W. James Metzger

Recurrent allergic vulvovaginitis: Treatment with Candida albicans allergen immunotherapy

Recurrent vaginal candidiasis is a difficult problem for many women who do not respond to the usual antifungal agents. Normally these women have recurrent disease for many years before they are referred for evaluation of local vaginal hypersensitivity. We evaluated 18 women with recurrent vulvovaginal candidiasis that was unresponsive to all other modalities of therapy and who were skin-test positive to Candida albicans with a positive prick test or intradermal skin test. Three patients had late-phase skin test reactions only. Of the 18 study participants, 16 responded with significant improvement in the mean incidence of episodes of vaginitis per year from 17.2 +/- 2.0 to 4.3 +/- 1.8 (p less than 0.0004). Overall, there was approximately 79% improvement in these patients. More than half the women were also atopic but were not first seen with these allergic symptoms. These data suggest that certain women who have chronic vaginal candidiasis may have a local hypersensitivity response to Candida that may improve with allergy immunotherapy with C. albicans extract. A double-blind, placebo-controlled trial in a homogeneous group of women with standardized extract is needed to establish this as a recommended form of therapy in this subgroup of patients.

Therapeutic approaches to asthma based on VLA-4 integrin and its counter receptors

Minimum inflammation can result in effective control mechanisms which protect against damage to surrounding tissues, but when these control mechanisms fail or are overwhelmed, inflammatory responses may result in human disease. An appropriate response to infection or allergens is regulated initially by the extravasation of intravascular fluid through the endothelium. A more potent response may result in extravasation of the cellular constituents of the intravascular fluid. Permeability appears to be controlled by intercellular adhesion and tethering, and the flow of cells through the endothelium by adhesion molecules on both endothelial lining cells and the cellular subsets. The pathophysiology of certain diseases, including asthma, atherosclerosis, ischemia-reperfusion injury, rheumatoid arthritis and graft rejection, may result from overwhelming cellular inflammation. Asthma, among these, is unique in that a single cell, the eosinophil, appears to be central to the pathogenesis of the various aspects of the syndrome including airway obstruction, which is usually reversible, edema, mucous secretion, and increased bronchial airway hyperresponsiveness (BHR). Because the eosinophil is peculiar to asthma, as well as other eosinophil-related diseases, and because eosinophils, in contrast to neutrophils, are dependent upon a specific interaction between endothelial cells and cellular adhesion molecules for transmigration into the interstitium, we have used these differences,to explore the potential role for antiadhesion molecules and their counter receptors in inhibiting the asthmatic response.

Once-Daily Budesonide Inhalation Powder (Pulmicort Turbuhaler®) is Effective and Safe in Adults Previously Treated with Inhaled Corticosteroids

This 12-week, double-blind, placebo-controlled, multicenter study evaluated the efficacy and safety of budesonide 400 µg administered once daily via TurbuhalerTM in adults previously treated with at least twice-daily dosing of inhaled corticosteroids. Pulmonary function (FEV1, PEF, FVC, FEF25–75%), asthma symptom scores, quality of life, and breakthrough medication use were significantly (p < 0.05) different in patients receiving once-daily budesonide Turbuhaler compared to placebo, and significantly (0 < 0.001) more patients receiving placebo discontinued the study. Adverse events were similar between study groups. Once-daily administration of budesonide Turbuhaler was safe and efficacious in patients previously treated with inhaled corticosteroids.

The many faces of systemic mastocytosis

OBJECTIVE This short review article will augment the readers knowledge of mast cell physiology and will offer an overview of current information on the pathophysiology, heterogeneity, and treatment of human mastocystosis. DATA SOURCES AND STUDY SELECTION Articles published since 1980, textbooks, information from computerized databases, references identified from bibliographies of relevant articles, and books published in the last 10 years. RESULTS AND CONCLUSIONS Mastocytosis is a complex disease with a multitude of clinical presentations, often misdiagnosed, which can embrace characteristics of other diseases and generate a chameleon-like picture. Mast cells possess many important physiologic functions in the human body, but as a consequence of poorly understood events, they can also start a cascade of pathologic reactions. Although a great deal is known about mechanisms involved in physiologic and pathologic processes of mast cells, many areas are waiting to be explored in this millennium.

Respirable Antisense Oligonucleotide (RASON) Therapy for Allergic Asthma

A new technology for treating respiratory disease, respirable antisense oligonucleotides (RASONs), has recently been developed by our group. RASONs are short, single-stranded nucleic acids, generally modified to reduce degradation. They differ from traditional drugs, which usually antagonise preformed proteins already functioning in a disease process. Instead, RASONs can attenuate the expression of disease-associated genes by targeting the messenger RNA (mRNA). Delivered directly to the target tissue, the lung, they avoid the problems of ineffective delivery encountered by other routes of administration. When an adenosine A1 antisense oligonucleotide was delivered to the lungs of allergic rabbits with up-regulated A1 adenosine receptors, desensitisation to the bronchoconstrictor effects of adenosine, histamine and a common aeroallergen (dust mite) occurred. The effect on A1 receptors persisted on average for nearly 7 days. RASON (the phosphorothioate antisense oligonucleotide EPI-2010) administered in low dosage was evenly distributed throughout the lung (with no detectable systemic active metabolites), and was excreted primarily in urine. These results demonstrate that RASONs can be efficiently and effectively delivered to the peripheral lung. They potently and selectively attenuate the expression of disease-associated genes, an approach to therapy which is now being extended to other potentially important mediators of bronchial asthma.

DNA Antisense Therapy for Asthma

Publisher Summary It is important to control asthma not only because it currently necessitates millions of dollars in prescription drug expenditure each year, but also because it causes loss of time from work, severely affects family life and the ability of patients to continue work and impedes a reduction in the high cost of medical health care placed upon hospitals and emergency rooms. Prevention of asthma now seems as important as treatment of asthma with medications. Avoidance of allergens, medications and allergy immunotherapy to prevent or reduce inflammation remain pre-eminent in the formulation of treatment guidelines for asthma. An antisense oligonucleotide (ODN) is designed to target the human adenosine A 1 receptor is found serendipitously to correspond to a region of complete homology for the rabbit adenosine A 1 receptor. This unique homology between human and rabbit in the the target mRNA for the adenosine A 1 receptor (not found in rat, bovine or other species in which the receptor has been cloned) permitted the use of the antisense ODN in the allergic rabbit model of human asthma.