Reference values for peak expiratory flow in Indian adult population using a European Union scale peak flow meter.

BACKGROUND: Reference values of peak expiratory flow (PEF) in Indian adults have to date been derived locally, using an old (Wright) scale peak flow meter. There are thus no reliable reference values for PEF for Indians and this formed the aim of the study. MATERIALS AND METHODS: A European Union (EU) scale peak flow meter (PFM) was used for the study. A respiratory health and demographic questionnaire was administered to 1000 male and female adults from randomly selected locations in the country in this multi centric study. The locations represented different geographic, ethnic, and socioeconomic backgrounds. Patients were stratified according to height and age. The PEF values were measured using the Breathometer™ (Cipla Ltd., India) with EU scale. Reference equations were derived from multiple regression analysis. RESULTS: A total of 3608 participants were excluded. In 80% of the remaining 6138 healthy adults (M: 3720; F: 2418), the predicted regression equations were derived. Gender, age, and height were the significant determinants of PEF. The equations in L/minute are: Females: PEF = -1.454 (Age) + 2.368 (Height) Males: PEF = -1.807 (Age) + 3.206 (Height). The derived equation was validated by comparing the predicted PEF values with the measured values in the remaining sample of 20% (Mean ΔPEF: M = 1.85 L/minute, CI = -2.76, 6.47; F = 1.64, CI = -2.89, 6.18). An Indian adult with average height and age was found to have approximately 30% lower PEF compared to the corresponding European adult using the Nunn and Gregg equation. CONCLUSION: We derived reference values of PEF for Indian adults using a validated EU scale peak flow meter.

Tiotropium administered by a pressurized metered dose inhaler (pMDI) and spacer produces a similar bronchodilator response as that administered by a Rotahaler in adult subjects with stable moderate-to-severe COPD.

BACKGROUND: Tiotropium is a new long-acting anticholinergic bronchodilator, which is recommended as first-line therapy in the management of chronic obstructive pulmonary disease (COPD). It is currently available in the form of a dry powder inhaler worldwide. Some COPD patients find it difficult to generate inspiratory flow rates of up to 40 l/min, which is required for the drug to reach the airways. To overcome this, a new pMDI form has been developed for administration of tiotropium in patients with COPD. The clinical efficacy of this mode of tiotropium delivery has, so far, not been compared with the currently available dry powder inhaler (DPI) devices. AIMS AND OBJECTIVES: To compare the bronchodilator effects of a single dose of 18 mcg of tiotropium administered via a pressurized meter dose inhaler (pMDI) and spacer with the currently available DPI form through Rotahaler. STUDY DESIGN: A randomized, double-blind, double-dummy, three-period, placebo-controlled, crossover, single-center study was conducted in 19 patients with stable COPD. Single doses of tiotropium (18 mcg) or placebo were administered on three separate study days (4-7 days apart) through a Rotahaler and pMDI with a non-static spacer (Zerostat, Cipla Ltd.). During each study visit forced expiratory volume in 1s (FEV(1)) and forced vital capacity (FVC) were measured over a period of 24 h at 11 different time points (0, 15, 30 min, 1, 2, 3, 4, 6, 8, 12 and 24h), using a bellows spirometer (Vitalograph) 2160, UK) while static parameters like inspiratory capacity (IC), residual volume (RV), intrathoracic gas volume (ITGV) and total lung capacity (TLC) were measured by bodyplethysmography (Jaeger Masterscreen, Germany) at 0 min, 3, 8 and 24 h. RESULTS: Tiotropium administered through both pMDI (and spacer) and DPI showed significantly better mean FEV(1) and mean FVC differences from baseline, in terms of mean maximum change and area under curve over a period of 24 h (AUC(0-24 h)), as compared to placebo. The mean IC and trough FEV(1) values also improved significantly with tiotropium administered through both the devices as compared to placebo. For all these parameters, there was no difference in the efficacy between pMDI and DPI. There was also no significant difference between the time to onset, time to maximum response and duration of response between tiotropium administered through both the study devices. On the other hand, there was no significant difference in RV, ITGV and TLC by a single dose of tiotopium delivered through either of the devices when compared with placebo over a period of 24 h. CONCLUSION: This is the first study to demonstrate that tiotropium administered by pMDI and spacer shows a superior time-dependent bronchodilator response when compared to placebo, and that this therapeutic efficacy is similar to tiotropium administered by DPI. We recommend the use of tiotropium administered through a pMDI and spacer to those COPD patients who prefer to use the pMDI device, and especially in those who cannot generate sufficient inspiratory flows required for dry powder inhaler devices.

Alpha1-adrenergic hypothesis for pulmonary hypertension.

Pulmonary hypertension (PH) is a chronic and disabling condition that affects the pulmonary vasculature. Once PH is diagnosed, the prognosis is generally poor with a rapid downhill course. PH management is largely empirical because the underlying pathophysiologic mechanisms that are responsible for the excessive vasoconstrictor and vascular smooth muscle proliferative responses are poorly understood. Based on new information concerning the role of adrenergic receptors in regulating various cellular functions, a new perspective on the genesis of PH has emerged, along with a unifying hypothesis for the role of alpha1-adrenergic receptors present in the pulmonary vasculature as the major contributor to the pathophysiologic changes associated with PH. Adrenergic receptors that are present on vascular smooth muscle cells regulate vascular tone and growth. The alpha1-adrenergic receptors that are present on the small- and medium-sized pulmonary arteries have a unique and greatly enhanced affinity and activity to alpha1-adrenergic agonists. Under physiologic conditions, this helps in regulating vascular tone and maintains an adequate ventilation/perfusion matching. However, the excessive stimulation of alpha1-adrenergic receptors produces not only smooth muscle contraction but also proliferation and growth. The conditions that produce an increase in alpha1-adrenoreceptor gene synthesis, density, and activity (such as hypoxia or changes in vessel wall pressure) or increase the levels of its agonists (such as norepinephrine, appetite suppressants, or cocaine) greatly enhance pulmonary vascular smooth muscle contractile and proliferative responses and lead to the development of PH. An understanding of the role played by these receptors in the pathophysiology of PH would not only help to avoid the use of alpha1-agonists for appetite suppression and other disease states, but also would help in developing new drugs to block these receptors. A further understanding of the alpha1-adrenoreceptor subtypes present in the pulmonary vasculature, the factors that regulate their expression, and their intracellular signaling pathways would help researchers to devise newer therapeutic strategies and, hopefully, to find a cure for this crippling condition.

Aspirin and asthma.

Aspirin is not only one of the best-documented medicines in the world, but also one of the most frequently used drugs of all times. In addition to its role as an analgesic, aspirin is being increasingly used in the prophylaxis of ischemic heart disease and strokes. The prevalence of aspirin intolerance is around 5 to 6%. Up to 20% of the asthmatic population is sensitive to aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) and present with a triad of rhinitis, sinusitis, and asthma when exposed to the offending drugs. This syndrome is referred to as aspirin-induced asthma (AIA). The pathogenesis of AIA has implicated both the lipoxygenase (LO) and the cyclooxygenase (COX) pathways. By inhibiting the COX pathway, aspirin diverts arachidonic acid metabolites to the LO pathway. This also leads to a decrease in the levels of prostaglandin (PG) E(2), the anti-inflammatory PG, along with an increase in the synthesis of cysteinyl leukotrienes (LTs). Evidence suggests that patients with AIA have increased activity of LTC(4) synthase, the rate-limiting enzyme in the cysteinyl LT synthesis, in their bronchial biopsy specimens, thereby tilting the balance in favor of inflammation. LT-modifying drugs are effective in blocking the bronchoconstriction provoked by aspirin and are used in the treatment of this condition. Aspirin desensitization has a role in the management of AIA, especially in patients who need prophylaxis from thromboembolic diseases, myocardial infarction, and stroke. This review covers the latest understanding of pathogenesis, clinical features, and management of AIA.

The anti-inflammatory effects of leukotriene-modifying drugs and their use in asthma.

Asthma is a chronic inflammatory disease of the airways. Anti-inflammatory drug therapy, primarily using corticosteroids, is now considered the first-line treatment in the management of all grades of asthma severity. Although corticosteroids are believed to be the most potent anti-inflammatory agents available, they do not suppress all inflammatory mediators involved in the asthmatic response. Leukotrienes, which are lipid mediators generated from the metabolism of arachidonic acid, play an important role in the pathogenesis of asthma. They produce bronchospasm, increase bronchial hyperresponsiveness, mucus production, and mucosal edema, and enhance airway smooth muscle cell proliferation and eosinophil recruitment into the airways, and their synthesis or release is unaffected by corticosteroid administration. The use of leukotriene synthesis inhibitors or leukotriene receptor antagonists as anti-inflammatory therapies in asthma has therefore been investigated. Beneficial effects of leukotriene-modifying drugs have been demonstrated in the management of all grades of asthma severity, and there is evidence that certain patient groups (such as those with exercise-induced asthma or aspirin-induced asthma) may be particularly suitable for such therapy.

Study of superior vena cava syndrome--aetiopathology, diagnosis and management.

Thirty two patients of superior vena cava syndrome (SVCS) were studied. Clinical features noted were diffuse neck swelling, breathlessness, chest pain, engorged neck veins, facial swelling and dilated engorged veins over chest wall. Radiography revealed a superior mediastinal mass in 31.2% of patients and right upper lobe mass in 50% patients. FNAC of lung showed aetiology in 34.5% patients and lymph node biopsy in 31.2% patients. Aetiology of SVCS was benign in 12.5% patients and malignant in 87.5% patients. Squamous cell carcinoma was the commonest cause of SVSC. Radiotherapy proved to be the most beneficial form of treatment. The mean survival period in patients due to malignant etiology was 6 months.

Acute exposure to diesel exhaust increases IL-8 and GRO-alpha production in healthy human airways.

We have previously demonstrated that short-term exposure to diesel exhaust (DE) for 1 h induced a marked leukocytic infiltration in the airways of healthy human volunteers involving neutrophils, lymphocytes, and mast cells along with increases in several inflammatory mediators. We hypothesized that the leukocyte infiltration and the various inflammatory responses induced by DE were mediated by enhanced chemokine and cytokine production by resident cells of the airway tissue and lumen. To investigate this, 15 healthy human volunteers were exposed to diluted DE and air on two separate occasions for 1 h each in an exposure chamber. Fiberoptic bronchoscopy was performed 6 h after each exposure to obtain endobronchial biopsies and bronchial wash (BW) cells. Using reverse transcriptase/polymerase chain reaction enzyme-linked immunosorbent assay (RT-PCR ELISA), a novel and sensitive technique to quantify relative amounts of cytokine mRNA gene transcripts, and immunohistochemical staining with computer-assisted image analysis to quantify expression of cytokine protein in the bronchial tissue, we have demonstrated that DE enhanced gene transcription of interleukin-8 (IL-8) in the bronchial tissue and BW cells along with increases in IL-8 and growth-regulated oncogene-alpha (GRO-alpha) protein expression in the bronchial epithelium, and an accompanying trend toward an increase in IL-5 mRNA gene transcripts in the bronchial tissue. There were no significant changes in the gene transcript levels of interleukin-1B (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), interferon gamma (IFN-gamma), and granulocyte macrophage colony-stimulating factor (GM-CSF) either in the bronchial tissue or BW cells after DE exposure at this time point. These observations suggest an underlying mechanism for DE-induced airway leukocyte infiltration and offer a possible explanation for the association observed between ambient levels of particulate matter and various respiratory health outcome indices noted in epidemiological studies.

Different airway inflammatory responses in asthmatic and healthy humans exposed to diesel.

Particulate matter (PM) pollution adversely affects the airways, with asthmatic subjects thought to be especially sensitive. The authors hypothesised that exposure to diesel exhaust (DE), a major source of PM, would induce airway neutrophilia in healthy subjects, and that either these responses would be exaggerated in subjects with mild allergic asthma, or DE would exacerbate pre-existent allergic airways. Healthy and mild asthmatic subjects were exposed for 2 h to ambient levels of DE (particles with a 50% cut-off aerodynamic diameter of 10 microm (PM10) 108 microg x m(-3)) and lung function and airway inflammation were assessed. Both groups showed an increase in airway resistance of similar magnitude after DE exposure. Healthy subjects developed airway inflammation 6 h after DE exposure, with airways neutrophilia and lymphocytosis together with an increase in interleukin-8 (IL-8) protein in lavage fluid, increased IL-8 messenger ribonucleic acid expression in the bronchial mucosa and upregulation of the endothelial adhesion molecules. In asthmatic subjects, DE exposure did not induce a neutrophilic response or exacerbate their pre-existing eosinophilic airway inflammation. Epithelial staining for the cytokine IL-10 was increased after DE in the asthmatic group. Differential effects on the airways of healthy subjects and asthmatics of particles with a 50% cut-off aerodynamic diameter of 10 microm at concentrations below current World Health Organisation air quality standards have been observed in this study. Further work is required to elucidate the significance of these differential responses.