Systemic versus topical glucocorticoid therapy for acute asthma.
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Acute Disease↗
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New insights into airway inflammation by endobronchial biopsy.
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Administration, Inhalation↗
Different effects of nasal and bronchial glucocorticosteroid administration on bronchial hyperresponsiveness in patients with allergic rhinitis.
Disorders of the upper respiratory tract, particularly allergic rhinitis, are commonly associated with bronchial hyperresponsiveness. The latter may be due to postnasal drip or to mediator or chemotactic factors into the lower airways that either directly alter airway reactivity or cause airway inflammation. The aim of this study was to compare the effect of an identical dose of nasal or bronchial corticosteroid administration on bronchial hyperresponsiveness in patients with allergic rhinitis. Eleven patients were studied. All of them were judged atopic on the basis of positive skin tests to common allergens. During control, spirometry, flow-volume curves, and specific airway conductance (SGaw) were measured. Bronchial challenges were then performed with increasing concentrations of carbachol, and dose-response curves were constructed. The concentration of carbachol that decreased SGaw by 35% from baseline (PD35) was determined by interpolating from the dose-response curve. Control measurements were repeated at 1-wk intervals to ensure that PD35 was stable in all the patients. Then the patients received for 2 wk, in a double-blind randomized crossover fashion, a topical administration of either an aerosol of 400 micrograms of beclamethasone dipropionate (B) into the nose (100 micrograms four times per day) or into the bronchi. During each trial period, identical sprays of placebo were used, the latter being administered into the nose when B was administered into the bronchi and vice versa. Measurements were then performed after 2 wk of intranasal administration and after 2 wk of intrabronchial administration.(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Inhalation↗
Effect of montelukast and fluticasone propionate on airway mucosal blood flow in asthma.
Asthma is associated with an increase in airway blood flow (Qaw), presumably as a manifestation of airway inflammation. We therefore determined the effect of the antiinflammatory agents montelukast (ML) and fluticasone propionate (FP) on Qaw in 12 patients with mild intermittent asthma. Using a double-blind approach, Qaw along with FEV(1) and Vmax(50) were determined before and after a 2-week treatment period with either ML (10 mg/day), FP (440 microg/day), or 10 mg of ML plus 440 microg of FP daily, separated by 2-week washout periods. Mean (+/- SEM) Qaw ranged from 68 +/- 4.2 to 71.8 +/- 5.9 microl x minute(-1) x ml(-1) anatomic dead space before the treatment periods. ML, FP, and ML plus FP decreased mean Qaw by 21.5, 20.8, and 26.9%, respectively (p < 0.05 for all). No significant difference was observed among the three regimens. FEV(1) and Vmax(50) were not changed by any of the treatments. We conclude that at the dosages used, ML and FP are equipotent in reducing Qaw in patients with mild asthma, and that the magnitude of the response is not greater if the two drugs are combined. The results also suggest that the vascular effects of these agents can be assessed independent of their effects on airway function.
Acetates↗
The impact of oral corticosteroid use on bone mineral density and vertebral fracture.
The use of oral corticosteroids is associated with an increased risk of fracture, but there is limited information on the relationship between corticosteroid dose, bone mineral density (BMD), and fracture. We examined this relationship in a community population (more than 50 years) taking oral corticosteroids for chronic lung disease. Details of corticosteroid use and lifestyle were obtained by questionnaire, general practice records, and patient interview. BMD was assessed at the lumbar spine and femur and vertebral fracture by morphometric X-ray absorptiometry. Of the 117 patients who participated (median age, 69), 48% were female. Fifty-eight percent had osteoporosis (a T score of less than -2.5), and 61% had a vertebral fracture. The presence of vertebral fracture was related to BMD at the femoral neck, with an odds ratio of 1.6 for a 1 SD reduction in BMD. The cumulative prednisolone dose ranged from 3.4 to 175 g and was strongly associated with vertebral fracture, with the odds ratio between the highest and lowest dose quartiles being 4.4 (95% confidence interval, 1.04, 18.8). The difference in femoral neck BMD between the same dose quartiles was only modest, however (0.5 SD; 95% confidence interval, 0.09, 0.94). In patients taking long-term oral corticosteroids for chronic lung disease, the relationship between vertebral fracture risk and BMD is similar to that seen in other populations. Cumulative prednisolone dose is strongly related to fracture risk, and this effect is independent of its more modest impact on BMD.
Administration, Inhalation↗
Suppression of asthma-like responses in different mouse strains by oral tolerance.
In this study we examined the effect of oral antigen (Ag) administration on the development of experimental asthma in different mouse strains. We selected BALB/c, BP2, CBA/Ca interleukin (IL)-5 transgenic, and BALB/c T-cell receptor-delta-deficient mouse strains because they exhibit different aspects of the asthma syndrome. Mice exposed to 1% ovalbumin (OVA), dissolved in the drinking water for 5 consecutive days, became unresponsive to subsequent immunogenic OVA challenges. This regimen of OVA administration induced Ag-specific unresponsiveness in all mouse strains tested, including gammadelta-deficient mice that are said to be resistant to tolerance induction. The Ag-specific unresponsiveness was characterized by reduced (almost absent) airway eosinophilic inflammation, airway hyperreactivity, and mucus production; also by low levels of T helper (Th) 2-type cytokines in bronchoalveolar lavage fluid, and decreased immunoglobulin (Ig) G1 and IgE OVA-specific antibody production. The unresponsive state was not associated with increased levels of the suppressive cytokines IL-10 and transforming growth factor (TGF)-beta or with immune deviation toward the Th1 pathway due to increased levels of interferon-gamma and IL-12. Moreover, treatment with anti- TGF-beta antibodies did not abrogate oral tolerance. Oral Ag administration was quite effective in suppressing the development of key features of asthma when initiated after primary immunization (Day 0) or after booster (Day 7), but not after challenge (Day 14) when it increased allergic responses. Collectively, our findings show for the first time the beneficial and detrimental effects of oral Ag administration on the development of experimental asthma.
Administration, Inhalation↗
Differential expression of tissue-specific adhesion molecules on human circulating antibody-forming cells after systemic, enteric, and nasal immunizations. A molecular basis for the compartmentalization of effector B cell responses.
Expression of the adhesion molecules CD44, L-selectin (CD62L), and integrin alpha 4 beta 7 by antibody-secreting cells (ASC) was examined in human volunteers after oral, rectal, intranasal, or systemic immunization with cholera toxin B subunit. Almost all blood ASC, irrespective of immunization route, isotype (IgG and IgA), and immunogen, expressed CD44. On the other hand, marked differences were observed between systemically and intestinally induced ASC with respect to expression of integrin alpha 4 beta 7 and L-selectin, adhesion molecules conferring tissue specificity for mucosal tissues and peripheral lymph nodes, respectively. Thus, most ASC induced at systemic sites expressed L-selectin, whereas only a smaller proportion of ASC expressed alpha 4 beta 7. In contrast, virtually all IgA- and even IgG-ASC detected after peroral and rectal immunizations expressed alpha 4 beta 7, with only a minor fraction of these cells expressing L-selectin. Circulating ASC induced by intranasal immunization displayed a more promiscuous pattern of adhesion molecules, with a large majority of ASC coexpressing L-selectin and alpha 4 beta 7. These results demonstrate that circulating ASC induced by mucosal and systemic immunization express different sets of adhesion molecules. Furthermore, these findings provide for the first time evidence for differential expression of adhesion molecules on circulating ASC originating from different mucosal sites. Collectively, these results may explain the anatomical division of mucosal and systemic immune responses in humans as well as the compartmentalization of mucosal immune responses initiated in the upper vs. the lower aerodigestive tract.
Administration, Inhalation↗
Disruption of antigen-induced inflammatory responses in CD40 ligand knockout mice.
The objective of this study was to investigate the contribution of the interaction between CD40 and its ligand (CD40L) to antigen-induced airways inflammatory responses. To this end, we used a model involving ovalbumin (OVA) sensitization followed by OVA aerosol challenge in CD40L knockout (KO) mice. OVA-specific IgE and IgG1 were detected in the serum of the sensitized control, but not in CD40L-KO mice. After antigen challenge, sensitized control mice developed airway inflammation that was primarily eosinophilic. This inflammatory response was dramatically reduced in CD40L-KO mice. In contrast, similar numbers of eosinophils were observed in both the bone marrow and the peripheral blood in the sensitized controls and mutant strains after antigen challenge. To investigate the mechanisms underlying these findings, we examined levels of the cytokines IL-5, IL-4, and TNFalpha in both bronchoalveolar lavage (BAL) and serum. Similar levels of IL-5 were detected in BAL and serum of control and CD40L-KO mice; however, negligible levels of IL-4 in BAL and serum and of TNFalpha in BAL were detected in CD40L-KO mice when compared with control mice. Furthermore, we demonstrated that endothelial cell expression of vascular cell adhesion molecule 1 in OVA-sensitized and -challenged CD40L-KO mice was, as detected by immunohistochemistry, markedly decreased compared with that observed in similarly treated control mice. In addition, we locally overexpressed IL-4 and TNFalpha by using an adenoviral (Ad)-mediated gene transfer approach. Intranasal administration of either Ad/TNFalpha or Ad/IL-4 into OVA-sensitized and -challenged CD40L-KO mice did not reconstitute airway eosinophilia. However, concurrent administration of Ad/TNFalpha and Ad/IL-4 upregulated endothelial expression of vascular cell adhesion molecule 1, and resulted in full reconstitution of the inflammatory response in the airways. Together, these findings demonstrate the importance of the CD40-CD40L costimulatory pathway in the full expression of the inflammatory response in the airways.
Adenoviridae↗
Comparison between isosorbide dinitrate in aerosol and in tablets for the treatment of hypertensive emergencies.
Sixty patients with a hypertensive emergency (mean arterial pressure >130 mm Hg and evidence of target organ damage) were randomly divided into two groups of 30 patients each. Group A received 1.25 mg of isosorbide dinitrate aerosol upon arrival and a second dose 15 minutes later when the mean arterial pressure reduction was < 15%. Group B received a single 5 mg tablet of sublingual isosorbide dinitrate. Electrocardiography was performed in both groups prior to and 30 minutes after the medication. Blood pressure was monitored for 6 hours. Blood pressure in Group A patients decreased in an average time of 10 minutes from 191 +/- 12/122.3 +/- 5 to 151.5 +/- 9.2/93 +/- 4 mm Hg, p < 0.005. Mean arterial pressure decreased by 22.8%: 145 +/- 7 to 112 +/- 7.5 mm Hg, p < 0.005. No adverse effects occurred. Five patients in Group B did not respond; in the rest of the group blood pressure decreased 45 minutes after receiving the medication from 194 +/- 8/125 +/- 5.5 to 160 +/- 11/98 +/- 6 mm Hg; p < 0.005. Mean arterial pressure decreased by 20.1%: 148.3 +/- 12 to 118.6 +/- 9 mm Hg, p < 0.002; ten patients suffered headache. Three patients in Group A had a subepicardial lesion in the first electrocardiograph, which disappeared with the use of the aerosol. In Group B, electrocardiography results were normal. These results seem to indicate that isosorbide dinitrate aerosol is better than tablets for the treatment of patients with a hypertensive emergencies.
Administration, Inhalation↗
ATSDR evaluation of health effects of chemicals. II. Mirex and chlordecone: health effects, toxicokinetics, human exposure, and environmental fate.
This document provides public health officials, physicians, toxicologists, and other interested individuals and groups with an overall perspective of the toxicology of mirex and chlordecone. It contains descriptions and evaluations of toxicological studies and epidemiological investigations and provides conclusions, where possible, on the relevance of toxicity and toxicokinetic data to public health. Additional substances will be profiled in a series of manuscripts to follow.
Administration, Cutaneous↗
The role of aerosol pentamidine prophylaxis.
Pneumocystis carinii pneumonia (PCP) is the most frequent opportunistic infection in patients with AIDS, occurring in 80% and recurring in 50% of patients within 12 months of the first episode. Prophylaxis for PCP is recommended if the CD4+ cell count is < 200 x 10(6)/l or 20% of the total lymphocyte count, or after an episode of PCP. The most effective prophylactic agent currently is trimethoprim-sulphamethoxazole and should be the drug of choice but alternatives such as aerosol pentamidine are being increasingly used for patients who cannot tolerate this combination or other oral preparations. If aerosol pentamidine is used and administered via a Respigard II Marquest nebulizer, the dosage should be higher than the currently recommended monthly dosage of 300 mg.
AIDS-Related Opportunistic Infections↗
Cardiac toxicity following short-term exposure to methomyl in spraymen and rabbits.
A health surveillance study in 22 healthy spraymen showed significant T-wave changes (including inversion) in most of the limb leads and chest leads following 5 d exposure to methomyl, a carbamate pesticide. Significant changes in plasma cholinesterase and lactic dehydrogenase activities were also noticed. The ECG changes could be reproduced in rabbits and were dose dependent. This type of ECG change following exposure to a carbamate compound is reported for the first time in occupationally-exposed subjects. The study results indicate that these changes are probably directly related to methomyl rather than its toxicity through cholinesterase inhibition. The significance of these changes remain to be investigated.
Administration, Inhalation↗
Biokinetics and biokinetic models in risk assessment.
Risk assessment of xenobiotics using animal data involves extrapolation from high doses to low ones, and from animal species to humans. In some cases it also involves extrapolation from one route of exposure to another. To assess the risk of exposure to xenobiotics, information on both biokinetics and biodynamics are needed. The contribution of biokinetics to risk assessment is the subject of this review. The review includes the general aspects of biokinetics of chemicals, the models available to describe the biokinetic behaviour of a chemical and a discussion of the class of biokinetic models that is considered most suited for application to risk assessment: the physiologically-based biokinetic (PBBK) models. The power of PBBK models is illustrated with a few examples.
Administration, Cutaneous↗
Possible short-term memory loss associated with nafarelin acetate.
OBJECTIVE AND DESIGN: A survey was conducted to determine the occurrence of short-term memory loss in patients using nafarelin acetate nasal spray. SETTING AND PATIENTS: A list of all patients receiving nafarelin acetate from our pharmacy over a four-month period was generated. We contacted and surveyed 16 women. INTERVENTIONS: Each patient was asked to repeat three words at the beginning of the survey and after a series of questions, each patient was asked to recall the three words. Patients were also asked if they believed that their memory was affected by nafarelin acetate nasal spray. RESULTS: Eleven patients (69 percent) recalled three words, 3 (19 percent) recalled two words, and 2 (13 percent) recalled one word at the conclusion of the survey. Nine of 16 patients (56 percent) reported some type of memory difficulty. CONCLUSIONS: Nafarelin acetate nasal spray may adversely affect short-term memory. This effect is not documented in current literature and further investigation is warranted in the possible relationship between gonadotropin releasing hormone agonists, estrogen deficiency, menopause, and short-term memory. Our survey also demonstrates the significance of communication between pharmacists and patients on newly marketed medications.
Administration, Inhalation↗
Oral N-acetylcysteine reduces bleomycin-induced lung damage and mucin Muc5ac expression in rats.
Oxidative stress is involved in the pathogenesis of pulmonary fibrosis, therefore antioxidants may be of therapeutic value. Clinical work indicates that N-acetylcysteine (NAC) may be beneficial in this disease. The activity of this antioxidant was examined on bleomycin-induced lung damage, mucus secretory cells hyperplasia and mucin Muc5ac gene expression in rats. NAC (3 mmol x kg(-1) x day(-1)) or saline was given orally to Sprague-Dawley rats for 1 week prior to a single intratracheal instillation of bleomycin (2.5 U x kg(-1)) and for 14 days postinstillation. NAC decreased collagen deposition in bleomycin-exposed rats (hydroxyproline content was 4,257+/-323 and 3,200+/-192 microg x lung(-1) in vehicle- and NAC-treated rats, respectively) and lessened the fibrotic area assessed by morphometric analysis. The bleomycin-induced increases in lung tumour necrosis factor-alpha and myeloperoxidase activity were reduced by NAC treatment. The numbers of mucus secretory cells in airway epithelium, and the Muc5ac messenger ribonucleic acid and protein expression, were markedly augmented in rats exposed to bleomycin. These changes were significantly reduced in NAC-treated rats. These results indicate that bleomycin increases the number of airway secretory cells and their mucin production, and that oral N-acetylcysteine improved pulmonary lesions and reduced the mucus hypersecretion in the bleomycin rat model.
Acetylcysteine↗
Alveolar nitric oxide in adults with asthma: evidence of distal lung inflammation in refractory asthma.
Recent studies have suggested that alveolar nitric oxide (NO) concentration is a noninvasive test of distal lung inflammation. The current study determined whether alveolar NO concentration can be measured in patients with asthma of varying severity, tested the hypothesis that there is an association between alveolar NO and bronchoalveolar lavage (BAL) eosinophil count and determined whether refractory asthma is characterised by a raised alveolar NO concentration. Finally, the present authors assessed the effect of 2 weeks of prednisolone (30 mg q.d.) on alveolar NO concentration. Alveolar NO concentration was both measurable and repeatable in patients with refractory asthma. A positive correlation was found between alveolar NO concentration and BAL eosinophil count but not with bronchial wash or sputum eosinophil count. Alveolar NO concentration was increased in patients with refractory asthma (7.1 ppb) compared with mild-to-moderate asthma (3.4 ppb) and normal controls (3.4 ppb) and reduced by treatment with prednisolone. In conclusion, these findings support the hypothesis that alveolar nitric oxide is a measure of distal airway inflammation and suggest that distal lung inflammation is present in refractory asthma.
Administration, Inhalation↗
Therapeutic efficacy and clinical acceptability of fusafungine in follicular pharyngitis.
Eighty-one patients suffering from follicular pharyngitis were treated for 7 days in a double-blind, multicentre controlled study of fusafungine versus placebo. Evaluations were performed at inclusion, after 7 days of treatment, and 3 weeks after the end of the treatment. The effects of the pharyngitis on day-to-day life, changes in symptoms, morphological changes of lesions, and general changes observed by the investigator and expressed by the patient were the parameters evaluated at each visit. Results confirmed the efficacy of fusafungine in the treatment of local and symptomatic manifestations of follicular pharyngitis. Effects of follicular pharyngitis on day-to-day life decreased after 7 days of treatment and the differences between the treatment group and the placebo group was close to significance in favour of fusafungine. For the majority of symptoms, the percentage of patients who did not display the symptoms at D7 was greater in the fusafungine group. Postnasal drip decreased significantly in the fusafungine group. The investigators' and patients' judgement was also in favour of the fusafungine treatment. These improvements were confirmed at least 3 weeks after the end of the treatment.
Administration, Inhalation↗
Concurrent crack and powder cocaine users from Sao Paulo: do they represent a different group?
BACKGROUND: Cocaine abuse is a serious and socially damaging illegal drug problem. Different routes of administration are associated with a specific progression of use, different degrees of abuse liability, propensity for dependence and treatment response. There have been relatively few studies comparing different cocaine users groups and no studies into the characterization of the group of individuals reporting concurrent use of powder cocaine and crack cocaine. METHODS: Six hundred and ninety-nine cocaine users were assessed during the period August 1997 to October 1998 in one outpatient and six inpatient clinics located in the São Paulo, Brazil. Patients were interviewed using a structured questionnaire schedule in Portuguese, designed specifically for the Brazilian population. The statistical analyses were performed using either ANOVA or a chi-squared test and focusing on their preferred form of use/route of administration and other variables. RESULTS: For 83% of the variables tested in this study, the Dual Users subgroup (using both powder and crack cocaine) demonstrated statistical differences from the single drug user subgroups. Those differences include the initiation of cocaine, the abuse of other illicit drugs, and rates of criminal history. CONCLUSION: These data suggest cocaine-dependent individuals who report use of both powder and crack cocaine are an at least partially, distinct subgroup. However, further studies will be necessary to confirm this and to determine if they also show a different treatment response.
Administration, Inhalation↗