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.

A comparison of dose-response curves in cognitive-behavioral and psychodynamic psychotherapies.

Changes in patient- and therapist-rated process items, and patient-rated symptom severity assessed over a maximum of 30 sessions of psychodynamic or cognitive-behavioral psychotherapy were compared in an outpatient mental-health clinic. Patients' ratings in psychodynamic psychotherapy on two of the process items were superior to ratings by patients in cognitive-behavioral therapy, and interactions with time were discovered for an interpersonal item. Comparisons between patients who reported their initial symptom severities as most severe and those with less severe symptoms also were made, with results indicating differential effects of treatment according to perceptions of symptom severity. Interactions between length of stay in treatment and number of sessions also were investigated. Findings indicated that patients benefit from psychotherapy over time and support the usefulness of a contextual model for psychotherapy funding.

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.).

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 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.

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.

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.

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.

Inducibility of RANTES mRNA by IL-1beta in human bronchial epithelial cells is associated with increased NF-kappaB DNA binding activity.

RANTES is a member of a large supergene family of proinflammatory chemokines that seems to play an important role in inflammatory processes. It is produced by many cell types in response to specific stimuli and during inflammatory reactions, but the marked differences in the pattern of induced expression suggest that different control mechanisms regulate transcription of RANTES in various tissue types. This is supported by the presence of a large number of potential binding sites for transcriptional factors in the promoter region of the RANTES gene. Our data indicate that expression of RANTES mRNA induced by IL-1beta in human lung epithelial cells is associated with the activation of the transcriptional factor NF-kappaB.

Endothelin-1 induces increased fibronectin expression in human bronchial epithelial cells.

Endothelin-1 may be involved in the pathogenesis of asthma by causing bronchial smooth muscle constriction and airway remodelling. Bronchial epithelial cells represent an important source of endothelin-1 in this disease, and increased release of epithelial cell-derived endothelin-1 may contribute to the genesis of subepithelial fibrosis by promoting fibroblast proliferation and collagen production. In this study, we demonstrate that endothelin-1 upregulates fibronectin gene expression and fibronectin release in bronchial epithelial cells via an ETA receptor. Fibronectin is an important component of the extracellular matrix which is deposited in excess in the subepithelial area of asthmatic bronchial mucosa, and it represents a potent chemotactic factor for fibroblasts. Thus, endothelin-1 may induce subepithelial fibrosis both directly and by the autocrine mechanism reported here.

Time course of IL1 and IL6 synthesis and release in human bronchial epithelial cell cultures exposed to toluene diisocyanate.

We have previously demonstrated that human bronchial epithelial cells release appreciable amounts of interleukin 1 (IL1) and interleukin 6 (IL6) when exposed to toluene diisocyanate (TDI) in vitro. TDI is an inflammatory and asthmogenic stimulus presumed to act at least in part through immunological mechanisms. The epithelial cell-derived IL1 and IL6 can promote T cell activation and proliferation in culture, and if this also happens in vivo they may contribute to the persistence of the inflammatory response of the bronchial mucosa observed in TDI-sensitive asthmatics. In this study, we confirmed the release of biologically active IL1 beta and IL6-like substances from bronchial epithelial cells exposed to isocyanates in vitro, and related the rate and the magnitude of the cytokine secretion with the pattern of IL1 beta and IL6 gene expression and the extent of epithelial cell injury. In the epithelial cell cultures exposed to TDI, there was a parallel, progressive increase in the expression of IL6 mRNA and in the secretion of IL6 protein between 48 hours and 6 days after exposure. By contrast, although increasing amounts of biologically active IL1 beta were detected in the supernatants of TDI-exposed epithelial cells throughout the 6-day period following exposure, augmented levels of IL1 beta mRNA were only evident 6 days after exposure, suggesting that TDI exposure might have initially affected the enzymatic cleavage of the intracellular IL1 beta precursor and the mechanisms which regulate the secretion of mature IL1 beta.

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.

Nedocromil sodium prevents the release of 15-hydroxyeicosatetraenoic acid from human bronchial epithelial cells exposed to toluene diisocyanate in vitro.

The in vivo exposure to an asthmogenic stimulus, toluene diisocyanate (TDI), causes airway epithelial damage associated with inflammation and increased bronchial hyperresponsiveness. The latter mechanisms might partly be mediated by the release of eicosanoids from bronchial epithelial cells. We have previously demonstrated that the in vitro exposure of bronchial epithelial cells to TDI results in the release of immunoreactive 15-hydroxyeicosatetraenoic acid (15-HETE), a product of activation of the 15-lipoxygenase pathway with inflammatory properties. In the present study we show that TDI-induced release of 15-HETE from epithelial cells can be prevented by nedocromil sodium, an anti-asthmatic drug with anti-inflammatory properties. This mode of action of the compound may explain its clinical effectiveness in asthma.

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.

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.

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.

Comparison of the performance of two mini peak flow meters.

Two mini peak flow meters commonly used to monitorize the peak expiratory flow rate (PEFR) are compared to assess their agreement, precision and, with respect to a standard pneumotachygraph, accuracy. Precision of the mini-Wright peak flow meter is greater, possibly as result of a systematic overestimation of PEFR values. The Assess peak-flow meter is more accurate, but its ability to reproduce the actual well-known PEFR variability is dependent from the absolute level of air flow. The agreement between two instruments is very poor, both in asthmatics and in normals, so that it is mandatory to use always the same mini peak flow meter in population studies and during the follow-up of asthmatic patients.

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.