administration on the suppression of plasma hydrocortisone, assessed with a pharmacokinetic model.

The influence of the time of dexamethasone (DEX) administration (0.5 mg i.v.) on the suppression of plasma hydrocortisone (HC) was investigated in six healthy subjects, by comparing dosage times of 8 and 20 hr. To estimate HC production after DEX administration a pharmacokinetic model was developed and applied to the time course of plasma HC. This model was based on the assumption that HC production could be described as a continuous i.v. infusion, that stops and starts instantaneously. After DEX at 8 hr, HC production was reduced instantaneously to a minimum level and HC disappeared rapidly from plasma with an elimination half-life of 1.32 +/- 0.28 hr (mean +/- S.D.). Almost complete suppression of HC production lasted for 20 hr. The nocturnal increase in HC production at 20 hr after DEX administration was still attenuated compared to the preceding night. After DEX administration at 20 hr, plasma HC was lower than control for about 20 hr, but it was not reduced to the very low level observed after DEX dosage in the morning. Approximately 20 hr after dosage of DEX at 20 hr, HC production seemed to follow the normal diurnal variation of the control values again. To explain the difference in HC suppression by DEX at different dosage times, we constructed a curve describing the relationship between DEX concentration and suppression of the sudden increase in HC production during the night. This curve indicates that HC suppression by DEX could be completely dependent on DEX concentration, without a DEX independent circadian variation.

Kinetic-dynamic modeling of lymphocytopenia induced by the combined action of dexamethasone and hydrocortisone in humans, after inhalation and intravenous administration of dexamethasone.

Ten healthy male volunteers received 5 mg of dexamethasone sodium phosphate (DEX) i.v. and, on an other occasion, by way of nebulization. Plasma DEX and hydrocortisone (HC) concentrations as well as blood lymphocyte count (BLC) were monitored over 12 hr and at 24 to 28 hr after DEX administration. Bioavailability of DEX after inhalation was about 27% of DEX i.v. DEX-induced depletion of plasma HC could be predicted with a pharmacokinetic model. The reonset rate of HC-production was dependent of DEX dose. BLCs declined after DEX administration, reaching a minimum between 4- and 8-hr postdosing. The DEX- and HC-induced depression of BLC could be described by an integrated pharmacokinetic-pharmacodynamic competitive-interaction model that assumes that both agonists act on the same receptor. With this model the potency and efficacy of DEX and HC with respect to lymphocytopenia could be estimated simultaneously. The potency of DEX was 10 times greater than the potency of HC. The estimated efficacy suggests that HC is only a partial agonist; the maximal lymphocytopenic effect (Emax) of HC was estimated at 80% (27-99%) of the efficacy of DEX. Our results indicate that DEX should be preferred instead of HC in conditions in which the lymphocytopenic effect is the primary systemic corticosteroid treatment goal.

Quantification of theophylline-induced eosinopenia and hypokalaemia in healthy volunteers.

The relationship between theophylline pharmacokinetics and its eosinopenic and hypokalaemic effects were studied in 6 healthy volunteers after an oral dose of theophylline 250 mg. The mean peak theophylline concentration (Cmax) of 8.33 +/- 2.16 mg/L occurred 1.02 +/- 0.26 h after ingestion. The delay between the Cmax and the subsequent eosinopenic or hypokalaemic nadirs was 4.52 +/- 1.73 and 3.65 +/- 1.32 h, respectively. The time courses of theophylline and its effects were linked by a sigmoid Emax effect model. The maximal eosinopenic and hypokalaemic effects (Emax) of the drug were 83 +/- 25.8% and 16 +/- 9.7% of the possible, respectively. The theophylline concentrations causing 50% of the Emax (EC50) were 5.06 +/- 1.84 and 5.04 +/- 2.09 mg/L, respectively. The data obtained with our methodology indicate that, in humans, theophylline induced eosinopenia could be mediated through a receptor and/or postreceptor mechanism unrelated to the mechanism of theophylline induced bronchodilation. We conclude that therapeutic theophylline plasma concentrations have a profound effect on the redistribution of blood eosinophils.

Quantification of metoprolol beta 2-adrenoceptor antagonism in asthmatic patients by pharmacokinetic-pharmacodynamic modelling.

An integrated pharmacokinetic-pharmacodynamic model was used to quantify the beta 2-blocking activity of metoprolol in seven asthmatic patients. The patients received a subcutaneous dose of terbutaline on two consecutive days. On day 1 they were pretreated with placebo and on day 2 with metoprolol 150 mg orally. Beta 2-adrenoceptor mediated changes of plasma potassium and FEV1 were related to plasma concentrations of terbutaline and racemic metoprolol. Metoprolol activity was measured as the competitive (blocking) interaction of racemic metoprolol on the terbutaline response. Plasma concentrations and effects were monitored over 7 h following terbutaline administration. Despite the relative beta 1-selectivity of metoprolol, the effects of terbutaline were considerably attenuated. The mean (racemic) metoprolol concentration that corresponds to 50% maximum metoprolol receptor occupancy (IC50) for the effects on FEV1 and hypokalemia were, respectively, 17 (+/- 8) and 22 (+/- 12) ng/ml and were not statistically discernible. We conclude that individual integrated pharmacokinetic-pharmacodynamic modelling of the concentration-effect relations of agonist and antagonist is a feasible and direct method of quantifying beta 2-blocker effects in asthmatic patients. In stable asthma patients receiving therapeutic doses of metoprolol, the terbutaline plasma concentration needs to be increased two- to four-fold to obtain the same effect on FEV1. Plasma potassium may be considered an appropriate alternative parameter to predict the effect on FEV1.

[A tuberculosis project in Ecuador]. / Een tuberculoseproject in Ecuador.

OBJECTIVE: Determination of the frequency of pulmonary tuberculosis in an Indian community in Ecuador among symptomatic patients and contacts of patients with tuberculosis. Pulmonary tuberculosis was defined as the presence of acid fast rods in sputum. SETTING: Pontificia Universidad Catolica del Ecuador, Quito, Ecuador. DESIGN: Sputum samples were collected with the aid of an educational drama. About 5000 persons were informed on tuberculosis by this performance. The sputum samples from 241 persons were examined for presence of acid-fast rods with a direct Ziehl-Neelsen (ZN) stain and a ZN stain after concentration of the sputum. If ZN stain was negative, the sputum was cultured on Löwenstein-Jensen medium or on Coletsos medium. The Löwenstein-Jensen medium was past the expiration date. RESULTS: Bacteriological examination of the sputum samples from 241 patients and controls brought to light 65 (26.9%) individuals with acid-fast rods in the sputum. Forty per cent of the affected patients were between the ages of 20 and 34. Investigation of 82 contact persons revealed 19 (23.2%) positive cases. The results of culturing of the sputum samples were disappointing: only 6 of 152 (3.9%) samples showed growth of acid-fast rods. CONCLUSIONS: The frequency of pulmonary tuberculosis (as defined by the presence of acid fast rods in sputum) is high in the community investigated, much higher than the official data on the prevalence of tuberculosis indicate. It is important to investigate contacts of patients with pulmonary tuberculosis to trace a source and to trace new cases.

Aerosol application of interferon-alpha in the treatment of bronchioloalveolar carcinoma.

10 patients with locally advanced bronchioloalveolar carcinoma were treated with interferon-alpha as an inhaled aerosol. Initial doses ranged between 1 and 10 MU daily or thrice weekly and were then increased to 20 MU daily. Treatment was continued until disease progression or excessive toxicity occurred, 9 patients were evaluable for toxicity. In 1 case treatment had to be stopped after 2 weeks due to fever, fatigue and progressive dyspnoea. 2 patients developed fever, 1 had malaise, fatigue and loss of appetite and 2 had dose-dependent transient dyspnoea. According to standard criteria no tumour responses could be detected. In 6 out of 8 evaluated for response to interferon, radiological stabilisation of disease for 7-43 weeks (median 15) was observed. These results point to the feasibility of aerosol inhalation of interferon-alpha, but also to its limited antitumour activity in locally advanced bronchioloalveolar carcinoma.

Pharmacokinetic-pharmacodynamic modeling of terbutaline bronchodilation in asthma.

The study of terbutaline pharmacodynamics in patients with asthma is hampered by interfering stimuli when steady-state methods are employed. With pharmacokinetic-dynamic modeling, many of these interferences can be avoided. Using this technique, we studied the effect of terbutaline on lung function in 10 asthmatic patients with greater than 15% lung function reversibility. Terbutaline plasma concentrations, forced expiratory volume in 1 second (FEV1) airway resistance (Raw), and specific airway conductance (sGaw) were measured before and during 7 hours after subcutaneous dosing with 0.75 mg terbutaline. A hyperbolic concentration-effect relation was found. Fitting the time course of the effects required an effect compartment in the integrated model. Thus the delay between plasma concentration and effect time course was characterized by the rate constant ke0. Essentially the same ke0 was found for FEv1, Raw, and sGaw, indicating that the concerning receptors are "localized" in the same pharmacokinetic compartment. Of the lung function measures, sGaw was less sensitive to terbutaline than Raw and FEV1, whereas the latter tended to be the most sensitive one.

67Ga scintigraphy, serum lysozyme and angiotensin-converting enzyme in pulmonary sarcoidosis.

67Ga scintigraphy, using a 67Ga accumulation score, was compared with serum lysozyme (LZM) and angiotensin-converting enzyme (ACE) levels in 34 patients with biopsy-proven, pulmonary sarcoidosis. Serum LZM and ACE values varied between 1.0 to 21.3 mg/l (mean 4.3 +/- 3.4 mg/l) and 33 to 146 U/l (mean 69 +/- 26 U/l), respectively. Normal values were found in 26 and 35% of the patients. All patients, however, had abnormal 67Ga uptake in the pulmonary hilar lymph nodes and/or parenchyma. The follow-up of untreated and treated patients supports the suggestion that 67Ga scintigraphy is more useful for assessing the extent and activity of the intrathoracic sarcoid lesions. Serum LZM and ACE measurements are helpful, but normal LZM and ACE values do not exclude activity and progression of disease in pulmonary sarcoidosis.