The Novartis view on emerging drugs and novel targets for the treatment of chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a debilitating lung disease characterized by airflow limitation and chronic inflammation in the lungs. The mainstay of drug therapy for COPD is represented by long-acting bronchodilators, an important aspect of Novartis' development program. Novel once-daily dosing bronchodilators, such as the long-acting muscarinic antagonist (LAMA) glycopyrronium and the LAMA/long-acting ß2-agonist (LABA) fixed-dose combination QVA149, have been shown to provide significant benefits to patients with COPD in terms of improvement in lung function, exercise tolerance, health-related quality of life, symptoms and reduction in the rate of exacerbations. Despite the benefits provided by these new treatment options, prevention of disease progression and control of exacerbations in certain patient phenotypes remain key challenges in the treatment of COPD. In order to address these needs and gain new insights into the complexity of COPD, Novartis is, in addition to bronchodilator-only therapies, developing LABA/inhaled corticosteroids (ICS) combinations to target inflammation, such as QMF149, as well as non-steroid based anti-inflammatory agents against key novel targets. These commitments are central to the Novartis' final goal of improving the standard of care in respiratory medicine and offering a better quality of life to patients with COPD.

The effect of intravenous administration of a chimeric anti-IgE antibody on serum IgE levels in atopic subjects: efficacy, safety, and pharmacokinetics.

CGP 51901 is a non-anaphylactogenic mouse/human chimeric anti-human IgE antibody that binds to free IgE and surface IgE of IgE-expressing B cells but not to IgE bound to high affinity IgE receptors (Fc epsilonR1) on mast cells and basophils or low affinity IgE receptors (Fc epsilonR2) on other cells. A phase 1 double-blind, placebo-controlled, single dose study with doses of 3, 10, 30, and 100 mg of CGP 51901 was conducted in 33 pollen-sensitive subjects who had raised levels of serum IgE and received either intravenous CGP 51901 or placebo. The administration of CGP 51901 was well tolerated and resulted in a decrease of serum free IgE levels in a dose-dependent manner, with suppression after 100 mg of CGP 51901 reaching > 96%. Time of recovery to 50% of baseline IgE correlated with the dose of administered antibody and ranged from a mean of 1.3 d for the 3 mg to 39 d for the 100 mg dose. Total IgE, comprised of free and complexed IgE, increased as stored and newly synthesized IgE bound to CGP 51901. Complexed IgE was eliminated at a rate comparable with the terminal half-life of free CGP 51901 (11-13 d at all doses). Only one subject showed a weak antibody response against CGP 51901. We conclude that the use of anti-human IgE antibody is safe and effective in reducing serum IgE levels in atopic individuals and provides a potential therapeutic approach to the treatment of atopic diseases.

Increase in bronchial responsiveness to methacholine and late asthmatic response after the inhalation of ultrasonically nebulized distilled water.

We studied ten subjects who had an asthmatic response after the inhalation of ultrasonically nebulized distilled water and did not show any refractory period to repeated challenge with such water. The change in responsiveness to methacholine after inhalation of distilled water and the occurrence of any water-induced late asthmatic response were investigated on separate days. All of the tested subjects showed a significant increase in bronchial responsiveness to methacholine after prior stimulation with ultrasonically nebulized distilled water, which waned within two hours in eight of them. The other two subjects showed a progressive increase in responsiveness to methacholine, and they also had a further reduction in the caliber of the airways three to four hours after inhalation of distilled water. The late responses were less severe than the initial responses and lasted four to five hours. After the spontaneous recovery, no significant increase in responsiveness to methacholine was detected. Our results confirm previous observations on hyperresponsiveness induced by ultrasonically nebulized distilled water and demonstrate the occurrence of late reactions after inhalation of such water.

A double-blind group comparative study of nedocromil sodium in the treatment of seasonal allergic rhinitis.

Thirty-eight patients with seasonal rhinitis due to grass pollen allergy took part in this double-blind study comparing 1% nedocromil sodium and placebo. Treatment was allocated by randomised coding sheet and consisted of 1% nedocromil sodium nasal spray or placebo given four times daily for four weeks during the peak pollen season. Highly significant (p less than 0.001) differences in favour of nedocromil sodium were seen for all signs and symptoms recorded at clinical assessments, and for diary card assessments of symptoms. In addition, time to effect and patient and clinician opinions of treatment significantly (p less than 0.001) favoured nedocromil sodium. Laboratory data on blood and urine samples taken before and after treatment showed no significant effects, and both treatments were well tolerated. Nedocromil sodium 1% nasal spray taken four times daily was shown to be an effective treatment for grass pollen rhinitis.

Psychosocial stressors in the lives of great jazz musicians.

Brief biographical information on four great jazz tenor saxophone players of the past is presented to illustrate the similar psychosocial stressors these men seemed to experience, namely, severe substance abuse, haphazard working conditions, lack of acceptance of their art form in the United States, marital and family discord, and a vagabond life style. Ages at death of 80 great jazz musicians may indicate that the stressful life style of jazz musicians may be reflected in a shortened life span, but a control group is needed.

Psychosocial stressors and the short life spans of legendary jazz musicians.

Mean age at death of 168 legendary jazz musicians and 100 renowned classical musicians were compared to examine whether psychosocial stressors such as severe substance abuse, haphazard working conditions, lack of acceptance of jazz as an art form in the United States, marital and family discord, and a vagabond life style may have contributed to shortened life spans for the jazz musicians. Analysis indicated that the jazz musicians died at an earlier age (57.2 yr.) than the classical musicians (73.3 yr.).

Height on the draw-a-person: comparison of figure drawings of black and white male drug abusers.

The Draw-A-Person Test was administered to 30 black and 30 white male drug abusers, in a residential therapeutic community. Mean height and mean area of the female figures drawn by the black subjects were greater than the mean height and mean area of the female figures drawn by the white subjects. More black subjects drew the female figure taller than the male figure. Data were discussed in regard to family background and socio-cultural considerations.

Narcissism and hostility.

The recent work of Hart and Joubert (1996) who reported correlations between scores on narcissism and hostility is commented upon with respect to expressions of hostility in narcissistic persons. Characteristics of the narcissistic personality observed in psychotherapy are noted, and suggestions are made regarding Hart and Joubert's call for research comparing the personality dimensions of hostile and nonhostile narcissistic persons.

MMPI diagnostic classification of substance abusers of the 1970s.

Retrospective analysis of the MMPI profiles of 160 substance abusers tested in the 1970s showed that 54% were classified as showing signs of characterological disorder, 32% thinking disturbance, and 9% emotional disturbance. Four percent of the profiles were asymptomatic. These findings are presented both to confirm the wider variety of psychopathology in substance abusers of the 1970s than earlier and to provide current researchers with comparative data.

Effects of familiar proctor on fifth and sixth grade students' test anxiety.

The effect of the proctor's familiarity on four groups of students in Grades 5 and 6 was investigated. The 137 children took a reading examination, half of which was administered by a familiar proctor, the other half by an unfamiliar one. Order of conditions was controlled. Analysis showed that students had significantly lower reading scores with the unfamiliar proctor. Students with midrange IQs had significantly lower reading scores than those in the low or high ranges. A significant relationship between test anxiety and effects of the unfamiliar proctor on test performance was shown. Test anxiety contributed significantly to the relationship between self-esteem and performance.

Effects of serial position on Bender-Gestalt errors using Koppitz's criteria.

The validity of the Koppitz Developmental scoring system in identifying organic impairment among functionally impaired adolescents was challenged in the current study. It was proposed that there are two distinct subtypes of errors in this system: those that are valid indicators of organic impairment (Category A) and those which are not but occur as a function of specific emotional factors (Category B). 46 male adolescents with a primary diagnosis of Conduct Disorder, Oppositional Defiant Disorder, or Attention-Deficit Hyperactivity Disorder were administered the Bender-Gestalt once using the standard order of administration and once in reverse order. It was hypothesized that more errors would be committed on cards presented later than those presented earlier in sequence for Category B but not Category A errors. Analysis provided partial support for this hypothesis.

Comparison of MMPI scores of drug abusers and Mayo Clinic normative groups.

Compared MMPIs of 80 male and 80 female drug abusers with MMPIs of 550 male and 695 female Mayo Clinic medical patients. Male drug abusers obtained significantly higher scores than male medical patients on all of the clinical scales and the F scale. They obtained a significantly lower score on K. Female drug abusers obtained significantly higher scores than female medical patients on seven clinical scales, D, Pd, Pa, Pt, Sc, Ma, and Si. They scored significantly higher on F and lower on L and K. Male and female drug abusers scored above 70 on Pd, Sc, and Ma, whereas medical patients did not exceed 60 on any scales. Findings were viewed as supporting the need for individualized, sophisticated, multidimensional psychological assessment and treatment of drug abusers in rehabilitation settings.

Sodium cromoglycate: a review.

Sodium cromoglycate is a drug widely used in the treatment of bronchial asthma. In vitro and animal models show that its effect is related to mast cell stabilization and to a direct action on inflammatory cells or the broncho-obstructive reflex. In man, sodium cromoglycate is able to prevent bronchoconstriction induced by a variety of stimuli including the 'late' reaction to allergen. It is also able to prevent the allergen-induced increase in hyperresponsiveness. Long-term therapeutic trials have confirmed its validity in the treatment of asthmatic patients.

Nedocromil sodium: a review of clinical studies.

Nedocromil sodium is a new compound for the long-term treatment of bronchial asthma. Its effect has been studied in prevention of bronchospasm induced by a variety of stimuli showing a broader spectrum of activity than SCG. Its clinical efficacy has been demonstrated in a number of trials involving patients regardless of asthma type.

Inhibition of fog-induced bronchoconstriction by nedocromil sodium and sodium cromoglycate in intrinsic asthma: a double-blind, placebo-controlled study.

The efficacy of pretreatment with two doses of nedocromil sodium (4 and 8 mg) and sodium cromoglycate 12 mg were compared with placebo in inhibiting the bronchoconstriction induced by inhalation of ultrasonically nebulized distilled water ('fog') in 10 subjects with intrinsic asthma. Each fog challenge consisted of three inhalations of 30, 60 and 120 s duration, respectively, given at 4-min intervals, and the bronchoconstrictor response was assessed as the postchallenge percentage fall in FEV1 from baseline. Statistically significant drug effects (p less than 0.05) were observed after 120 s of fog challenge: both nedocromil sodium 4 and 8 mg and sodium cromoglycate were significantly more effective than placebo in inhibiting fog-induced bronchoconstriction; in addition, nedocromil sodium 4 mg proved statistically significantly more effective than sodium cromoglycate.