RESUMO
A new formulation of mometasone furoate (MF) for administration by dry powder inhaler (DPI) was evaluated for the treatment of asthma. A 12-week, double-blind, placebo-controlled dose-ranging study compared the efficacy and safety of three doses of MF DPI (100, 200 and 400 mcg b.i.d) with beclomethasone dipropionate (BDP) 168 mcg b.i.d. administered by metered dose inhaler in 365 adult or adolescent patients being treated with inhaled glucocorticoids. The mean change from baseline to endpoint (last treatment visit) for forced expiratory volume in 1 sec (FEV1) was the primary efficacy variable. Secondary efficacy variables included other objective measures of pulmonary function [forced vital capacity (FVC), forced expiratory flow 25-75% (FEV25-75%.) and peak expiratory flow rate (PEFR)] as well as subjective measures of therapeutic response (patients' daily evaluation of asthma symptoms and physicians' evaluation). At endpoint, all four active treatments were significantly more effective than placebo (P < 0.01) in improving FEV1 (MF DPI 5 to 7%, BDP 3%, placebo -6.6%) and all other measures of pulmonary function (FVC: MF DPI 4 to 5%, BDP 2%, placebo -4.7%; FEF25-75%: MF DPI 6 to 18%, BDP 7.5%, placebo -9.5%; PEFR (AM): MF DPI 5 to 10%, BDP 5.7%, placebo -7%). A consistent trend was observed for better improvement in patients treated with MF DPI 200 mcg b.i.d. than with MF DPI 100 mcg b.i.d., with no apparent additional benefit of MF DPI 400 mcg b.i.d. Results for the MF DPI 100 mcg b.i.d. and BDP 168 mcg b.i.d. treatment groups were similar. Patients' and physicians' subjective evaluations of symptoms found similar improvement in the MF DPI 200 and 400 mcg b.i.d. treatment groups, which were slightly better than that in the MF DPI 100 mcg b.i.d. group. Symptoms tended to worsen in the placebo group. MF DPI was well tolerated at all dose levels and the most frequently reported treatment-related adverse effects were headache, pharyngitis and oral candidiasis. No evidence of HPA-axis suppression was detected in any treatment group. In summary, all doses of MF DPI were well tolerated and significantly improved lung function and MF DPI 400 mcg (200 mcg b.i.d.) was the optimal dose in this study of patients with moderate persistent asthma.
Assuntos
Antialérgicos/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Asma/tratamento farmacológico , Adolescente , Adulto , Idoso , Antialérgicos/efeitos adversos , Anti-Inflamatórios/efeitos adversos , Criança , Método Duplo-Cego , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Masculino , Fluxo Máximo Médio Expiratório/efeitos dos fármacos , Pessoa de Meia-Idade , Furoato de Mometasona , Pico do Fluxo Expiratório/efeitos dos fármacos , Pregnadienodiois , Resultado do Tratamento , Capacidade Vital/efeitos dos fármacosRESUMO
This study was a single center trial comparing the effects of the nonsedating antihistamine terfenadine, at a dose of 120 mg twice a day, with placebo in the treatment of rhinitis symptoms associated with the common cold. Forty-nine subjects were treated with terfenadine, 120 mg twice each day, and 48 subjects were treated with placebo twice each day for four or five days. Evaluations by both subjects and physicians suggest that terfenadine at 120 mg given twice daily marginally improved sneezing and total symptom scores at day 4. When comparing terfenadine to placebo, neither the symptoms nor signs of the common cold improved in a clinically or statistically significant manner. Terfenadine was well tolerated and had a low incidence of side effects. Terfenadine was found to be ineffective in the treatment of the signs and symptoms of the common cold.
Assuntos
Resfriado Comum/tratamento farmacológico , Terfenadina/uso terapêutico , Administração Oral , Adolescente , Adulto , Idoso , Criança , Resfriado Comum/patologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terfenadina/administração & dosagem , Terfenadina/efeitos adversos , Fatores de TempoRESUMO
Pemirolast is a potent, long-acting, orally effective antiallergic agent evaluated for clinical activity in prevention of symptoms of seasonal allergic rhinitis. It was evaluated in a randomized, double-blind, placebo-controlled parallel group in season trials to test its safety, tolerance, and prophylactic activity. Thirty-one patients with a history of fall seasonal allergic rhinitis were treated for 6 weeks with pemirolast, 50 mg bid, or placebo beginning approximately 2 weeks before the onset of the ragweed season in Atlanta. Daily evaluation of symptom scores disclosed statistically significantly less sneezing, rhinorrhea, and stuffy nose during treatment with pemirolast. There was, however, no difference for other evaluated symptoms or for the use of rescue medicines. There were no side effects during this short study. This preliminary study indicates that pemirolast may warrant further evaluation for the treatment of allergic rhinitis.
Assuntos
Antagonistas dos Receptores Histamínicos/uso terapêutico , Piridinas/uso terapêutico , Pirimidinonas/uso terapêutico , Rinite Alérgica Sazonal/prevenção & controle , Adolescente , Adulto , Eosinófilos , Feminino , Seguimentos , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Mucosa Nasal/patologiaRESUMO
Test-to-test reproducibility, user variability, and the effect of positive reactions on adjacent negative sites were evaluated for the Multi-Test skin testing device. Twenty-five subjects had skin tests with 24 histamine (1 mg/ml), four glycerosaline controls, and four "dry" controls on two testings 7 days apart. To assess reproducibility from large and smaller histamine reactions and/or their effect on adjacent negative controls, 10 of the 25 subjects were retested once with the same testing format, but histamine at 10 mg/ml was substituted. To determine whether large allergen reactions affect adjacent negative controls differently than histamine reactions, 24 additional patients were retested on arms and back with negative controls adjacent to allergens to which they had prior 3+ to 4+ skin test reactions. Conclusions from 2688 skin tests on 49 patients are as follows: large (mean > 10 mm) histamine reactions reproduced better than smaller (mean < 7 mm) responses--coefficients of variation were 12.3 and 21.4 respectively. A 14% user variability occurred when comparing mean wheal sizes from histamine produced by each nurse and 1.2% when comparing their coefficients of variation. Neither small histamine reactions nor large reactions from histamine and allergens affected adjacent negative controls. We conclude that Multi-Test is a highly reliable skin testing technique that provides good reproducibility of results and low user variability.
Assuntos
Hipersensibilidade Imediata/diagnóstico , Testes Cutâneos/instrumentação , Adolescente , Adulto , Estudos de Avaliação como Assunto , Reações Falso-Negativas , Reações Falso-Positivas , Feminino , Histamina/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos TestesRESUMO
A multicentered trial compared the effects of the non-sedating antihistamine, loratadine, 5 mg plus pseudoephedrine 120 mg with a placebo on the signs and symptoms of the common cold. One hundred forty-two (142) subjects were treated with the loratadine/pseudoephedrine combination and 141 subjects were treated with placebo twice daily for five days. Evaluations by both subjects and physicians suggest that this antihistamine/decongestant combination is superior to placebo in relieving symptoms of the common cold. Specific differences were found in symptoms including nasal congestion, sneezing, postnasal drainage, and nasal discharge. Differences between groups for the following side effects were found: dry mouth (9% for the combination vs 2% for placebo), insomnia (6% vs 3%), and nervousness (4% vs 2%). There were no differences between groups for the frequency of drowsiness.
Assuntos
Resfriado Comum/tratamento farmacológico , Ciproeptadina/análogos & derivados , Efedrina/uso terapêutico , Antagonistas dos Receptores Histamínicos/uso terapêutico , Adolescente , Adulto , Idoso , Criança , Ciproeptadina/uso terapêutico , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Humanos , Loratadina , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como AssuntoRESUMO
BACKGROUND: Despite current recommendations, many patients with persistent asthma are still treated with bronchodilators alone. OBJECTIVE: The safety and efficacy of two once daily dosing regimens (200 microg and 400 microg) of mometasone furoate (MF) administered in the morning by using a dry-powder inhaler (DPI) were compared with those of a twice daily dosing regimen (200 microg administered twice daily) in patients with mild-to-moderate persistent asthma previously taking only inhaled beta(2)-adrenergic agonists. METHODS: All patients (306 patients; age range, 12-70 years) were given a diagnosis of asthma for at least 6 months before enrollment in this 12-week, placebo-controlled, double-blind, randomized study. The primary efficacy variable was change in FEV(1) from baseline to endpoint (last evaluable visit). RESULTS: At endpoint, FEV(1) was significantly improved (P < or =.02) after MF-DPI 400 microg once daily morning treatment and MF-DPI 200 microg twice daily treatment (16.0% and 16.1%, respectively) compared with placebo (5.5%). The improvement seen with MF-DPI 200 microg once daily morning treatment (10.4%) was not significantly different from that with placebo. Secondary efficacy variables also showed significant improvement for the MF-DPI 400 microg once daily morning treatment group and the MF-DPI 200 microg twice daily treatment group compared with the placebo group. All doses of MF administered by means of a DPI were well tolerated. CONCLUSION: This is the first study to demonstrate that a total daily dose of 400 microg of MF administered by means of a DPI is an effective treatment for patients with mild-to-moderate persistent asthma previously taking only inhaled beta(2)-adrenergic agonists. This treatment was equally effective when administered either as a once daily or twice daily regimen.
Assuntos
Anti-Inflamatórios/administração & dosagem , Asma/tratamento farmacológico , Pregnadienodiois/administração & dosagem , Adolescente , Adulto , Idoso , Albuterol/administração & dosagem , Albuterol/efeitos adversos , Anti-Inflamatórios/efeitos adversos , Ritmo Circadiano , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Furoato de Mometasona , Pregnadienodiois/efeitos adversos , Testes de Função RespiratóriaRESUMO
BACKGROUND: Astemizole, an H1-histamine-receptor antagonist prescribed for seasonal allergic rhinitis, has a slow onset of action and a strong suppressive effect on the wheal and flare reaction, which interferes with skin testing results. The newer antihistamine cetirizine appears to have a rapid onset of action and a low potential to interfere with posttreatment skin testing results. OBJECTIVE: To compare the efficacy, safety, and skin test inhibition of astemizole and cetirizine in the treatment of seasonal allergic rhinitis. METHODS: In a double-blind, parallel-group study conducted at six sites during ragweed pollination season, 263 subjects were randomized to receive 10 mg of astemizole, 5 mg of cetirizine, or 10 mg of cetirizine daily for 2 weeks. The subjects rated seven allergic rhinitis symptoms daily, the subjects and investigators provided global assessments of the responses to the treatments, and the subjects rated their satisfaction with the treatments. Thirty-nine subjects at one study site underwent quantitative skin testing before and after treatment. RESULTS: As measured by reduction from baseline in total symptom severity score, which was the primary efficacy measure in the study, all three treatments significantly relieved the symptoms of allergic rhinitis (P less than .05). This finding was supported by the global ratings and the subject satisfaction ratings. There were no significant differences among the three treatments for reduction from baseline in total symptom severity score. The mean subject satisfaction score with 10 mg of cetirizine was significantly greater than that with astemizole (P less than .05). In the skin tests performed 3, 7, and 14 days after the end of antihistamine treatment, the subjects who had received the cetirizine doses had significantly greater mean sum of wheal and mean sum of erythema values than those who had received the astemizole dose (P less than .05). Sensitivity to ragweed pollen extract returned to 90% of baseline within three days of the end of cetirizine treatment. Both drugs were well tolerated and their adverse event profiles were similar. CONCLUSIONS: Astemizole and cetirizine are effective and well tolerated in alleviating the symptoms of ragweed-induced allergic rhinitis. Cetirizine inhibits skin test results to a much lesser extent than does astemizole. Physicians may wish to consider the potential for skin test inhibition when selecting an antihistamine for patients with allergic rhinitis.
Assuntos
Astemizol/efeitos adversos , Astemizol/uso terapêutico , Cetirizina/efeitos adversos , Cetirizina/uso terapêutico , Testes Intradérmicos , Rinite Alérgica Sazonal/diagnóstico , Rinite Alérgica Sazonal/tratamento farmacológico , Adolescente , Adulto , Idoso , Análise de Variância , Antialérgicos/efeitos adversos , Antialérgicos/farmacologia , Antialérgicos/uso terapêutico , Astemizol/farmacologia , Cetirizina/farmacologia , Criança , Método Duplo-Cego , Feminino , Antagonistas dos Receptores Histamínicos H1/efeitos adversos , Antagonistas dos Receptores Histamínicos H1/farmacologia , Antagonistas dos Receptores Histamínicos H1/uso terapêutico , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
The development of tolerance to the bronchodilator effects of beta2-agonists used in asthma therapy has been the subject of debate. We conducted two placebo-controlled crossover studies to assess the bronchodilator response to a short-acting beta2-agonist before and after chronic therapy with salmeterol. Patients in one study were corticosteroid-naive; patients in the other study were using inhaled corticosteroids. Changes in FEV1 after cumulative doubling doses of inhaled albuterol were assessed after a 2-wk beta-agonist washout period, before administering study medication on Day 1, and again after 28 d of therapy. Ipratropium bromide was provided as rapid-relief treatment for asthma, and use of any beta2-agonist except the study treatment was prohibited. On both assessment days for salmeterol, and during placebo administration periods, significant increases from predose FEV1 values were observed beginning with the lowest dose of albuterol and continuing throughout the dose-response assessment (p = 0.001). These increases in FEV1 were maintained for 6 h after the last dose of albuterol (p < 0.05). There were no statistically significant differences in the albuterol dose response following salmeterol or placebo. These studies indicate that irrespective of concurrent corticosteroid treatment, chronic therapy with salmeterol does not result in tolerance to the bronchodilator effects of albuterol.
Assuntos
Agonistas Adrenérgicos beta/uso terapêutico , Albuterol/análogos & derivados , Albuterol/uso terapêutico , Asma/tratamento farmacológico , Broncodilatadores/uso terapêutico , Adulto , Albuterol/efeitos adversos , Asma/fisiopatologia , Pressão Sanguínea/efeitos dos fármacos , Broncodilatadores/efeitos adversos , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Resistência a Medicamentos , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Xinafoato de SalmeterolRESUMO
The objective of this study was to determine the time to onset of symptom relief following a single dose of mometasone furoate nasal spray (MFNS) in symptomatic patients with seasonal allergic rhinitis (SAR). This was a single-center, placebo-controlled, double-blind, randomized, parallel-group study with a 7-day run-in period followed by a single-dose administration of medication or placebo in an outdoor park setting. The park site provided an acute exposure to seasonal (tree and grass) pollens. Patients remained in the park of approximately 12 hours after dosing, during which time hourly assessments of SAR symptoms were recorded on a diary card. Two hundred thirty-nine patients with symptoms of SAR entered the study. Patients receiving any concurrent medication for treatment of their symptoms were excluded. Patients were randomized in a 1:1 ratio to receive treatment with either a single dose of MFNS (200 micrograms/or matching placebo nasal spray. Outcome measures included an assessment of overall therapeutic response and change from baseline in total nasal plus non-nasal sign/symptom severity score, total nasal sign/symptom severity score, and total non-nasal sign/symptom severity score. Improvement in total nasal symptom scores, total non-nasal symptom scores, and total nasal plus non-nasal symptom scores were greater and more sustained in patients receiving MFNS than in patients receiving placebo. The mean decrease from baseline in total nasal plus non-nasal symptom scores was significantly greater in MFNS-dosed patients than in placebo-dosed patients at 5 hours after dosing (p < 0.01). The mean decrease from baseline in total nasal symptom scores was significantly greater in MFNS-dosed patients than in placebo-dosed patients at 7 hours after dosing (p < 0.01). The between-treatment differences in total nasal plus non-nasal symptom scores and total nasal symptom scores remained significant for all subsequent hourly assessments through 12 hours post-dose. Patient assessments of overall response to therapy at end point were significantly different between treatment groups (p < 0.01) with 60.5% of MFNS-treated patients reporting complete, marked, or moderate relief compared with 46.5% of placebo-treated patients. Mometasone furoate nasal spray produces a statistically significant improvement in nasal symptom scores in patients with SAR by 7 hours after administration of a single 200 micrograms dose (100 micrograms in each nostril).
Assuntos
Antialérgicos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Mucosa Nasal/efeitos dos fármacos , Pregnadienodiois/uso terapêutico , Rinite Alérgica Sazonal/tratamento farmacológico , Administração Tópica , Adolescente , Adulto , Criança , Método Duplo-Cego , Meio Ambiente , Feminino , Glucocorticoides , Humanos , Masculino , Pessoa de Meia-Idade , Furoato de Mometasona , Nebulizadores e Vaporizadores , Pólen , Rinite Alérgica Sazonal/fisiopatologia , Resultado do TratamentoRESUMO
BACKGROUND: Mometasone furoate nasal spray (MFNS, NASONEX ), is a new synthetic corticosteroid with considerable efficacy in the treatment of seasonal and perennial rhinitis and less than 0.1% systemic absorption. This study was designed to evaluate the time of onset of action of MFNS. The subjects were evaluated over the course of 2 weeks during the spring allergy season. METHODS: The effects of MFNS 200 microg given once daily for 2 weeks were evaluated in a randomized, multicenter, double-blind, placebo-controlled study in 201 patients with seasonal allergic rhinitis. Clinically significant onset of action was assessed prospectively by special patient diary cards kept during the first 3 days of treatment. RESULTS: By 12 h after initial dosage (the earliest evaluation), 28% of patients in the MFNS group experienced clinically significant relief, compared with 13% of those given placebo (P = 0.01). Median time to at least moderate symptom relief in patients who received MFNS was 35.9 h, compared with more than 72 h in patients given placebo (P<0.01). By 72 h, 64% of the patients receiving MFNS experienced at least moderate relief, compared with 40% of those treated with placebo (P<0.01). Both patient and physician ratings of symptom severity, response to treatment, and overall condition of rhinitis indicated significant (P<0.01) superiority of MFNS over placebo. MFNS was well tolerated, with adverse events comparable to placebo. CONCLUSIONS: MFNS provided rapid onset of clinically significant symptom relief in patients with seasonal allergic rhinitis.
Assuntos
Antialérgicos/administração & dosagem , Pregnadienodiois/administração & dosagem , Rinite Alérgica Sazonal/tratamento farmacológico , Administração Intranasal , Adolescente , Adulto , Criança , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Furoato de Mometasona , Autocuidado , Fatores de TempoRESUMO
This multicenter, randomized, investigator-blinded, parallel group study compared the effects of converting patients from a q12h extended-release theophylline preparation (Theo-Dur) to a q24h extended-release product (Uni-Dur). Patients (n = 133) first received open-label Theo-Dur treatment with dosage titrated to achieve peak serum theophylline concentrations of 10-20 micrograms/ml. Patients then were randomized to continue Theo-Dur (n = 64) or to convert to Uni-Dur (n = 60) with peak serum theophylline concentrations maintained in the desired range. Pulmonary function tests were performed during the open-label and blinded periods; patients maintained diaries and performed peak flow measurements before each dose of study treatment. Adverse events were recorded throughout the study. Respiratory status during blinded treatment was rated as the same or improved compared with open-label treatment by > 87% of evaluable patients and physicians, regardless of treatment group. There were no significant differences in mean peak serum theophylline concentrations at baseline, at the final evaluation, or at any point during the study. Few dosage adjustments were necessary (5/52, Uni-Dur; 9/57, Theo-Dur). There were no significant changes in pulmonary function test results or patient diary entries between the open-label and blinded periods. Headache and nausea were the most commonly reported adverse events. In conclusion, converting patients from twice- to once-daily theophylline treatment resulted in no significant changes in any measures of pulmonary function, and there were no significant differences between the groups during the blinded treatment period.
Assuntos
Asma/tratamento farmacológico , Bronquite/tratamento farmacológico , Enfisema Pulmonar/tratamento farmacológico , Teofilina/administração & dosagem , Adulto , Testes de Provocação Brônquica , Broncodilatadores/uso terapêutico , Preparações de Ação Retardada , Esquema de Medicação , Feminino , Humanos , Masculino , Testes de Função Respiratória , Teofilina/efeitos adversos , Teofilina/sangueRESUMO
BACKGROUND: Topical nasal corticosteroids are rapidly gaining acceptance as first-line therapy for seasonal allergic rhinitis, but there is a desire for effective corticosteroids with an improved safety profile over existing products. OBJECTIVE: A multicenter, double-blind dose ranging study was conducted to compare the activity and tolerance of four doses of mometasone furoate nasal spray (tradename Nasonex) and placebo in adult patients with seasonal allergic rhinitis. METHODS: Four hundred eighty patients with seasonal allergic rhinitis were enrolled and randomized to receive mometasone furoate nasal spray 50 micrograms (n = 96), 100 micrograms (n = 95), 200 micrograms (n = 98) or 800 micrograms (n = 95), or placebo vehicle (n = 95) once daily for 28 days. RESULTS: All of the doses of mometasone furoate nasal spray showed activity in reducing the severity of rhinitis. The 200-microgram dose reduced total nasal symptom scores and total symptom scores throughout the study (P < .05 versus placebo vehicle). The 50-microgram dose and the 100-microgram dose showed less consistent activity at early timepoints (days 3 and 7), while the 800 microgram dose did not provide significant additional benefits over the 200-microgram dose. All dose levels were well tolerated CONCLUSION: The results of this trial indicate that 200 micrograms once daily is the optimum dose of mometasone furoate nasal spray for the treatment of seasonal allergic rhinitis.
Assuntos
Anti-Inflamatórios/administração & dosagem , Pregnadienodiois/administração & dosagem , Rinite Alérgica Sazonal/tratamento farmacológico , Administração Intranasal , Adolescente , Adulto , Idoso , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Glucocorticoides , Humanos , Masculino , Pessoa de Meia-Idade , Furoato de MometasonaRESUMO
BACKGROUND: The efficacy and safety of mometasone furoate aqueous nasal spray (MFNS; Nasonex) 200 microg once daily for the treatment and prophylaxis of seasonal allergic rhinitis (SAR) and treatment of perennial rhinitis have been demonstrated in adults. However, the dose response of MFNS in pediatric patients has not yet been characterized. OBJECTIVE: This study was conducted to determine the dose-response relationship of 3 different doses of MFNS in a pediatric population. METHODS: This was a multicenter, double-blind, active- and placebo-controlled study of 679 children 6 to 11 years of age with histories of SAR and documented positive skin test responses. Patients were randomized to one of the following treatment groups for 4 weeks: MFNS 25 microgram once daily, MFNS 100 microgram once daily, MFNS 200 microgram once daily, beclomethasone dipropionate 84 microgram twice daily (168 microgram/day), or placebo. Physician evaluations were performed at days 4, 8, 15, and 29, and patient evaluations were analyzed for days 1 to 15 and 16 to 29. RESULTS: The mean reduction from baseline in physician-evaluated total nasal symptom scores at day 8 (the primary efficacy variable) was significantly greater in the MFNS and beclomethasone dipropionate groups than in the placebo group (P =.02). No significant differences were observed among the 3 MFNS groups. However, as treatment continued, symptoms in patients treated with MFNS 100 or 200 microgram once daily continued to improve, whereas those treated with MFNS 25 microgram once daily demonstrated little further improvement. By day 29, MFNS 100 and 200 microgram once daily both were significantly more effective than MFNS 25 microgram once daily in relieving symptoms of SAR, but MFNS 200 microgram provided no additional benefit over MFNS 100 microgram. All doses of MFNS were well tolerated, and cosyntropin stimulation tests performed before and after treatment found no evidence of hypothalamic-pituitary-adrenal axis suppression. CONCLUSION: These results indicate that the most appropriate therapeutic dosage of MFNS in the treatment of SAR in children 6 to 11 years of age is 100 microgram once daily. In addition, MFNS at doses up to 200 microgram once daily for 4 weeks was well tolerated and had no detectable effects on hypothalamic-pituitary-adrenal axis function.