[Economic burden of COPD: the SCOPE study]. / Impact economique de la BPCO en France: etude SCOPE.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is a major health problem. Few data about COPD economic burden are available. METHODS: SCOPE was an observational economical retrospective and prospective study conducted in France in 2001, by 114 general practitioners (GPs) and 57 lung specialists. The aim was to describe the burden of COPD patients and to estimate the annual cost according to severity stages. Health resource utilization was collected by questionnaires over a 12-month period for 285 patients. RESULTS: It was a cost-of-illness analysis. COPD patients followed by a lung specialist were more severe than patients followed by a GP and had a higher level of medical resource consumption. The COPD disease and its complications explained 66% of the total cost. The main cost drivers were inpatient care (35%, or 1509,9 euros/year/patient) and prescription medications (31%, or 1340,6 euros/year/patient). The direct total cost varied according to COPD severity on account of inpatient care and respiratory assistance. DISCUSSION: This study confirmed the economic burden of COPD in France. Actions allowed to slow down the disease's evolution and to anticipate the exacerbation could reduce the cost.

Characteristics of intermittent and persistent allergic rhinitis: DREAMS study group.

BACKGROUND: In the Allergic Rhinitis and its Impact on Asthma (ARIA) classification, intermittent and persistent rhinitis were proposed to replace seasonal and perennial allergic rhinitis (AR). AIM: To better understand the ARIA classification of rhinitis. METHODS: A cross-sectional study was carried out in 591 patients consulting ENT or allergy specialists for AR and 502 control subjects. The diagnosis of AR was based on a score for allergic rhinitis (SFAR) > or =7. Patients were classified according to the four ARIA classes (mild intermittent, mild persistent, moderate/severe intermittent and moderate/severe persistent). Allergen sensitization (skin prick tests (SPTs) or specific IgE) and co-morbidities were examined according to the ARIA classes. RESULTS: Ten percent of patients had mild intermittent rhinitis, 14% mild persistent rhinitis, 17% moderate/severe intermittent rhinitis and 59% moderate/severe persistent rhinitis. Most patients with intermittent rhinitis had a pollen sensitivity, but 5% had a single house dust mite (HDM) sensitization. Over 50% of patients with persistent rhinitis were allergic to pollens or HDM. Asthma was present in 24% of rhinitis patients and in only 2% of the control population (P<0.0001). Patients with moderate/severe persistent rhinitis had the highest asthma prevalence (33%). DISCUSSION: Intermittent and persistent rhinitis are not synonymous of seasonal and perennial rhinitis. Most patients consulting specialists have severe rhinitis. Asthma prevalence increases with duration and severity of rhinitis supporting the ARIA major recommendation that patients with persistent rhinitis should be evaluated for asthma.

Prevalence of nasal polyposis in France: a cross-sectional, case-control study.

BACKGROUND: The prevalence of nasal polyposis (NP) has never been established in France due to the lack of diagnostic tools for population-based studies. METHODS: Using a recently validated questionnaire/algorithm (90% specificity and sensitivity) in a population-based random sample, the present cross-sectional, case-control study allowed to determine NP prevalence and describe the principal aspects of NP epidemiology. A total of 10 033 subjects (>/=18 years) were screened. After identification of subjects with NP and those without, another questionnaire was submitted to NP patients only for further data collection. Controls were individuals without NP, matched by gender and age to NP patients. RESULTS: Nasal polyposis prevalence was 2.11% (95% CI 1.83-2.39). NP patients (n = 212, 45% males) were aged 49.4 +/- 17.6 years. No gender preponderance was observed, but NP tended to increase with age. Mean duration of nasal symptoms was 22.4 +/- 15.7 years. Among the 145 patients having already seen a doctor for their symptoms, 77.2% have been referred to a specialist, and 18.6% had a diagnosis of NP. Rhinorrhoea was reported by 39.9% of NP patients, blocked nose by 30.8%, and anosmia by 28.9%. Only 6.9% reported facial discomfort while 24.6% complained about general discomfort. Most NP patients (61.3%) had a pharmacological treatment, a nasal spray for the major part (76.9%). CONCLUSION: The present study provides valuable and reliable information on NP epidemiology in France; the collected information are in accordance with most published international data.

The SCOPE study: health-care consumption related to patients with chronic obstructive pulmonary disease in France.

OBJECTIVE: The main objective of the SCOPE study was to estimate the total direct medical costs of patients with treated chronic obstructive pulmonary disease (COPD) in France according to severity stages. METHODS: Total medical resources consumption of a sample of COPD patients was collected over a 12-month period through a national physician survey (including both general practitioners and lung specialists). This survey was completed for 255 patients. Data were then extrapolated to all patients with diagnosed and treated COPD in France. Average total medical resources consumption of a COPD patient per year was 4366 euros. Among this cost 41% was directly related to COPD follow-up, 25% to COPD-related complications (mainly exacerbations), and 34% to other diseases. More than one-third of the total direct COPD cost was related to hospitalizations and 31% to drug consumption. COPD-related costs increased markedly with severity based on FEV1 (but data suggested the existence of a threshold effect). SCOPE data did not show any evidence of a significant relationship between direct medical cost and patient age, sex, addiction to tobacco, or duration of COPD. The total medical consumption of COPD patients in France was 3.5 billion euros and accounted for 3.5% of the total medical expenditures (prevalence of COPD was estimated 1.3% in the general population). RESULTS: The SCOPE study revealed the high level of medical resources consumption of patients with COPD. CONCLUSIONS: The burden of COPD itself and its complications appeared to be of considerable magnitude in France especially for severe COPD.

The score for allergic rhinitis (SFAR): a simple and valid assessment method in population studies.

BACKGROUND: No validated assessment of allergic rhinitis (AR) is presently available that can be used in population studies in the absence of medical diagnosis and of objective measurements of allergy. To compensate for this lack, a quantitative Score For Allergic Rhinitis (SFAR) ranging between 0 and 16 has been developed by experts. METHODS: The SFAR, encompassing eight features of AR, was validated in three different ways: 1) among 269 outpatients taking the specialist's diagnosis of AR and skin prick tests (SPT) positivity as a gold standard (diagnosis validation); 2) using psychometric methods (internal validation); and 3) in a random population-based sample of 3001 individuals by telephone interview (population acceptability). RESULTS: A SFAR value > or = 7 allowed satisfactory discrimination between the outpatients with AR from those without (sensitivity = 74% [95% confidence interval CI: 0.69,0.79], specificity = 83% [0.79, 0.87], positive predictive value = 84% [0.80, 0.88], negative predictive value = 74% [0.69, 0.79] and Youden's index = 0.57, respectively). Internal consistency of the score was also high (among others, Cronbach's alpha coefficient = 0.79). On average, it took only 3 min for the individuals interviewed on the phone to complete the questionnaire, the questions of which were well understood. Among these subjects, the prevalence of AR was 21% [95% CI: 19.5%, 22.5%], which is comparable to other determinations in France. CONCLUSIONS: The newly a priori proposed Score For Allergic Rhinitis (SFAR) is easy to use and can be useful to estimate prevalence and to study causation of AR in population settings.

[Evaluation of an educational program on asthma for pharmacists]. / Evaluation d'une action de formation de pharmaciens officinaux sur l'asthme.

OBJECTIVES: The purpose of this work was to assess the impact of an educational program on asthma for dispensing pharmacists and their teams aimed at improving patient awareness and self-care (use of consultations, drug use, inhalation techniques). METHODS: This retrospective study used a before-after design (T0/T1 year). The patients were recruited by their primary care physician in the vicinity of dispensing pharmacies that had participated in the educational program. Data were collected with a self-administered questionnaire. The study population was divided into two groups, patients who were clients at a pharmacy that had participated in the program ("educated patients") or not ("non-educated patients"). RESULTS: After 1 year, there were fewer emergency consultations, more frequent follow-up visits, greater use of chronic inhalation therapy, better control of drug use techniques, and better knowledge of the asthmatic disease in "educated" patients. DISCUSSION: This study demonstrates the importance of educational programs for dispensary teams: better response to the demands of patients and physicians, better management of the disease and its treatment, better observance and consequently better control of asthma.

Reduction of soluble ICAM-1 levels in nasal secretion by H1-blockers in seasonal allergic rhinitis.

ICAM-1, a transmembrane glycoprotein promoting adhesion in immunologic and inflammatory reactions, was found to be increased on nasal epithelial cells of patients with allergic rhinitis. Loratadine, an H1-blocker, was found to reduce in vitro the expression of ICAM-1 on nasal epithelial cells. A double-blind, parallel-group study was carried out during the pollen season to compare the effect of two H1-blockers, cetirizine (10 mg OD) and loratadine (10 mg OD), on the release of soluble ICAM-1 in nasal secretions. A group of untreated patients was used as a control group. sICAM-1 was measured by enzyme immunoassay before and after 2 weeks of treatment. Symptoms were significantly decreased in the actively treated groups. sICAM-1 levels were unchanged in the control group but were significantly reduced in the two treated groups (P < 0.015, Wilcoxon's W test). This study shows that two H1-blockers, loratadine and cetirizine, have a similar effect on sICAM-1 released in nasal secretions during the pollen season.

Lack of subsensitivity to mizolastine over 8-week treatment.

Mizolastine is a new, nonsedating antihistamine providing satisfactory symptom relief in allergic rhinitis and urticaria. The purpose of this study was to use the wheal and flare skin reactions model to assess the maintenance of the pharmacodynamic effect of mizolastine, administered for 2 months. This double-blind, parallel-group study involved 60 atopic patients randomly allocated, after a 1-week placebo run-in, to once-daily 10 mg mizolastine (n = 29) or placebo (n = 31) groups. Treatment continued for 8 weeks. Prick tests were performed in duplicate with histamine chlorhydrate (10 mg/ml), codeine phosphate (9%), and five increasing concentrations (1-500 reactivity index/ml) of standardized allergen extracts (grass pollen or mites) at days 0, 7, 28, 42, and 56. After 7 days of treatment, inhibition of histamine-induced wheal was -76% and +20%, respectively, with mizolastine and placebo (P = 0.0001), in comparison with baseline; inhibition of flare was -86% and +5%, respectively, with mizolastine and placebo (P = 0.0001). Suppression was maintained to a similar extent throughout the study. Results were consistent between histamine-, codeine-, and allergen-induced tests. Safety was satisfactory in both groups. The study confirms mizolastine as a potent antihistamine which does not induce subsensitivity when taken for 8 weeks, and which can be safely recommended in allergic conditions.

Seasonal variations of interleukin-4 and interferon-gamma release by peripheral blood mononuclear cells from atopic subjects stimulated by polyclonal activators.

IgE synthesis is controlled by interleukin (IL)-4 and interferon (IFN)-gamma, but there is heterogeneity in the IL-4 response depending on the sensitization of patients and natural allergen exposure. In patients sensitized to various allergens, we studied the synthesis of IL-4, IFN-gamma, and IgE to determine to what extent their in vitro immune response may be influenced by pollen season, depending on their sensitization. We studied 12 nonallergic individuals, seven patients sensitized to cypress pollen, 12 sensitized to grass pollen, 14 sensitized to several pollens, and 42 patients with polysensitization. The release of IL-4 and IFN-gamma from peripheral blood mononuclear cells stimulated by polyclonal agents (calcium ionophore A23187 and phorbol myristate acetate) was measured by ELISA. The spontaneous and IL-4-induced release of IgE was measured by ELISA. In patients with cypress pollen allergy, IL-4 and IgE release were significantly lower than in patients with other allergies. In the pollen-sensitized group, IL-4 and IgE release were significantly higher during the pollen season than out of it. No variation in IL-4 or IgE release was observed in the polysensitized group. IFN-gamma production was not affected by the pollen season. These data show that the seasonal variations of IL-4 and IgE synthesis differ according to the sensitization of patients.

Evaluation of a composite scoring system in conjunctival challenge with allergen: reproducibility and evolution during loratadine treatment.

The reproducibility of any challenge and its sensitivity to change during therapeutic interventions should always be examined before any drug trial is conducted. Conjunctival challenge has been widely used to assess objectively the efficacy of antiallergic treatments. A double-blind, placebo-controlled, crossover study was carried out in 26 patients allergic to grass pollen to test the reproducibility of a composite symptom score during placebo and control days, and to check the ability of loratadine to increase the provocative dose inducing a positive challenge. Conjunctival challenge was carried out with increasing concentrations of a standardized orchard grass pollen extract until a composite symptom score of 5 was reached. The provocative dose inducing a positive challenge was similar for the baseline (6.94 +/- 8.7 index of reactivity (IR)) and placebo days (20.0 +/- 32.5 IR) and was significantly increased (P < 0.01 and P < 0.001) when patients received loratadine (117.3 +/- 136.8 IR). This study shows that the composite score used was reproducible and sensitive to change, making it possible to use in drug trials.

Prevention of pollen rhinitis symptoms: comparison of fluticasone propionate aqueous nasal spray and disodium cromoglycate aqueous nasal spray. A multicenter, double-blind, double-dummy, parallel-group study.

Fluticasone propionate aqueous spray, a new intranasal corticosteroid preparation, and disodium cromoglycate 2% aqueous nasal spray, an established preventive treatment for seasonal allergic rhinitis, were compared in a double-blind, double-dummy, parallel-group, multicentric study in France. A total of 218 patients with seasonal allergic rhinitis caused by grass pollen (verified by positive skin prick test) were preventively treated before the onset of the grass pollen season with either fluticasone propionate 200 micrograms once daily or disodium cromoglycate 5.2 mg four times daily. Half of these doses was given in each nostril. Treatment started before the onset of the pollen season in most patients (178/218). Diary cards, including symptoms of rhinitis and usage of nasal sprays, were filled in twice daily for 6 weeks. Terfenadine in 60-mg tablets and eye-drops could be used as rescue medications. We treated 110 patients with fluticasone propionate and 108 patients with disodium cromoglycate. Patients treated with fluticasone propionate had significantly more days free of primary efficacy symptoms of sneezing (P < 0.001) and nasal discharge during the day (P = 0.002), as well as free of all the other nasal symptoms (P < 0.01), and significantly lower median scores (P < 0.05) for all nasal symptoms except nasal discharge than patients treated with disodium cromoglycate. There was no difference in eye symptoms or in rescue medication use between the two groups. Compliance with the treatment was assessed.(ABSTRACT TRUNCATED AT 250 WORDS)

Precision of conjunctival provocation tests in right and left eyes.

BACKGROUND: Conjunctival provocation tests (CPTs) are used for assessing the efficacy of antiallergic treatments, but their reproducibility is not well characterized. A study was carried out to assess the reproducibility of CPTs and the release of mediators during CPTs. METHODS: Both eyes of 30 grass-pollen-allergic patients were challenged with threefold increasing concentrations of a standardized orchard grass pollen extract. The positivity of the CPT was assessed by a cumulative symptom score. The release of mediators was examined by means of histamine (radioimmunoassay), prostaglandin D2 and leukotrienes C4 and D4 (enzyme immunoassay). RESULTS: There was a significant correlation between the concentrations of allergen inducing a positive CPT in both eyes (p < 0.0001, Spearman). All but one patient had a significant release of at least one mediator. After allergen CPT there was a significant release in both eyes in 13 of 20 patients for prostaglandin D2, 11 of 19 for leukotrienes C4 and D4 and 15 of 18 for histamine. The correlations between the levels of mediators released during diluent and allergen challenges in both eyes were significant for prostaglandin D2 (diluent and allergen challenges) and leukotrienes C4 and D4 (allergen challenge). CONCLUSION: Considering the whole group of patients, CPT is reproducible in both eyes, but the results are less satisfactory when patients are examined individually.

Differences in clinical and immunologic reactivity of patients allergic to grass pollens and to multiple-pollen species. II. Efficacy of a double-blind, placebo-controlled, specific immunotherapy with standardized extracts.

The IgE response of patients only allergic to grass pollens differs from response of patients allergic to multiple-pollen species. The IgE immunoblots to orchard-grass pollens confirmed that polysensitized patients had more proteins revealed than patients only allergic to grass pollens. To determine if both groups of patients present a different response toward specific immunotherapy (IT), a double-blind, placebo-controlled study was performed in 70 patients. Patients receiving the active treatment had a rush IT with either a standardized orchard grass-pollen extract or with a standardized mixed-pollen extract prepared, depending on the sensitivity of the patients. The maintenance dose was defined as that dose effective in grass-pollen IT in previous experiments. The same equipotent maintenance dose was administered for all pollen species. Symptom-medication scores during the pollen season and nasal challenge with orchard grass-pollen grains demonstrated that grass pollen-allergic patients had a significantly improved efficacy by comparison to placebo treatment, whereas polysensitized patients had a nonsignificant improvement. Serum grass-pollen IgG was significantly increased after IT in both treated groups. This study demonstrate that the response toward specific IT differs in patients only allergic to grass pollens by comparison to polysensitized patients.

Clinical and immunologic reactivity of patients allergic to grass pollens and to multiple pollen species. I. Clinical and immunologic characteristics.

The heterogeneity of pollen-allergic individuals is well-known but poorly characterized. Twenty-six patients were studied to characterize their immunologic and clinical patterns. Thirteen patients were allergic only to grass pollens, and 13 other patients were allergic to grass-pollen and other pollen species, including Cupressaceae, plane tree, olive, and Parietaria. The IgE response was assessed by the titration of serum total IgE and orchard grass-specific IgE, as well as by IgE immunoblots to orchard-grass pollens. Clinical reactivity was assessed by nasal challenge with orchard-grass pollens before the pollen season and nasal and bronchial symptom-medication scores between April 1 and June 15. Pollen counts were obtained during this period of survey. Polysensitized patients had significantly increased levels of serum total and specific IgE and a greater heterogeneity of IgE immunoblots, suggesting an enhanced qualitative and quantitative IgE immune response. Polysensitized patients had nasal and bronchial symptoms occurring earlier than grass pollen-allergic individuals, confirming the priming effect caused by other plans flowering with an earlier season for both nasal and bronchial mucosa. Alternatively, the early symptoms may be attributable to the tree pollens or might reflect the higher grass-pollen IgE level in the polysensitized group. Bronchial symptoms appeared a few weeks after nasal symptoms. Nasal challenges were similar in both groups, and the severity of nasal symptoms during the season was not significantly different in both groups, suggesting that the intensity of symptoms is not related to the sensitization nor to the IgE immune response of the subjects.

Lack of subsensitivity to loratadine during long-term dosing during 12 weeks.

The development of subsensitivity to first-generation H1 blockers often occurs within days or weeks of treatment. It is manifested by a decrease in efficacy and a waning of the inhibition of skin reactivity to allergen or histamine. Subsensitivity to loratadine was investigated in a double-blind, placebo-controlled parallel group study in 20 allergic subjects (22 to 35 years) who received either placebo or loratadine (10 mg one daily) for 12 weeks. Skin prick tests were done with six threefold increasing concentrations of standardized allergen extracts (orchard grass or mite) and histamine-coated Phazet. Skin tests were done before any treatment and after 7, 28, 56, and 84 days. Wheals and flares were measured. Compliance was monitored strictly during the study. Statistical analysis was done by parallel line bioassay and Wilcoxon W test. Skin test reactivity to histamine or allergen did not change throughout the trial in the placebo-treated group. Patients treated by loratadine had a significantly smaller wheal-and-flare reaction after 7 days. This effect was greater at 28 days and lasted throughout the treatment period. This study demonstrates that subsensitivity to loratadine measured by histamine and allergen skin tests does not develop during a 12-week period.

Comparison between RAST and Pharmacia CAP system: a new automated specific IgE assay.

RAST represents the standard technique to titrate serum-specific IgE and was found to have a higher efficiency in the diagnosis of IgE-mediated allergy than other in vitro tests. Pharmacia CAP system (CAP) is a new solid-phase immunoassay, fully automated, used for the titration of specific IgE antibodies. Results are listed in kilounits per liter, equilibrated against the World Health Organization standard for IgE. RAST and CAP were compared in 106 unselected patients (6 to 59 years) characterized by a detailed clinical history and skin prick tests with standardized allergen extracts. IgE to cat, Dermatophagoides pteronyssinus, Alternaria, orchard grass, olive, and Parietaria pollen were tested; 470 tests were run. The specificity, sensitivity, and efficiency of both in vitro tests ranged from 85.5% to 100% except for olive pollen, in which the sensitivity of both in vitro tests was low (68.2% for the new test and 63.6% for RAST). Except for orchard-grass pollen, the sensitivity and specificity of CAP were better than that of RAST. There was a highly significant correlation between both tests (r range, between 0.864 to 0.987). CAP competes favorably with RAST and has the advantage of being automated and eliciting results in kilounits per liter.

Comparison between modified skin prick test with standardized allergen extracts and Phazet.

Skin prick tests (SPTs) represent one of the most common techniques of skin testing and are of great value, especially when standardized extracts are used. Phazet is a puncture test involving needles coated with standardized allergens. Phazet and SPTs have been compared in 130 subjects tested with six standardized allergen extracts: orchard-grass, olive, and mugwort pollens, cat dander, Dermatophagoides pteronyssinus, and Alternaria. Patients have been carefully selected on the basis of a suggestive clinical history, SPTs, and RAST. For all allergenic species, at least 20 nonsensitive individuals have been tested. The sensitivity (true positive in percent of patients with disease) of Phazet was 99.4%, and its specificity (true negative in percent of patients without disease) was 99.2%. It is concluded that Phazet and SPTs with standardized extracts are equally effective in the diagnosis of immediate-type allergy and that standardized extracts have improved the diagnosis of allergy, especially for previously poorly characterized extracts, such as Alternaria.

Correlation between symptoms and the threshold for release of mediators in nasal secretions during nasal challenge with grass-pollen grains.

Nasal challenges with pollen grains represent one of the techniques of provocation. However, the clinical criteria of positivity are not clearly established. Nasal challenges with increasing numbers of orchard-grass pollen grains were performed in 60 patients allergic to grass pollens and 20 normal subjects. Before any challenge, the nose was washed three times with saline and then lactose, and 50, 150, 450, 1350, and 4050 orchard-grass pollen grains were insufflated into the nostrils until a symptom score of 5 was reached. This score was mainly based on major symptoms of allergic rhinitis, for example, rhinorrhea, nasal obstruction, sneezes, and to a lesser extent, on minor symptoms, such as pruritus, conjunctivitis, and pharyngitis. Nasal secretions were obtained after each challenge by lavage. Histamine was titrated by a radioimmunoassay with a monoclonal antibody against acylated histamine. Prostaglandin D2 (PGD2) was assayed with an enzyme immunoassay with a polyclonal antibody against PGD2 methoxamine. None of the normal subjects had a symptom score greater than 2; 55/60 patients had a positive challenge. The release of PGD2 was significantly (p less than 0.001, Kruskal-Wallis test) correlated with a symptom score of 5; 74.5% of patients had a significant release of PGD2 in nasal secretions. In contrast, although 58.2% of patients had a release of histamine in nasal secretions when the challenge was positive, the correlation with symptom scores was not significant. PGD2 in nasal secretions increased 3.7-fold after a positive nasal challenge.(ABSTRACT TRUNCATED AT 250 WORDS)

Antiallergic activity of H1-receptor antagonists assessed by nasal challenge.

Most oral drugs used for the treatment of allergic rhinitis are classified as H1-receptor antagonists, and although they represent major sales throughout the world, their mechanism of action is still poorly known. In an attempt to understand better the in vivo therapeutic effects of these drugs, a double-blind, crossover study was carried out. The study compared the effects of terfenadine and loratadine, nonsedative H1-receptor antagonists, on the immediate allergic response of the upper airways to challenge with orchard-grass pollens in 14 highly allergic subjects. Increasing numbers of pollen grains were insufflated into the nostrils, and the response of the subjects was assessed by examining symptoms and measuring the release of histamine and prostaglandin D2 in nasal secretions. Each drug was administered for a week before challenge. This study demonstrated the clinical efficacy of both drugs by comparison to that of a control day, since symptoms were observed for a significantly (p = 0.014) greater number of pollen grains. Only one patient had a significant release of histamine when they were treated with loratadine versus 10 during control day (p less than 0.0023) and six when they were treated with terfenadine (p less than 0.01). Prostaglandin D2 release occurred with a higher allergen dose when patients were treated with both drugs. This study indicates that some H1 antagonists also possess antiallergic activities.

Non-specific histamine release activity of busereline, LH-releasing hormone.

Busereline acetate is an LH-RH agonist that was found to induce local reactions at the injection site or generalized minor skin reactions in some patients. Since these reactions may represent the first reaction of systemic anaphylaxis, we tested the non-specific histamine releasing activity of this drug by intradermal skin tests. It was found that all subjects tested had a positive wheal and flare reaction, the flare being significantly decreased by terfenadine. Benzyl alcohol, the preservative used in commercial preparation of busereline acetate, did not elicit a positive wheal and flare reaction in two patients who had experienced a clinically noticeable reaction. It is concluded that busereline is likely to be a non-specific histamine releasing compound.