Time course of pharmacological modulation of peak eosinophilic airway inflammation after mite challenge in guinea pigs: a therapeutic approach.

BACKGROUND: It is well known that eosinophilic airway inflammation develops after allergen challenge in sensitized humans and animals. However, the detailed time course of suppression of early eosinophilic airway inflammation by pharmacological agents given just after challenge has not been discussed. Therefore, we aimed to evaluate the time course relationship of the suppression of peak eosinophilia by anti-cytokines and pharmacological agents given several hours after the aerosol challenge by a therapeutic approach. METHODS: We used crude mite extract as an allergen to create a sensitization and inhalation challenge, and performed bronchoalveolar lavages (BAL) after the inhalation challenge to observe the degree of eosinophilic airway inflammation in guinea pigs. Various anti-cytokines (anti-IL-3 and anti-IL-5) and pharmacological agents (dexamethasone, theophylline, and roxithromycin) were given within several hours after the acute aeorosol challenge to evaluate the suppressive effect on peak eosinophilia in BAL fluid, which occurred 24 h after the challenge. RESULTS: Our results show that anti-IL-5 and dexamethasone, given within 4 and 8 h after the inhalation challenge, respectively, inhibit the acute allergen-induced peak eosinophilia in BAL fluid. However, anti-IL-3, theophylline, and roxithromycin had no effect on peak eosinophilic airway inflammation after challenge. CONCLUSION: These observations suggest that several hours are needed to complete the process of cytokine-induced recruitment of eosinophils from the blood to the airways after acute allergen challenge. This may be the optimal time to administer anti-cytokines and dexamethasone to attenuate the subsequent eosinophilic airway inflammation after acute allergen-induced asthmatic attacks.

Mite-induced allergic airway inflammation in guinea pigs.

BACKGROUND: Mites are the most common aeroallergen in human allergic asthma. However, no animal model of mite-induced allergic airway inflammation has been reported before. In this study, an animal model of mite-induced allergic airway inflammation in guinea pigs was developed. METHODS: Firstly, we found that two intraperitoneal injections of 100 micrograms crude mite extract (CME), but not multiple aerosol inhalations of 10 mg/ml CME, can cause sensitization in guinea pigs. The sensitization to mites was confirmed by the measurement of serum antimite antibody titer and the detection of anaphylactic bronchoconstriction after intravenous injection of CME solution. Then, single or multiple aerosol challenges with different concentrations (8, 4 or 1 mg/ml) of CME in these sensitized animals were performed. The total white cell and differential counts in the bronchoalveolar lavage (BAL) fluids were studied at different time intervals after challenge in different animals, and tracheal pathology was performed to detect the allergic airway inflammation. For comparison with the study in animals treated with CME, a BAL study in animals treated with ovalbumin was also performed. RESULTS: The inhalation challenge of CME aerosol in sensitized animals caused prolonged eosinophilia in BAL fluid which persisted for at least 7 days after single challenge. Neither inhalation challenge at higher concentrations of CME aerosol nor repeated inhalation challenges increased the degree of eosinophilia in BAL fluid compared to a single challenge. Using the same procedures, we also found that the mite model caused more eosinophilia in BAL fluid than did ovalbumin. CONCLUSION: This is the first report of an animal model of mite-induced allergic airway inflammation in guinea pigs which can provide us with a useful model to study airway inflammation of mite-induced asthma in humans.

The effects of food and divided dosing on the bioavailability of oral vinorelbine.

The effects of food and divided dosing on the bioavailability of a liquid-filled gelatin capsule formulation of vinorelbine (Navelbine), a semisynthetic vinca alkaloid with broad clinical activity, was evaluated in patients with advanced solid tumors. A group of 13 patients were randomized to treatment with the oral formulation at the recommended phase II dose of 80 mg/m2 per week either in the fasting state or after ingestion of a standard meal. Patients were treated 1 week later in the alternate state relative to their first dose. The effects of divided dosing were assessed during the 3rd week, at which time vinorelbine was administered in two divided doses. After the completion of pharmacokinetic and bioavailability studies, patients received the oral formulation at a dose of 80 mg/m2 per week in two divided doses to evaluate the feasibility of chronic oral drug administration. Both manipulations resulted in small, albeit statistically significant, reductions in the relative bioavailability of this oral formulation. The relative bioavailability decreased by 22 +/- 28% when treatment followed the ingestion of a standard meal, possibly due to a delay in gastrointestinal transit time. The mean time of maximum plasma concentration (Tmax) increased from 1.3 +/- 1.6 h in the fasting state to 2.5 +/- 1.6 h in the fed state, although this difference was not statistically significant. Similarly, the relative bioavailability declined by 16 +/- 51% when vinorelbine was administered in two divided doses. An analysis of dose proportionality revealed disproportionate increases in dose-normalized Cmax and AUC values with single oral doses above 120 mg, which may account for this phenomenon. The high clearance of vinorelbine, which approaches hepatic blood flow, and the lack of dose proportionality after oral administration, indicate that there is a large first-pass effect which may be saturable, or nonlinear, above single doses of 120 mg. In addition, the toxicological and pharmacological characteristics of oral vinorelbine indicate that treatment after a standard meal or on a divided dosing schedule is safe. Chronic oral administration of the agent in two divided doses was also well tolerated. However, the small reduction in the relative bioavailability following the ingestion of a standard meal and with divided dosing suggest the need for further pharmacodynamic studies to determine if reductions in drug exposure of this magnitude may portend diminished antitumor activity.

[Continuing hospice care of cancer--a three-year experience].

The hospice at Mackay Memorial Hospital was established in February 1990. A group of team workers including physicians, nurses, social workers and the clergy were involved in this holistic care program for terminal cancer patients. Four hundred and seventy-nine patients were eligible for the program up to February 1993. Regarding duration of stay, 62.5% of patients resided for 14 days. Those surviving under 90 days constituted 75.5% of patients. Fifty-one point eight percent of patients died in the hospice and 18.2% died at home soon after being discharged from the hospice. Pain is the most common symptom among the patients. Treatment strategies vary according to the three-step-ladder protocol designed by WHO. Total pain relief was achieved in 80% of patients. Opportune private talking and family conferences formed the basis of the "peer model". Through this model, treatment decisions including physical, psychosocial and spiritual issues were made. Before the peer model, only 36 (10.3%) patients agreed with the idea of hospice care, while 257 (73.6%) patients agreed after the model was established. Awareness of dying was evident in 412 (86%) patients. Two hundred and eighty (68%) patients became aware of the prospect of death through guessing, while the other 132 (32%) patients were informed by medical staff. Problems encountered by the team workers included 1) needs in education and training, 2) psychological pressure, 3) management of loss and grief, 4) needs in supportive system and 5) troubles caused by families' lying to patients. The team workers were satisfied with the quality of care in 38.4% of patients and fairly satisfied with 30.7% of patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Bronchoprovocation test by forced oscillation technique: airway hyperresponsiveness in chronic cough and psychogenic dyspnea subjects.

By measuring the respiratory resistance (Rrs) with the forced oscillation technique, we evaluated the airway responsiveness to methacholine in four groups of subjects (30 normal, 21 asthmatic, 60 chronic cough, and 30 psychogenic dyspnea subjects). After evaluating the airway responsiveness of normal and asthmatic subjects, four patterns of dose-response curves were found. All of the asthmatic subjects were responders (types III and IV), whereas all but two of the normal subjects were nonresponders (types I and II). The responders had more bronchoconstriction than the nonresponders who presented with a significant decrease in FEV1 after the test. If airway hyperresponsiveness to methacholine was defined as Cmin < or = 12.5 mg/mL, then this test showed 100% sensitivity, 97% specificity, a positive predictive value of 95.5%, and a negative predictive value of 100%. According to these criteria, 18 of 60 (30%) chronic cough subjects and six of 30 (20%) psychogenic dyspnea subjects had airway hyperresponsiveness. We conclude that bronchoprovocation test by the forced oscillation technique is a simple, safe and time-saving tool for measuring airway hyperresponsiveness. We also found that airway hyperresponsiveness is a common finding in subjects with chronic cough, and is also present in some subjects with psychogenic dyspnea.