Magnitude of efficacy measurements in grass allergy immunotherapy trials is highly dependent on pollen exposure.

BACKGROUND: The objective was to evaluate the association between grass pollen exposure, allergy symptoms and impact on measured treatment effect after grass sublingual immunotherapy (SLIT)-tablet treatment. METHODS: The association between grass pollen counts and total combined rhinoconjunctivitis symptom and medication score (TCS) was based on a post hoc analysis of data collected over six trials and seven grass pollen seasons across North America and Europe, including 2363 subjects treated with grass SLIT-tablet or placebo. Daily pollen counts were obtained from centralized pollen databases. The effect of treatment on the relationship between the TCS and pollen counts was investigated, and the relative difference between grass SLIT-tablet and placebo as a function of average grass pollen counts was modelled by linear regression. RESULTS: The magnitude of treatment effect based on TCS was greater with higher pollen exposure (P < 0.001). The relative treatment effect in terms of TCS for each trial was correlated with the average grass pollen exposure during the first period of the season, with predicted reduction in TCS = 12% + 0.35% × pollen count (slope significantly different from 0, P = 0.003; R(2)  = 0.66). Corresponding correlations to the entire grass pollen season and to the peak season were equally good, whereas there was a poor correlation between difference in measured efficacy and pollen exposure during the last part of the season. CONCLUSIONS: In seasonal allergy trials with grass SLIT-tablet, the observed treatment effect is highly dependent on pollen exposure with the magnitude being greater with higher pollen exposure. This is an important relationship to consider when interpreting individual clinical trial results.

Evaluation of in vivo breast fine needle aspirates by flow cytometry: an efficacy study.

BACKGROUND: Malignancy of the breast is frequently diagnosed through fine needle aspiration. In the hands of a skilled aspirator and cytopathologist, this can be a highly accurate procedure. PURPOSE: This study was undertaken to evaluate whether sufficient residual cells in the bore of the needle could be harvested and analyzed efficiently by flow cytometry analysis. The goal was then to determine the value of routine flow cytometry as an adjunctive technology in the interpretation of breast fine needle aspirations. METHODS: Cells were rinsed from the needles of 83 consecutive diagnostic fine needle aspirates after preliminary inspection had confirmed adequate material was obtained for cytopathology. Cells were washed, and nuclei prepared by detergent treatment. After ribonuclease treatment, DNA was stained with the fluorescent marker propidium iodide. DNA content per cell was determined by flow cytometry by measurement of right-angle fluorescence. RESULTS: Less than 4% of the samples were rejected for inadequate cell numbers. Flow cytometry criteria for evidence of malignancy included the presence of a DNA aneuploid population or an elevated rate of proliferation (13% or higher) of a diploid population. Accuracy of flow cytometry was based on cytopathologic interpretation in all cases except two which were based on results of excisional biopsy. The sensitivity of the flow cytometry analysis was 76%; the specificity was 100%, with results from flow cytometry pivotal in the correct diagnoses for two patients whose cytopathologic results were equivocal. Analysis of histograms indicated acceptable coefficients of variation for all populations. Gating analysis indicated the suitability of the material for this type of study, with an average of 85% of the events selected, or "gated in." Low recoveries were associated with the presence of necrotic debris in the sample. CONCLUSION: Flow cytometry can be a valuable adjunctive technology, capable of providing the cytopathologist with additional information regarding the character of cells analyzed.

Aerosol beclomethasone dipropionate compared with theophylline as primary treatment of chronic, mild to moderately severe asthma in children.

OBJECTIVE: To compare the benefits and adverse reactions of theophylline and beclomethasone (BDP) in the long-term control of mild to moderate chronic asthma in children. DESIGN: Multicentered, double-blind, double-placebo, randomized, controlled trial. PATIENTS: One hundred ninety-five children between the ages of 6 and 16 years with mild to moderate asthma. INTERVENTION: Treatment with either BDP, 84 micrograms four times a day, or sustained-release theophylline administered twice daily in doses adjusted for optimum control of symptoms. MAIN OUTCOME MEASURES: Daily diary record of symptoms, peak flow rates, supplemental bronchodilator and glucocorticoid treatment, doctor and hospital visits, absence from work and school, and side effects. RESULTS: Aerosol BDP and sustained-release theophylline were effective primary treatments for mild to moderate chronic asthma. Beclomethasone resulted in comparable symptom control with less bronchodilator use and fewer courses of systemic steroids than did theophylline. Side effects were observed significantly more frequently with theophylline than with BDP. Growth velocity suppression was noted with BDP and was more pronounced in boys. Suppression was not associated with alterations in cortisol measurements either at baseline or following stimulation. CONCLUSION: Both theophylline and BDP are effective therapy for mild to moderate asthma. Caution must be used with the administration of BDP in children because of possible growth velocity suppression.

A comparison of commercial jet nebulizers.

Seventeen commercially available jet nebulizers from 15 commercial sources were studied (Acorn-I, Acorn-II, AquaTower, AVA-NEB, Cirrhus, Dart, DeVilbiss 646, Downdraft, Fan Jet, MB-5, Misty Neb, PARI LC JET, PARI-JET, Salter 8900, Sidestream, Updraft-II, Whisper Jet). All nebulizers were filled with 2 ml of saline solution plus 0.5 ml of albuterol and powered with the same source (DeVilbiss PulmoAide). We compared total output (TO), time for total output (TTO), and percent output in respirable range (PORR). The TO was obtained by weighing before nebulization and at the point of eight-fold decline in output. The TTO was calculated from initiation of nebulization to the point of eightfold decline in output. The PORR was measured by a laser particle analyzer in continuous nebulization to the same point of abrupt drop in output. The TO varied from 0.98 To 1.86 ml (p < 0.0001) with the Acorn-I, Acorn-II, Updraft-II, and Sidestream, significantly greater than the others (p < 0.05). The TTO varied from 2.28 to 20.95 min (p < 0.0001). The AquaTower, PARI LC JET and PARI-JET, DeVilbiss, and Dart were significantly shorter than the others (p < 0.05). The PORR varied from 21.89 to 71.95 percent (p < 0.0001). The Sidestream was significantly greater than all others (p < 0.05). The PARI LC JET and PARI-JET were, in turn, significantly greater than the remaining models (p < 0.05). To combine these characteristics, we calculated respirable particle delivery rate (RPDR) by dividing TO by TTO and multiplying by PORR. The RPDR varied from 0.03 ml/min to 0.26 ml/min (p < 0.0001). The PARI LC JET (0.24 ml/min) and the PARI-JET (0.26 mg/min) had a RPDR that was significantly greater than the other models except the AquaTower, which, however, had a markedly variable performance. The Sidestream (0.19 mg/ml) did not differ significantly from the above group, nor from the DeVilbiss and Downdraft. All other models had significantly lower outputs (p < 0.05). We conclude that the output characteristics of commercial nebulizers vary greatly and will impact on the time required for treatment as well as the total amount of drug delivered to the lungs.

Theophylline and aerosolized terbutaline in the treatment of bronchial asthma. Double-blind comparison of optimal doses.

The bronchodilator response to aerosolized terbutaline and optimal doses of theophylline, given singly and in combination, was studied in ten patients with perennial asthma. Optimal doses of theophylline were determined (mean peak theophylline level of 20.9 micrograms/ml). Patients then received this theophylline dose plus 500 micrograms aerosolized terbutaline by metered-dose nebulizer qid for one week. Placebo was then substituted for one of the active agents for two weeks, followed by both active agents again for one week, and finally, placebo substituted for the second agent for a two-week period. The therapeutic response was determined by measurement of peak expiratory flow rate four times daily at different intervals following medication and the patient's subjective assessment of each period. The combination was found to be superior to either theophylline or terbutaline alone (P < .05). Theophylline alone and aerosolized terbutaline alone were equally effective. No side effects were encountered with any of the treatment regimens.

Efficacy of atropine methylnitrate alone and in combination with albuterol in children with asthma.

The bronchodilator effect of nebulized AMN, albuterol and their combination was evaluated in 16 steroid-dependent asthmatic children. In phase 1, maximal bronchodilation was determined by dose-response studies on separate days. Maximal bronchodilator dose of each drug was administered either alone or in combination during phase 2. In phase 1, 0.11 +/- 0.01 mg/kg of albuterol and 0.03 mg/kg of AMN produced maximum bronchodilation. In phase 2, the peak response to albuterol occurred within 30 min and to AMN, at 60 min. Maximal FEV1 achieved after AMN was 90 percent of the maximal achieved after albuterol. AMN FEV1 response was better than for placebo for 3 h; that for albuterol was better for 4 h. Combination therapy produced a peak response similar to that of albuterol but was better than albuterol by 6 h. Thus, the maximum bronchodilator effect of AMN is less than that of albuterol in asthmatic children, but the combination may extend the period of bronchodilatation.

Addition of terbutaline to optimal theophylline therapy. Double blind crossover study in asthmatic patients.

The efficacy and side effects of oral or inhaled terbutaline were examined in 13 mild-to-moderate asthmatic patients (ages 12 to 71 years) on maintenance theophylline (levels 10 to 25 micrograms/ml). In a crossover design, each patient received for two weeks oral terbutaline, 5 mg qid, inhaled terbutaline, 400 micrograms qid, or identical placebo tablets or metered-dose inhalers. Prior to each double-blind period, terbutaline was given for two weeks to ensure development of beta-adrenergic subsensitivity. Home-monitored peak flows and need for supplementary bronchodilators were significantly improved with both oral and inhaled terbutaline, but only the inhaled drug significantly decreased symptoms. Long-term terbutaline, either oral or inhaled, added to maintenance theophylline improved the patients' pulmonary function. The inhaled drug also improved the patients' clinical status as reflected by asthma symptom scores and need for extra bronchodilator. Combining terbutaline with theophylline did not produce evidence of cardiotoxicity.

Comparison of PEFR and FEV1 in patients with varying degrees of airway obstruction. Effect of modest altitude.

Measurements of FEV1 and PEFR performed on a Jones Pulmonor Spirometer (JPF) were compared with PEFR obtained with a mini-Wright peak flow meter (WPF) in 102 patients. Data were converted to percent predicted. Standard deviations of triplicate measurements were: FEV1, 3.01 percent; JPF, 7.22 percent; and WPF, 5.12 percent. Correlation of best of three measurements was FEV1-JPF r = .758; FEV1-WPF r = .744; and JPF-WPF r = .846. The mean percent predicted of the best of three values of FEV1 was 74.8 percent, JPF 91.4 percent, and WPF 94 percent. These higher values for percent predicted PEFR were obtained throughout the range of FEV1 values. Studies on nine normal volunteers in an atmospheric chamber suggested that higher altitudes may account for higher PEFR values. We conclude that PEFR, measured by either waterless spirometer or mini-Wright peak flow meter, has greater intrasubject variability than FEV1, and it tends to underestimate the degree of pulmonary impairment.

Extreme variability in aerosol output of the DeVilbiss 646 jet nebulizer.

Ten new jet nebulizers (DeVilbiss 646) were studied to determine their consistency of output. Each nebulizer, containing 2 ml of saline solution, was run for 1 min in triplicate at four different straw (capillary tube) positions, keeping all other variables constant. Total output in milliliters per minute and volume of aerosol in the respirable range (1.0 to 5.0 microns) were measured. There was significant variability in output and volume of output in the respirable range (VORR) for every nebulizer at each of the tested straw positions (p less than 0.0001). Irregularities in manufacture of the bowl and straw appear to be responsible for this significant variability. In summary, there is considerable intranebulizer and internebulizer variability that could influence both patient care and medical use for diagnostic purposes.

Optimal duration of nebulized albuterol therapy.

The output from a jet nebulizer was analyzed for aerosol profile, solution output, and delivery of albuterol at three different initial volume fills to determine the changes that occur during the course of nebulization. Increasing diluent volume led to significantly greater delivery of the albuterol initially placed in the nebulizer. Albuterol delivery from the nebulizer ceased completely following the onset of inconsistent nebulization (sputtering) as determined audibly and by laser particle analysis. Aerosol output rate declined by one-half within 20 s of the onset of sputtering. The albuterol concentration in the nebulizer solution increased significantly once the aerosol output declined. The weight of solution delivered as determined by change in weight of the nebulizer could not be fully accounted for as aerosol volume. It appeared that this discrepancy represented loss of water by evaporation. Aerosolization past the point of initial jet nebulizer sputtering is unproductive.

Oral glucocorticosteroid-sparing effect of budesonide administered by Turbuhaler: a double-blind, placebo-controlled study in adults with moderate-to-severe chronic asthma. Pulmicort Turbuhaler Study Group.

OBJECTIVE: To determine the ability of budesonide via an inhaler (Pulmicort Turbuhaler; Astra Draco AB) to replace oral glucocorticosteroids (GCSs) in adult subjects with moderate-to-severe asthma. DESIGN: Double-blind, randomized, and placebo-controlled study, with parallel groups. SETTING: Multicenter study in outpatient setting. PARTICIPANTS: Eighty men and 79 women, aged 20 to 69 years, with moderate-to-severe asthma and a mean FEV1 of 58.3% predicted normal. All subjects were receiving oral GCS treatment and 79% of subjects were also receiving inhaled beclomethasone dipropionate (BDP). The mean daily doses of prednisone at baseline, including converted dose of BDP, for the placebo, budesonide 400 microg, and budesonide 800 microg, respectively, were 19.7 mg, 19.5 mg, and 18.7 mg. MEASUREMENTS AND INTERVENTIONS: After a 2-week baseline period, subjects entered a 20-week treatment period, during which the oral dose of prednisone was reduced by forced down-titration at 2-weekly intervals. RESULTS: Subjects receiving 400 microg or 800 microg bid of budesonide achieved a significantly greater reduction (82.9% and 79.0% respectively) in oral GCS dose compared with placebo-treated subjects (27%; p<0.001). Two thirds of the subjects receiving budesonide were able to achieve sustained oral corticosteroid cessation, compared with 8% in the placebo group. Additionally, both doses of budesonide resulted in significant improvement in results of pulmonary function tests and asthma symptoms scores, and a significant decrease in the use of bronchodilator therapy. The mean plasma cortisol levels before and after adrenocorticotropic hormone stimulation increased most toward the normal range in the budesonide-treated groups compared with placebo-treated subjects. CONCLUSION: Budesonide administered via Turbuhaler has a significant oral GCS-sparing capacity with maintained or improved asthma control in adult subjects with moderate-to-severe asthma.

Vitamin B6 levels in patients with carpal tunnel syndrome.

Vitamin B6 levels were determined in patients with idiopathic carpal tunnel syndrome. Results from this limited study strongly suggest that vitamin B6 deficiency may accompany carpal tunnel syndrome. This study did not address the question of the causal relationship between vitamin B6 status and development of symptoms.

Once-daily mometasone furoate nasal spray: efficacy and safety of a new intranasal glucocorticoid for allergic rhinitis.

Once-daily mometasone furoate nasal spray (MFNS) is a new intranasal glucocorticoid for the treatment of seasonal allergic rhinitis and perennial rhinitis, and for the prophylaxis of seasonal allergic rhinitis. This paper reviews key findings from the clinical development program for MFNS, comprising more than 20 clinical trials with more than 6000 patients worldwide. MFNS exhibits strong anti-inflammatory activity in vitro and in vivo, and has a rapid onset of action, affording clinically significant symptom relief in 28% of patients within 12 hours of the first dose. Once-daily MFNS is at least as effective as other intranasal glucocorticoids, including twice-daily beclomethasone dipropionate and once-daily fluticasone propionate and budesonide. MFNS is well tolerated and has no detectable effect on the hypothalamic-pituitary-adrenal axis, even at up to 20 times the recommended daily dose. MFNS does not cause atrophy of the nasal mucosa; in fact, prolonged treatment tends to restore the nasal mucosa to a more normal phenotype. The once-daily dosing schedule of MFNS may improve patient compliance, while its high margin of systemic safety and rapid onset of action may enhance patient and physician acceptance.

Effectiveness of specific immunotherapy in the treatment of allergic rhinitis: an analysis of randomized, prospective, single- or double-blind, placebo-controlled studies.

BACKGROUND: The effectiveness of specific immunotherapy (SIT) in the treatment of allergic rhinitis has been supported by empirical evidence and clinical experience. OBJECTIVE: This report is an analysis of multiple studies involving patients with documented allergic rhinitis. METHODS: All studies of the effectiveness of SIT in the treatment of allergic rhinitis published in English between the years 1966 and 1996 were identified through a MEDLINE search. All prospective, single- or double-blind, placebo-controlled studies were included in the analysis. One author (R.N.R.) extracted data from the studies. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random-effects model for a variety of clinical measures in studies that permitted the extraction of numbers of patients with positive and negative outcomes. RESULTS: Data were extracted from 16 studies of the clinical effectiveness of SIT in the treatment of allergic rhinitis, involving 759 patients (546 adults, 53 children, 160 all ages). In 15 (94%) of the studies, investigators concluded that SIT was effective. In the remaining study (the only one conducted in children), investigators concluded that SIT was not effective. Symptoms of allergic rhinitis were more likely to improve in patients receiving SIT than in the comparison patients (OR 1.81, 95% CI 1.48 to 2.23). Symptom-medication scores were significantly lower in patients receiving SIT than in the comparison patients in all studies using such measures (P < 0.05). CONCLUSION: Results of this analysis support the conclusion that SIT is effective in the treatment of allergic rhinitis.

Effectiveness of specific immunotherapy in the treatment of asthma: a meta-analysis of prospective, randomized, double-blind, placebo-controlled studies.

BACKGROUND: Despite decades of positive experience with specific immunotherapy (SIT) in the treatment of asthma, outcomes associated with SIT have not been evaluated. OBJECTIVE: This meta-analysis was conducted to compare the effects of SIT plus medical treatment with those of SIT without medical treatment in patients with asthma. METHODS: All studies of SIT in patients with asthma published in English between the years 1966 and 1998 were identified through a MEDLINE search. All prospective, randomized, double-blind, placebo-controlled studies of SIT identified by the search were included in the meta-analysis. One author (R.N.R.) extracted data from these studies. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random-effects model. RESULTS: Data were extracted from 24 identified studies of the clinical effectiveness of SIT in the treatment of asthma, involving 962 asthmatic patients with documented allergy. Immunotherapy was judged effective in 17 (71%) of the 24 studies, ineffective in 4 (17%), and equivocal in 3 (12%) (chi2 = 15.25, df = 2, P = 0.0005). Symptoms of asthma were more likely to improve in patients who received SIT than in patients who received placebo (OR 2.76, 95% CI 2.22 to 3.42). Results also favored the immunotherapy group for improvement in pulmonary function (OR 2.87, 95% CI 1.82 to 4.52), protection against bronchial challenge (OR 1.81, 95% CI 1.32 to 2.49), and reduced need for medications (OR 2.00, 95% CI 1.46 to 2.72). CONCLUSION: The findings of this meta-analysis support the conclusion that SIT is effective in a population of patients with allergen-triggered asthma.

Effectiveness of specific immunotherapy in the treatment of hymenoptera venom hypersensitivity: a meta-analysis.

BACKGROUND: For most people, Hymenoptera stings produce a transient, local inflammatory reaction (pain, redness, swelling). However, for those who are allergic to components of this venom, the reactions can be severe, frightening, and sometimes fatal. Specific immunotherapy (SIT) has been the only means of desensitizing patients who have experienced a systemic reaction to this venom. OBJECTIVE: This meta-analysis was conducted to compare the effects of SIT in the treatment of Hymenoptera venom hypersensitivity. METHODS: All studies of SIT in the treatment of Hymenoptera venom hypersensitivity published in English between the years 1966 and 1996 were identified through a MEDLINE search. Because of the ethical difficulties involved in designing a double-blind, placebo-controlled study in this patient population, most of the studies were open and not placebo-controlled. One author (R.N.R.) extracted data from the studies. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random-effects model. RESULTS: Data were extracted from 8 studies involving 453 patients; 1 study was conducted in adults (n = 20), 2 in children (n = 188), and 5 in all ages (n = 245). The symptoms of Hymenoptera venom hypersensitivity were prevented in 80 (79%) of the 101 patients receiving SIT versus 49 (36%) of 136 comparison patients. The symptoms were not prevented in 21 (21%) of the patients receiving SIT versus 87 (64%) of the comparison patients (OR 2.20, 95% CI 1.72 to 2.81). CONCLUSION: The findings of this meta-analysis support the conclusion that SIT is effective in the treatment of Hymenoptera venom hypersensitivity.

Pirbuterol hydrochloride: evaluation of beta adrenergic agonist activity in reversible obstructive pulmonary disease and congestive heart failure.

Pirbuterol hydrochloride is a beta 2 adrenergic agonist with a structure similar to that of albuterol, except for the substitution of a pyridine ring for the benzene ring. It is comparable in duration of action to albuterol when given by inhalation, but it is threefold less potent by weight. In man, pirbuterol and albuterol have similar beta 2 selectivity. In the acute therapy of chronic obstructive pulmonary disease, pirbuterol is most effective in oral doses of 15-20 mg, and by aerosol in doses of 400 micrograms or greater. Long-term studies of oral pirbuterol in doses between 30-60 mg/day are promising, but further research is warranted. The combination of pirbuterol's beta 2 and lesser beta1 activity has proven helpful in the therapy of refractory congestive heart failure. Improvement of function of both right and left ventricles and systemic and pulmonic circulations has been demonstrated acutely. Drug effect wanes, as with other beta adrenergic agonists, due to the development of tolerance; however, long-term benefit appears to persist in both pulmonary and cardiac patients. Pirbuterol will be marketed in the United States as 10 and 15 mg tablets and as a 200 micrograms per actuation metered dose aerosol for use in pulmonary patients only; it will not be approved for use in congestive heart failure. In terms of beta 2 selectivity, duration of action, potency and frequency of side effects, pirbuterol is comparable to the two beta 2 agonists already available in the United States, albuterol and terbutaline.

Nutritional immunity: a prospective study of thirty-three patients with acute appendicitis.

During a recent 12-month period, serum iron levels, total iron binding capacities (TIBC), and latent iron binding capacities (LIBC) were studied preoperatively and 72 hrs postoperatively in 33 consecutive patients with pathologically confirmed acute appendicitis. Preoperative serum iron levels were significantly reduced in these patients (mean serum iron 32 micrograms/dl; P less than .0001) compared to established normal values (mean 100 micrograms/dl). LICBs were correspondingly elevated whereas TIBCs and mean hemoglobin values remained within the normal range. The reduced availability of serum iron in response to an acute infectious challenge such as appendicitis supports earlier experimental studies by others which suggest that nutritional immunity participates in host resistance to infection. In this study, the degree of serum iron suppression was directly related to the severity of disease (P less than .01).

Use of modified radioallergosorbent testing in determining initial immunotherapy doses.

Proponents of the modified radioallergosorbent test (RAST) for allergy diagnosis claim an advantage over skin testing in that immunotherapy may often be safely begun at higher initial concentrations and maintenance achieved with fewer injections than with conventional schedules. The resulting fewer visits would offset the greater initial cost and the delay in obtaining results. The most important allergen for 58 consecutive patients with seasonal allergic rhinitis beginning immunotherapy was determined from the history, skin testing, and aeroallergen surveys. A modified RAST was performed for these allergens. Thirty-nine patients (67%) had a modified RAST class 5 (most severe); 18 patients (31%) were class 4, and one patient was class 3. Since the initial concentration and total number of injections projected to reach maintenance vary little between our conventional schedule (1:100,000 w/v, 23 injections), and those for class 5 (1:62,500 w/v, 27 injections) and class 4 (1:12,500 w/v, 21 injections), the modified RAST offers no advantage over skin testing and conventional immunotherapy dosing in our patient population.