Inhaled mannitol and cystic fibrosis. Unnecessary bronchial irritation.

Cystic fibrosis is a life-threatening genetic disease mainly characterised by accumulation of viscous secretions in the airways. In the absence of a better alternative, inhaled dornase alfa is used to liquefy bronchial secretions and thereby facilitate their drainage. Mannitol, in the form of capsules of powder for inhalation, is authorised in the European Union for use as a mucolytic in adults with cystic fibrosis. Two double-blind randomised trials have compared two doses of inhaled mannitol (400 mg or 50 mg, twice a day) in a total of 642 patients (57% adults) with cystic fibrosis. After 26 weeks of treatment, there was no difference between the groups in terms of clinical criteria such as the frequency of pulmonary exacerbations, quality of life, hospitalisation, or rescue antibiotic use. Inhaled mannitol increases the risk of bronchospasm and can also cause coughing and haemoptysis. A pretreatment test, used to exclude patients with bronchial hyperresponsiveness to mannitol, can also have noteworthy adverse effects. Treatment is inconvenient, requiring inhalation of the contents of 10 mannitol capsules morning and evening; the capsules have to be placed one by one in the inhalation device, and the device must be replaced every week. In practice, patients with cystic fibrosis would be well advised to avoid inhaled mannitol.

[Pediatric exposures to laundry pods or capsules: more toxic than traditional laundry products?]. / Expositions des enfants aux lessives capsules, écodoses ou pods : plus toxiques que les lessives traditionnelles ?

UNLABELLED: New concentrated laundry pods, available on the European market for approximately 10 years, are associated with more severe intoxications compared to classic laundry detergents. AIM: To compare symptoms and severity after exposure to classic laundry detergents and new laundry pods in a pediatric population. MATERIAL AND METHODS: Retrospective study conducted between 1st January 2002 and 30th June 2013 including all laundry detergent exposure patients admitted to our tertiary level pediatric emergency unit. Collected data were age, sex, date, time and location of exposure, type of product (powder, liquid, tablets, pods), estimated ingested quantity, time of admission, clinical symptoms, severity, complications, and progression. RESULTS: Descriptive analysis: eighty-nine children were included. The mean age was 2.1 ± 1.5 years (range, 36 days to 10 years), 65% of patients were aged less than 2 years. The male:female ratio was 1.5 (males, 60%). After exposure, 57% of children were symptomatic and most frequently developed digestive symptoms (75%). Comparative analysis: compared to classic laundry detergent, children exposed to laundry pods were more symptomatic (96% versus 51%, P<0.0001), had more digestive signs (P=0.003), more frequently had bronchospasm (P=0.02), had a higher risk of ocular lesions (P=0.04), and exposure was more severe (poisoning severity score grade 2, 92% versus 59%, P<0.0001). COMMENTS: Laundry pod toxicity is more severe. The chemical composition of laundry pods has a higher concentration of surfactants and ethoxylated alcohols; they have a higher viscosity and hydrotropic power. The addition of water seems to modify the alkalinity, which explains the severity of ENT, gastric, and corneal lesions. CONCLUSION: The declaration to national poison centers of these intoxications should be pursued by emergency pediatricians, physicians, and pediatric intensivists. Family physicians can encourage parents to declare adverse effects to the National Consumer Product Safety Commission. Parents need to be better informed of the risk of laundry pods and strictly keep this type of product out of the reach of children. Given that it took 7 years after the first warning by the French poison centers to obtain safety recommendations for manufacturers, it is important to maintain pressure on companies to obtain the necessary modification of the physicochemical properties and child-resistant packaging.

Study on the mechanism of the bronchodilatory effects of Cynodon dactylon (Linn.) and identification of the active ingredient.

ETHNOPHARMACOLOGICAL RELEVANCE: In the traditional medicine, Cynodon dactylon (Linn.) is used in asthma, but scientific studies to provide evidence for medicinal uses are sparse. Thus this study was undertaken to provide evidence for medicinal use in asthma as a bronchodilator, and to identify active ingredient(s). MATERIALS AND METHODS: In vivo, acetylcholine (Ach)-induced bronchospasm was conducted in guinea pig while isolated rat tracheal strip was suspended in organ bath to measure the concentration response curve using multichannel data acquisition system. RESULTS: The chloroform extract of Cynodon dactylon (CECD) protected against Ach-induced bronchospasm in guinea pigs, similar to atropine. In the in vitro studies, CECD relaxed carbachol (CCh) and high K+-induced contraction of rat tracheal strip, similar to atropine and verapamil respectively, suggesting antimuscarinic and calcium channel blocking (CCB) activities, which were confirmed by right ward shifting of CCh and Ca(+2) concentration response curve (CRC). The phosphodiestrase (PDE) inhibitory activity was confirmed by potentiation of isoprenaline-induced inhibitory response, similar to papaverine. Densitometry analyses led to the identification of scopoletin as an active ingredient. Effectively, it significantly inhibited high K+, and Ca(+2) induced contractile response, similar to verapamil. The phosphodiestrase (PDE) inhibitory activity was confirmed by direct evidence of potentiation of isoprenaline-induced inhibitory response, similar to papaverine. CONCLUSIONS: These results suggest that the bronchodilator activity of CECD is partly due to presence of scopoletin, and mediated possibly through CCB and PDE inhibition.

Phytopharmacological evaluation and anti-asthmatic activity of Ficus religiosa leaves.

OBJECTIVE: To discuss phytopharmacological potential and anti-asthmatic activity of Ficus religiosa (F. religiosa) (L.). METHODS: Fresh leaves of F. religiosa were obtained from Vastrapur Lake, Ahmedabad, and dried to obtain powder. Histamine and acetylcholine were used to guinea pigs to establish bronchospasm model. In in vivo study, the aqueous extract of F. religiosa leaves (AEFR) at doses of 150 and 300 mg/kg was administrated to guinea pigs, and the broncho-protective activity of AEFR was compared with aminophylline at 25 mg/kg. While in in vitro study, and 10 g/mL, 20 g/mL, 30 g/mL of AEFRL was administrated to guinea pigs, respectively, and mast cell stabilizing activity of AEFR was compared with ketotifen at 10 g/mL. RESULTS: In the in-vivo model, pre-treatment with aminophylline (25 mg/kg, ip.) could significantly delay the onset of histamine induced pre-convulsive dyspnea, compared with vehicle control. Administration of AEFRL (150 and 300 mg/kg, ip.) also produced significant effect on latency to develop histamine & acetylcholine induced pre-convulsive dyspnea. In the mast cell stabilizing model, AEFRL at 10, 20 and 30 µg/mL could significantly increase the number of intact cells. CONCLUSIONS: It can be concluded that AEFRL is effective on histamine & acetylcholine induced bronchospasm in guinea pigs. In addition, AEFRL can potentiate the number of intact cells in the mast cell stabilizing model.

Evaluation of the effect of Myrica sapida on bronchoconstriction and bronchial hyperreactivity.

The present investigation was undertaken to evaluate the bronchodilator and bronchial hyperreactivity of the stem bark of Myrica sapida. Experimental models studied were histamine induced bronchospasm in guinea pigs, bronchoalveolar lavage fluid (BALF) in egg albumin sensitized guinea pigs, histamine release from the lung tissues of sensitized guinea pigs and histopathological studies. Ethanolic extract of M. sapida (75 mg/kg, p.o., for 7 days) showed significant protection against histamine aerosol induced bronchospasm. Significant decrease in the total and differential leukocyte counts in BALF and prevention of egg albumin induced histamine release from chopped lung tissues of sensitized guinea pigs was observed on chronic administration of ethanolic extract of M. sapida (75 mg/kg, p.o., for 15 days). Histological examination of the section of lung from sensitized guinea pigs treated with ethanolic extract of M. sapida (75 mg/kg, p.o., for 15 days) was comparable to that of the control group. These results suggest that M. sapida possesses not only bronchodilator activity but also decreases bronchial hyperresponsiveness by decreasing the infiltration of inflammatory mediators like eosinophils, neutrophils in BALF and inhibiting histamine release from lungs of sensitized guinea pigs.

Biological and analytical characterization of two extracts from Valeriana officinalis.

The anticoronaryspastic and antibronchospastic activities of ethanolic and aqueous extracts of Valeriana officinalis L. roots were investigated in anaesthetized guinea-pigs and the results were correlated with the qualitative/quantitative chemical composition of the extracts in order to account for some of the common uses of this plant. The protective effects of orally administered ethanolic and aqueous extracts (50, 100 and 200 mg/kg) were evaluated against pitressin-induced coronary spasm and pressor response in guinea-pigs and were compared with those of nifedipine. Furthermore, the protective effects against histamine-induced and Oleaceae antigen challenge-induced bronchospasm were evaluated. Finally, the two valerian extracts were analytically characterized by qualitative and quantitative chromatographic analysis. The results showed that the two valeriana extracts possessed significant anticoronaryspastic, antihypertensive and antibronchospastic properties. These were similar to those exhibited by nifedipine and are due to the structural features of the active principles they contain. This study justifies the traditional use of this plant in the treatment of some respiratory and cardiovascular disorders.

Inhibition of histamine-induced bronchospasm in guinea pigs treated with Cecropia glaziovi Sneth and correlation with the in vitro activity in tracheal muscles.

A standardized aqueous extract (AE) and a purified fraction (BuF) of Cecropia glaziovi Sneth leaves were tested in unrestrained guinea pigs challenged with histamine. Changes of the respiratory pressure and rate were recorded in a whole body plethysmograph before and after treatment. The concentration of histamine necessary to produce bronchospasm was increased by five-fold following administration of AE (1.0 g/kg p.o.), and by two-fold after treatment with the semi-purified procyanidin/flavonoids enriched BuF (0.1 g/kg p.o.). Both effects were blocked by previous treatment with propranolol (10.0 mg/kg i.p.). In vitro incubation of BuF (0.1-1.0 mg/ml) decreased by 13-55% the maximal response of guinea pig tracheal muscle to histamine, without significant change of EC50. The results confirmed old reports on the useful pulmonary effects of Cecropia extracts. The bronchodilation observed in vivo seems to be related to beta-adrenergic activity observed in vitro only with high concentrations of the purified extract.

Anti-asthmatic effects of Perilla seed oil in the guinea pig in vitro and in vivo.

The aim of this study was to investigate the anti-asthmatic effects of Perilla seed oil in vitro and in vivo in sensitized guinea pigs. Aerosolized antigen caused an immediate bronchoconstriction. Perilla seed oil per os inhibited the increase in lung resistance and the decrease in dynamic lung compliance in a dose-dependent manner with an ED50 (95 % confidence interval, CI) of 1.10 (0.98 - 1.24) g/kg and 1.07 (0.94 - 1.22) g/kg, respectively. Infiltration of leukocytes, mononuclear cells, eosinophils and neutrophils induced by inhaling antigen was also inhibited by Perilla seed oil in a dose-dependent manner with an ED50 (95 % CI) of 1.00 (0.86 - 1.15), 1.24 (1.10 - 1.38), 0.63 (0.51 - 0.77) and 0.61 (0.38 - 0.98) g/kg, respectively. Perilla seed oil (5 - 500 microg/mL) inhibited the slow reaction substance of anaphylaxis (SRS-A) release induced by antigen challenge in lung tissue of sensitized guinea pigs. It also inhibited calcium ionophore (A(23187))-induced leukotriene (LT) D4 release from the lung tissue of non-sensitized guinea pigs in a concentration-dependent manner with an IC50 (95 % CI) of 50 (36 - 69) microg/mL. These results indicate that Perilla seed oil may improve lung function in asthma by controlling eicosanoid production and suppressing LT generation.

Antiallergic and antihistaminic effect of two extracts of Capparis spinosa L. flowering buds.

The antiallergic properties of two lyophilized extracts obtained from Capparis spinosa L. flowering buds (capers) by methanol extraction, carried out at room temperature (CAP-C) or with heating at 60 degrees C (CAP-H), were investigated. The protective effects of CAP-H and CAP-C, orally administered (14.28 mg[sol ]kg), were evaluated against Oleaceae antigen challenge-induced and histamine-induced bronchospasm in anaesthetized guinea-pigs. Furthermore, the histamine skin prick test was performed on humans, applying a gel formulation containing 2% CAP-C (the only extract able to protect against histamine-induced bronchospasm) on the skin for 1 h before histamine application and monitoring the erythema by reflectance spectrophotometry. The CAP-H showed a good protective effect against the bronchospasm induced by antigen challenge in sensitized guinea-pigs; conversely, a significant decrease in the responsiveness to histamine was seen only in CAP-C pretreated animals. Finally, the CAP-C gel formulation possessed a marked inhibitory effect (46.07%) against histamine-induced skin erythema. These two caper extracts displayed marked antiallergic effectiveness; however, the protective effect of CAP-H was very likely due to an indirect mechanism (for example, inhibition of mediator release from mast cells or production of arachidonic acid metabolites); conversely, CAP-C is endowed with direct antihistaminic properties. The different mechanisms of action of CAP-H and CAP-C may be related to a difference in the extraction procedure and, thus, in their qualitative[sol ]quantitative chemical profile.

Efecto del extracto acuoso liofilizado de Ocimun tenuiflorum L. sobre la anafilaxia pasiva cutánea, espasmo y tonicidad bronquial / Effect of the frozen dried aqueous extract of Ocimun tenuiflorum L. on passive cutaneous anaphylaxis, spasm and bronchial tonicity

Para demostrar las propiedades antialérgicas conferidas a Ocimum tenuiflorum L., se estudió su posible influencia sobre los mediadores anafilácticos y el espasmo bronquial inducido por histamina, así como su posible efecto broncodilatador. En la prueba de anafilaxia pasiva cutánea se emplearon ratas Wistar machos a las cuales se les administró el extracto en dosis de 250, 500 y 1000 mg/kg por vía oral durante 10 días. Se empleó como control positivo ketotifeno 3 mg/kg, la intensidad de la anafilaxia se determinó cuantificando la cantidad de azul de Evans extravasado. El efecto broncodilatador y protector del espasmo bronquial se determinó en cobayos Hartley machos, induciendo brococonstricción por administración intravenosa de histamina y determinando la presión bronquial. Como resultado de este trabajo se encontró que el extracto acuoso liofilizado de Ocimum tenuiflorum L. inhibió la anafilaxia pasiva cutánea y no presentó efecto protector del espasmo bronquial inducido por histamina, tampoco demostró propiedades broncodilatadoras en el modelo farmacológico empleado(AU)

Antiasthmatic property of polyherbal preparation E-721 B.

E-721B and its aqueous extract were studied for its antiasthmatic effect in various experimental models using rats and guinea pigs. E-721B produced significant and dose-dependent inhibition of peritoneal mast-cell degranulation induced by compound 48/80 and egg-albumin in sensitised rats. The inhibition was comparable to that with disodium cromoglycate, ketotifen, and prednisolone. E-721B administered 2 h before the experiment and once daily for seven days significantly increased the preconvulsion time of acetylcholine and histamine aerosol-induced bronchospasm. It also significantly reduced mortality in guineapigs produced by egg albumin-induced anaphylactic shock and also reduced bronchoalveolar fluid eosinophil count in the same animals. E-721B significantly inhibited the acetylcholine and histamine-induced contraction of different isolated smooth muscle preparations from rats and guinea pigs. Contrary to these findings E-721B produced dose-dependent contraction of the rat anococcygeus muscle which was blocked by prazosin. Thus our observations establish the antiasthmatic potential of this herbal formulation.

Antiasthmatic activity of the methanol extract of leaves of Passiflora incarnata.

The methanol extract of the leaves of P. incarnata was evaluated for its antiasthmatic effects against acetylcholine chloride (Ach)-induced-bronchospasm in guinea-pigs at doses of 50, 100 and 200 mg/kg. Using a 7-day treatment regimen, significant prevention of dyspnoea-related-convulsions was noted in the animals treated with a 100 mg/kg dose of this extract. No preventive effect was exhibited by the 50 mg/kg dose and at a higher dose, i.e. 200 mg/kg, the preventive effects against Ach-chloride-induced-dyspnoea were also reduced. This may be due to defective alpha-adrenoceptor function reported after excessive or continuous administration of an alpha-receptor agonist.

Tracheospasmolytic activity of viteosin-A and vitexicarpin isolated from vitex trifolia.

The n-hexane extract that has shown activity in the tracheospasmolytic bioassay was fractionated by solvent extraction and from the major active fraction two compounds were isolated and identified as viteosin-A and vitexicarpin. These compounds blocked spontaneous contraction of isolated male guinea pig trachea induced by histamine; however only vitexicarpin was active in a model using sensitized guinea pig trachea stimulated by ovalbumin up to minimum dose of 1.3 x 10(-5) M. The result suggests that vitexicarpin is able to block effects of histamine released from sensitized mast cells possibly by stabilizing the mast cells membrane function.

Airway anesthesia alone does not explain attenuation of histamine-induced bronchospasm by local anesthetics: a comparison of lidocaine, ropivacaine, and dyclonine.

BACKGROUND: Lidocaine inhalation attenuates histamine-induced bronchospasm while evoking airway anesthesia. Because this occurs at plasma concentrations much lower than those required for intravenous lidocaine to attenuate bronchial reactivity, this effect is likely related to topical airway anesthesia and presumably independent of the specific local anesthetic used. Therefore, the authors tested the effect of dyclonine, lidocaine, and ropivacaine inhalation on histamine-induced bronchospasm in 15 volunteers with bronchial hyperreactivity. METHODS: Bronchial hyperreactivity was verified by an inhalational histamine challenge. Histamine challenge was repeated after inhalation of dyclonine, lidocaine, ropivacaine, or placebo on 4 different days in a randomized, double-blind fashion. Lung function, bronchial hyperreactivity to histamine, duration of local anesthesia, and lidocaine and ropivacaine plasma concentrations were measured. Statistical analyses were performed with the Friedman and Wilcoxon rank tests. Data are presented as mean +/- SD. RESULTS: The inhaled histamine concentration necessary for a 20% decrease of forced expiratory volume in 1 s (PC20) was 7.0 +/- 5.0 mg/ml at the screening evaluation. Lidocaine and ropivacaine inhalation increased PC20 significantly to 16.1 +/- 12.9 and 16.5 +/- 13.6 mg/ml (P = 0.007), whereas inhalation of dyclonine and saline did not (9.1 +/- 8.4 and 6.1 +/- 5.0 mg/ml, P = 0.7268). Furthermore, in contrast to saline and lidocaine, inhalation of both ropivacaine and dyclonine significantly decreased forced expiratory volume in 1 s from baseline (P = 0.0016 and 0.0018, respectively). The longest lasting and most intense anesthesia developed after dyclonine inhalation (48 +/- 13 vs. 28 +/- 8 [lidocaine] and 25 +/- 4 min [ropivacaine]). CONCLUSION: Both lidocaine and the new amide local anesthetic ropivacaine significantly attenuate histamine-induced bronchospasm. In contrast, dyclonine, despite its longer lasting and more intense local anesthesia, does not alter histamine-evoked bronchoconstriction and irritates the airways. Thus, airway anesthesia alone does not necessarily attenuate bronchial hyperreactivity. Other properties of inhaled local anesthetics may be responsible for attenuation of bronchial hyperreactivity.

Pharmacological activity of Abies pindrow.

The widely known tree Abies pindrow (Talisapatra) (family: Pinaceae), famous for its diverse clinical uses in Ayurvedic medicines, was investigated to rationalise some of the ancient claims. The petroleum ether (PE), benzene (BE), chloroform (CE), acetone (AE) and ethanol (EE) extracts of A. pindrow leaf were found to have mast cell stabilizing action in rats. The EE, AE and BE extracts offered bronchoprotection against histamine challenge in guinea-pigs. The BE, CE and PE extracts had protective role in aspirin-induced ulcer in rats. The results suggest that while terpenoids, flavonoids, glycosides and steroids are involved in mast cell protection, terpenoids and flavonoids are brochoprotective against histamine-induced bronchospasm. The ulcer protective action of PE, BE and CE fractions of A. pindrow may be attributable to steroids contents only because though all the extracts tested positive for glycosides, the extracts EE and AE did not have any ulcer protective role.

The effect of antihistamine, endothelin antagonist and corticosteroid prophylaxis on contrast media induced bronchospasm.

Bronchospasm is a well recognized adverse reaction to radiographic contrast media (RCM) and may occur more frequently in asthmatics and atopics. This study was designed to identify RCM which are most likely to cause bronchospasm and to investigate underlying mechanisms mediating this response. Guinea pigs (mean body weight 550 g, n = 46) were anaesthetized with Hypnorm (5 ml kg-1) and Hypnovel (2 ml kg-1) and tracheal, jugular and pleural cannulae introduced. Total airways resistance (Raw) was calculated from the slope of the pressure/flow relationship. The effects of RCM (diatrizoate 370 mgI ml-1, ioxaglate 320 mgI ml-1, iotrolan 300 mgI ml-1 and iopromide 300 mgI ml-1) at a dose of 4 ml kg-1 body weight or control solutions matched for volume, pH and osmolarity administered via the jugular vein on Raw were studied. The effects of pre-treatment (30 min before the administration of RCM) with antihistamine (Mepyramine (30 mg kg-1 i.p.)) or non-selective endothelin receptor antagonist (SB209670 (1 mg kg-1 i.v.)) were investigated. The effectiveness of corticosteroids prophylaxis (prednisolone (20 mg kg-1 i.p.)) administered 18-24 h and 1 h pre-RCM was also assessed. Control animals received normal saline pre-treatment before RCM administration. Lungs were taken for histological examination 30-40 min post-administration of RCM. Only ioxaglate caused a significant (p < 0.05) increase in Raw (5.19 +/- 0.58 to 13.95 +/- 3.53 mmHg ml-1 min-1). Neither mannitol nor saline control solutions had any effect on Raw. Pre-treatment with Mepyramine, SB209670 or prednisolone caused no significant change in the ioxaglate induced increase in Raw. Histological examination of lung tissue from ioxaglate treated animals showed no important abnormalities. In summary, only the ionic dimer ioxaglate caused an increase in Raw. This effect was independent of osmolarity and could be the result of the chemical composition of the contrast agent. It was not an inflammatory response and could not be prevented by prophylactic treatment with antihistamine, endothelin antagonist or corticosteroids. The mechanisms responsible for the increase in Raw remain uncertain.