Beta-carbolines: synthesis and neurochemical and pharmacological actions on brain benzodiazepine receptors.

We have prepared a series of tetrahydro-beta-carbolines (TH beta C), beta-carbolines (beta-C), and other nitrogen heterocycles and evaluated them in vitro with respect to their ability to bind to benzodiazepine receptors. The fully aromatic beta-C's were more potent than their corresponding TH beta C derivatives. When substituents possessing a carbonyl (CO2Me, COCH3, CHO) were introduced at the beta-C 3-position the in vitro potency was augmented. Alcohol substituents (CH2OH, CHOHCH3) demonstrated decreased in vitro potency. The importance of the carbonyl moiety was further demonstrated when beta-carboline-3-carboxylic acid was shown to bind tighter to benzodiazepine receptors at lower pH. A lower pH increases the concentration of the acid and decreases the concentration of the anion. 3-(Hydroxymethyl)-beta-carboline (24), 3-formyl-beta-carboline (25) and 3-acetyl-beta-carboline (27) were benzodiazepine antagonists in vivo. Methyl isoquinoline-3-carboxylate (31a) also had in vitro activity. The same structure-activity relationships seen in beta-C's were also observed for isoquinolines.

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.

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.

Thoracoscopic management of descending necrotizing mediastinitis.

Descending necrotizing mediastinitis (DNM) is a lethal process originating from odontogenic, pharyngeal, or cervical infectious sources that descends along fascial planes into the mediastinum. Despite earlier use of antibiotics and surgical drainage, the mortality (>50%) has changed little since the first large series reported in the preantibiotic era. The surgical management remains controversial, with support ranging from cervical drainage alone to cervical drainage and routine thoracotomy. We report a case of thoracoscopic drainage and debridement of a mediastinal abscess resulting from descending necrotizing mediastinitis. The decreased morbidity of this approach compared with posterolateral thoracotomy and the improved drainage of the mediastinum compared with cervical drainage support this method as an attractive management of patients with DNM.

The role of methotrexate in the management of steroid-dependent asthma.

Severe asthma often requires high-dose corticosteroid therapy. However, steroid therapy is fraught with many side effects. There are conflicting reports in the literature regarding the role of methotrexate in reducing the steroid requirements of these patients. This study examined the role of low-dose methotrexate in the management of steroid-dependent asthma. Eleven subjects with stable steroid-dependent asthma were enrolled in a placebo-controlled double-blind crossover trial. Patients received methotrexate, 15 mg/wk, or placebo each for two 12-week periods. There was significant improvement of pulmonary function and reduction of prednisone requirement in both placebo and methotrexate treatment periods. However, methotrexate was not superior to placebo. Only 3 of 11 patients responded to methotrexate. Although low-dose methotrexate therapy may have a role in a small select group of steroid-dependent asthmatics, it provided no additional benefit overall.

Onset of action of aqueous beclomethasone dipropionate nasal spray in seasonal allergic rhinitis.

Beclomethasone dipropionate nasal spray is widely used in the treatment of seasonal allergic rhinitis; however, the time of onset of action has not been determined. This study assessed the onset of action, level of relief, and efficacy of beclomethasone nasal spray in patients with seasonal allergic rhinitis. In a double-blind, randomized, placebo-controlled, parallel-group, multicenter, 7-day study, symptomatic patients were administered two inhalations of beclomethasone dipropionate (n = 80) or placebo (n = 81) into each nostril twice daily. Patients assessed the onset of action and level of relief at 6, 24, and 48 hours and at days 3 and 7. Investigators evaluated symptoms at days 0, 3, and 7 and response to therapy at days 3 and 7. The difference in the cumulative number of patients reporting relief of symptoms was statistically significant in favor of beclomethasone dipropionate by hour 24 (P = 0.05). Patients in the beclomethasone dipropionate group experienced a greater level of relief than patients receiving placebo at hour 24, and improvement increased over the 7-day study compared with a decrease in relief in the placebo group. Beclomethasone dipropionate was significantly more effective than placebo in reducing symptoms (P < or = 0.02), and patients in the beclomethasone dipropionate group showed a more favorable response to treatment than did patients in the placebo group (P < 0.01). Adverse events were minor in both groups. Beclomethasone dipropionate nasal spray produced significant onset of relief of symptoms the first day of treatment; improvement was sustained and increased over the course of the study.

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.

Allergens.

The environment contains a huge array of allergens, primarily proteins or glycoproteins, to which the atopic individual may become sensitized. In situations of high exposure and highly reactive substances, even nonatopic individuals may develop allergic antibodies. The individual's response depends on the underlying immune responsiveness, the dosage, frequency, route, and possibly the chemical nature of the allergen. Most allergenic sources contain multiple allergenic determinants, as demonstrated by characterization of pollen and mold extracts. Major allergens are acidic proteins with weights in the 20,000 to 40,000 dalton range, and pIs in the 4 to 6 range. Minor allergens may be larger or smaller and either acidic or basic. These conclusions are based on the isolation of a relatively small number of allergens. Cross-reactivity data, especially with the pollens, are useful in the rational formulation of immunotherapy extracts. Considering the wealth of allergenic pollens, information available to date is very scanty. Data on molds, epidermals, and mites are even more preliminary or conflicting. As further research proceeds on purifying and characterizing allergens, a number of these questions and conflicts will be resolved.

The origin and spread of the new daisy rust in Britain.

Since 1997, wild and cultivated daisies in Britain and other European countries have been suffering from a rust fungus epidemic that menaces the future cultivation of horticultural varieties. The causal fungus was first discovered in Australia 100 years ago and may have evolved there from another rust fungus on daisies previously introduced from Europe. At present, ornamental daisies can be grown successfully only when protected by fungicide sprays.

[Carotenoids and fatty acids in red yeasts Sporobolomyces roseus and Rhodotorula glutinis]. / Karotinoidy i zhirnye kisloty v krasnykh drozhzhakh Sporobolomyces roseus i Rhodotorula glutinis.

Rhodotorula glutinis and Sporobolomyces roseus, grown under different aeration regimes, showed differential responses in their carotenoid content. At higher aeration, the concentration of total carotenoids increased relative to biomass and total fatty acids in R. glutinis, but the composition of carotenoids (torulene > beta-carotene > gamma-carotene > torularhodin) remained unaltered. In contrast, S. roseus responded to enhanced aeration by a shift from the predominant beta-carotene to torulene and torularhodin, indicating a biosynthetic switch at the gamma-carotene branch point of carotenoid biosynthesis. The overall levels of total carotenoids in highly aerated flasks were 0.55 mol-percent and 0.50 mol-percent relative to total fatty acids in R. glutinis and S. roseus (respectively), and 206 and 412 microg g(-1) dry weight (respectively).

Immunotherapy with allergens.

Allergen immunotherapy has been shown to be efficacious in numerous studies for the clinical indications of allergic asthma and rhinitis, as well as hymenoptera venom hypersensitivity. How allergen immunotherapy improves clinical symptoms is still not entirely clear. Decreases in specific IgE follow a complex cascade of effects: a shifting of the cytokine milieu from T(H)2 to T(H)1 predominance, with resultant decrease in interleukin 4, decreased recruitment and activation of eosinophils, and decreased proliferation of mast cells. Allergen exposure has a lessened ability to stimulate an inflammatory cell response, with decreased target organ hyperreactivity. Since allergen immunotherapy is not without risk, the decision needs to be made whether injection therapy is safe and provides benefit not achievable by medical management. The continued clarification of optimal allergen concentrations through careful studies of standardized extracts will allow better control of adverse events by limiting unnecessarily potent mixtures.

Food additives and allergy.

There is ample evidence that food additives of several sorts may precipitate adverse reactions. Some of these have catastrophic potential such as sulfite sensitivity in asthmatic patients. Fortunately, asthmatic responses to a variety of additives are certainly not as prevalent as once feared, and are probably unusual. Restricted diets are of no general benefit in asthmatic patients. In contrast to asthma, urticarial or other cutaneous reactions to food additives are more common. A restricted diet for a few months' duration may be beneficial, although the mechanism through which this is achieved is unclear. Suspected food additive sensitivities are best documented by oral challenges, preferably in a double-blind manner. Challenges in asthmatic patients need to be done with patients continuing on their routine medications to avoid false positives. All care should be taken to titrate the doses and schedule the doses appropriately, since several of these agents could provoke large drops in pulmonary function. With urticarial patients, an adequate baseline of urticarial activity needs to be established before the challenges so that fluctuations in normal activity are not construed as a positive result. Despite a large number of studies evaluating the role of food additives in hyperkinesis, results are not uniform. Evidence does suggest that there is a small subset of primarily younger children in whom additives will impact on behavior. As with asthma and additives, the problem appears to be much smaller than originally postulated.

Pollen identification.

LEARNING OBJECTIVES: The purpose of this review is to introduce the reader to a systematic approach to categorizing pollen types. This will enable the reader to recognize pollen characteristics of the most common botanical sources and determine the relevant contributors to the local aeroallergen burden. DATA SOURCES: Allergenic plant and pollen atlases for pollen characteristics, allergy texts for procedures and overviews, and relevant reviews from the English medical literature (1985 to present). RESULTS: By applying a visual gestalt utilizing grain number, size, shape, surface structures, and internal detail, one is able to identify pollen source to the appropriate botanical taxonomic level. Identification may be possible only to the family or order, but most frequently to the genus, and occasionally to the species. CONCLUSIONS: Outdoor sampling allows the identification of aeroallergen burden in a locale. In conjunction with field work, the relevant sources can be identified as well as time of pollination. This allows the physician to correlate symptoms with exposure and relevant sensitization.

Occupational asthma and rhinoconjunctivitis from inhalation of crystalline bovine serum albumin powder.

A 24-year-old white female laboratory technician developed recurrent rhinoconjunctivitis and wheezing immediately following repeated exposure to purified lyophilized bovine serum albumin (BSA). Prick and titrated intradermal skin tests revealed strongly positive results in the patient and negative results in normal controls. A titrated double-blind, placebo-controlled bronchial inhalation challenge with an aqueous BSA solution was positive at 10 mg/mL. Use of an albuterol metered dose inhaler and avoidance of laboratory exposure to BSA have resulted in resolution of symptoms. These results are consistent with an IgE-mediated mechanism, and this case represents the first reported instance of occupational asthma and rhinoconjunctivitis to inhaled BSA powder.

Aerosolized terbutaline in asthmatics. Comparison of dosage strength, schedule, and method of administration.

Sixteen patients with bronchial asthma participated in three studies of inhaled terbutaline. Onset of action, duration, and peak effects were compared for a dose of 0.5 mg given in one, two, or four inhalations at 1 min intervals from a freon-propelled, metered-dose aerosol. There was no significant difference in the response between the schedules. Dose-response curves were compared for terbutaline from a metered-dose aerosol, and pressure nebulized with and without intermittent positive pressure breathing (IPPB). There was no difference between the response with IPPB and simple nebulization. Improvement continued to the total dose administered of 9.0 mg. For a given bronchial response, six to eight times as much terbutaline was required by pressure nebulization as from the metered-dose aerosol.

Aerosolized terbutaline in asthmatics: development of subsensitivity with long-term administration.

The peak response and the duration of bronchodilator effect were measured after four inhalations at 20 min intervals of 250 micrograms of aerosolized terbutaline in 13 patients with bronchial asthma. Patients were initially studied after strict avoidance of all adrenergic agents for 2 wk; they were then studied at 2 wk intervals for 12 wk while receiving 500 micrograms of aerosolized terbutaline q.i.d. The initial testing (TI) and the testing at the end of 12 wk (TII) were double blind. Both peak response and duration of action decreased significantly between TI and TII. Cumulative dose-response curves showed that further improvement occurred after each inhalation during TI but that there was significant improvement only after the first inhalation during TII.

Methotrexate in the treatment of steroid-dependent asthma.

A double-blind, placebo-controlled, crossover study was designed to compare steroid requirements between placebo and methotrexate (MTX) treatment in subjects with corticosteroid-requiring asthma. Subjects began with a steroid taper and then were randomized to a 3-month trial of drug or placebo therapy. Subjects received 15 mg of MTX a week or identical placebo. A 1-month washout period was completed before the crossover trial. Symptom scores, peak flow rates, spirometry, and beta-agonist frequency were closely monitored. Ten subjects completed the study. The average dose of prednisone during the placebo-treatment period was 11.97 mg/day compared to 8.37 mg/day while subjects were taking MTX. This was a 30% reduction in daily steroid requirement (p less than 0.01). Symptom scores and spirometry did not differ between the crossover trials, and overall clinical status was not altered. Complications from MTX were mild and included anorexia, alopecia, and stomatitis. All complications resolved with dose reduction or when MTX was stopped at the end of the study. No subjects withdrew from the study because of MTX complications. Low-dose MTX significantly reduced the steroid requirement in this group of subjects with steroid-dependent asthma. This reduction in steroid requirement was obtained without altering clinical status and without significant complication.