Effect of nitric oxide synthases inhibitors on exogenous irritant-induced bronchial hyper-reactivity in guinea pigs.

Nitric oxide (NO) is an important endogenous mediator involved in many biological functions in both physiological and pathological conditions. Many of studies suggest that high level of NO may play a role in the pathogenesis of various diseases including respiratory diseases with bronchial hyper-reactivity (BHR). The aim of our study was to examine the relationship between NO production and BHR. The reactivity of tracheal and lung tissue smooth muscle to histamine and acetylcholine was measured in vitro in male guinea pigs pre-treated with NO synthase (NOS) inhibitors. The drugs were administered in vivo during either 3 or 17 days. Furthermore, the animals were exposed in vivo to the toluene vapours after administration of agents. NOS inhibitors showed mainly beneficial effect in the presented study. They decreased the hyper-reactivity of the tracheal and lung tissue smooth muscle evoked by toluene. The decrease was dependent on the duration of their administration and on the type of inhibitor. Short-term administration of inhibitors was more effective than long-term one. A more significant effect was recorded after the pre-treatment with non-selective inhibitor L-NAME. The results showed possible participation of constitutive forms of NOS in the BHR.

Enalapril and diltiazem co-administration and respiratory side effects of enalapril.

A persistent, chronic dry cough is the most common adverse effect of angiotensin converting enzyme (ACE) inhibitors therapy. The mechanism of this respiratory adverse effect is related to the inhibition of ACE and the accumulation of bradykinin, substance P, prostanoids and other inflammatory neuropeptides in the airways. The aim of this study was to follow the relationship between 15-day administration of enalapril and the defense reflexes (cough and bronchoconstriction) of the airways in experimental animals, as well as the possibility of their pharmacological restriction with simultaneous diltiazem administration. Cough reflex was investigated by the method of mechanical irritation of laryngopharyngeal and tracheobronchial area in non-anesthetized cats. The reactivity of tracheal smooth muscles of the airways to bronchoconstrictor mediators (histamine 10 nM - 1 mM, acetylcholine 10 nM - 1 mM and KCl 1 mM - 100 mM) was evaluated by an in vitro method in guinea pigs. Enalapril 5 mg/kg/day and diltiazem 30 mg/kg/day were administered perorally for 15 days. The results showed that long-lasting administration of enalapril resulted in a significant increase of measured cough parameters and increased reactivity of tracheal smooth muscle to histamine and KCl. Simultaneous administration of enalapril together with diltiazem significantly decreased the enalapril induced cough, and decreased enalapril induced hyperreactivity of tracheal smooth muscles to KCl. The results showed a partially protective effect of diltiazem and enalapril co-administration on the respiratory adverse effects induced by enalapril therapy.

A biologically active fructan from the roots of Arctium lappa L., var. Herkules.

From the roots of Arctium lappa L., var. Herkules a low-molecular-weight fructofuranan of the inulin-type has been isolated by water extraction and ethanol precipitation, followed by ion-exchange chromatography and gel filtration of the crude precipitate. The methods employed in structural determination were methylation analysis and 1H and 13C NMR spectral measurements. In tests for antitussive activity in cats the fructan was found to be equally active as some non-narcotic, synthetic preparations used in clinical practice to treat coughing, and in mitogenic and comitogenic tests its biological response was comparable to that of the commercial Zymosan immunomodulator.

Antitussive activity of the fruit extract of Emblica officinalis Gaertn. (Euphorbiaceae).

The antitussive activity of Emblica officinalis Gaertn. (E. officinalis, Fam. Euphorbiaceae) was tested in conscious cats by mechanical stimulation of the laryngopharyngeal and tracheobronchial mucous areas of airways. The results showed that at a dose of 50 mg/kg body wt. perorally, the cough suppressive effect of E. officinalis is not unambiguous. A higher dose (200 mg/kg body wt.) of this substance perorally was more effective, especially in decreasing the number of cough efforts (NE), frequency of cough (NE/min(-1)) and the intensity of cough attacks in inspirium (IA+) and expirium (IA-) was more pronounced. These results showed that the cough suppressive activity of E. officinalis is dose-dependent. We could also demonstrate that the antitussive activity of E. officinalis is less effective than shown by the classical narcotic antitussive drug codeine, but more effective than the non-narcotic antitussive agent dropropizine. It is supposed that the antitussive activity of the dry extract of Emblica officinalis is due not only to antiphlogistic, antispasmolytic and antioxidant efficacy effects, but also to its effect on mucus secretion in the airways.

Antitussive activity of a glucuronoxylan from Rudbeckia fulgida compared to the potency of two polysaccharide complexes from the same herb.

An alkali-extracted low-molecular glucuronoxylan and two water-extractable polysaccharide complexes isolated from various parts of Rudbeckia fulgida were tested for antitussive activity on mechanically induced cough in nonanaesthetized cats. Glucuronoxylan consisted of a (1-->4)-linked beta-D-xylopyranosyl backbone with about 18% of 4-0-methyl-D-glucuronic acid attached to 0-2 of the chain xylose residues. The polysaccharide complexes differed from each the other regarding the in qualitative and quantitative composition of the sugar components. It was found that peroral administration of all the compounds led to a significant suppression of the cough reflex without negative influence on expectoration. Glucuronoxylan and the complex from the aerial parts of the herb exhibited much higher antitussive activity than the complex from the roots which did not contain any uronic acid component. Their activity (48.2% and 46.5%, respectively) highly surpassed the activity of the complex from the roots (23.5%) as well as that of the peripherally acting drugs dropropizine (28.3%) and prenoxdiazine (24.7%).

Mucolytics and antioxidant activity.

We investigated effects of the mucolytics ambroxol and N-acetylcysteine on airways reactivity evoked by histamine in guinea pigs exposed to toluene vapors. We did not find significant changes in reactivity of tracheal smooth muscle from animals treated with mucolytics compared to the control group. However, the administration of ambroxol and N-acetylcysteine caused a significant decrease in lung tissue reactivity. The effect of ambroxol was more pronounced after intraperitoneal injection than after inhalation, while N-acetylcysteine was only effective after inhalation. The protective effects of mucolytics in the lung tissue may be due to their antioxidant activity together with other mechanisms.

ACE-inhibitors and defence reflexes of the airways.

The group of angiotensin-converting enzyme (ACE) inhibitors is one of the drugs of choice for the treatment of hypertension and congestive heart disease. However, it has been reported that in some of patients ACE-inhibitors induce hyperreactivity of the airways with occurrence of a persistent dry cough, dyspnoe and wheezing. We supposed that the mechanism of these hyperreactivity is connected to accumulation of bradykinin, tachykinins and other inflammatory mediators in the airways. Increased local concentration of inflammatory neuropeptides stimulates bronchial C fibres and rapidly adapting receptors and provoke the cough reflex. Inflammatory processes in the airways could be followed by contraction of airway smooth muscle. In this study, our aim was to measure the changes of the number and intensity of mechanical induced cough in cats, which were treated for days with enalapril (5 mg/kg b.w.). After 15 days of treatment the reactivity of the lung and tracheal smooth muscles to the bronchoconstrictor mediator histamine was estimated. As to our finding 15 days of administration of enalapril results in significant increase of cough parameters measured with a more significant sensitivity of the laryngopharyngeal part. In the experimental animals we observed increased reactivity of bronchial smooth muscle to histamine after 15 days of enalapril treatment. The reactivity of the lung smooth muscle to the histamine was not significantly changed. These results confirmed the increased cough sensitivity and increased bronchial reactivity after enalapril treatment. These experimental animal model may be useful for the investigation of the pharmacological minimization of respiratory adverse effect of ACE-inhibitors.

Effects of irritants on airways reactivity.

The authors observed reactivity changes of airways smooth muscles after exposure of experimental animals to toluene and hyperoxia. The pretreatment with antioxidants did not prevent these changes.

[The antitussive effect of theophylline]. / Sledovanie antitusického úcinku teofylínu.

Theophylline belongs to a group of medicaments used in asthma therapy. It yields an antiinflammatory effect, reduces allergic reactions, and in respiratory airways it improves the mucociliary clearance and eminently dilates smooth muscles. Therefore, the main aim of our interest is its effect on the cough reflex. Cough was evoked by mechanical irritation of the airways in cats with chronic tracheal cannula. It has been discovered that theophylline, when dosed 10 mg per kg of body weight i.p. achieved a more intensive effect than dextromethorphane, namely in evaluation of cough parameters, but it had a lower suppressive effect than codeine. (Fig. 3, Ref. 13.)

[Antitussive action of extracts and polysaccharides of marsh mallow (Althea officinalis L., var. robusta)]. / Antitussive Wirkung des Extraktes und der Polysaccharide aus Eibisch (Althaea officinalis L., var. robusta).

The complex extract and the polysaccharide isolated from the roots of marsh mallow were tested for antitussive activity in unanaesthetized cats of both sexes. Cough was elicited by mechanical stimulation of laryngopharyngeal and tracheobronchial mucous area of the respiratory system with a Nylon fibre (diameter 0.35 mm). Cough was evaluated on the basis of the changes in lateral tracheal pressure. The polysaccharide and the complex extract were administered p.o. in a dose of 50 and 100 mg/kg b.w., respectively. The efficiency of the mentioned compounds was compared with the cough-suppressing effect of drugs belonging to the non-narcotic antitussics. The results of the experiments showed that administration of the polysaccharide led to a statistically significant decrease of the number of cough efforts both from laryngopharyngeal and tracheobronchial areas of the the respiratory system. The polysaccharide in a dose of 50 mg/kg b.w. was as effective in inhibition of the cough reflex as Sirupus Althaeae in a dose of 1000 mg/kg b.w. and more effective than prenoxdiazine in a dose of 30 mg/kg b.w. However, the cough-suppressing effect of the polysaccharide was lower than that of dropropizine. The extract was less effective than the polysaccharide.

Relationship between the antitussic and analgesic activity of substances.

The authors studied relationship between the antitussic and analgesic activity of substances. The antitussic effect of codeine, tilidine, tramadol and pentazocine has been studied in nonanesthetized healthy cats. The drugs except tilidine, were administered intraperitoneally in a dose of 10 mg/kg body weight. Tilidine was administered intramuscularly in the same dose. Cough induced in nonanesthetized cats by mechanical irritation of laryngopharyngeal and tracheobronchial areas was evaluated by changes of the lateral tracheal pressure. A significant decrease of the subsequent cough parameters was observed after the application of codeine, tilidine, tramadol and pentazocine. Naloxone given 5 min before the application of the drug has not prevented the cough-suppressing effect due to codeine. Naloxone alone administered in a dose of 1 mg/kg body weight has not significantly influenced the experimentally-induced cough reflex in nonanesthetized cats.

Objective assessment of cough suppressants under normal and pathological experimental conditions.

The influences of the antitussive activity of glaucine were studied in 56 non-anaesthetized cats under normal and pathological conditions. Cough was induced by mechanical stimulation of the airways with a nylon fibre. The authors found that if glaucine was administered at a dose of 5.0, 7.5 and 10.0 mg/kg b.w., i.p., it evoked statistically significant suppression on single cough components. After inflammation of the airways was induced with unsoluted croton oil, no decrease in antitussive activity of glaucine could be observed, according to the number of cough efforts, frequency, intensity of maximal cough effort, and intensity of cough attack during expiration. Glaucine used under such conditions was not found to be powerful enough to suppress either the intensity of maximal cough effort or the intensity of cough attack during inspiration. The antitussive effect of glaucine was stronger under pathological conditions (Staphylococcus-induced inflammation). The antitussive effect of glaucine was approximately the same as with codeine if administered in equal doses.

[Action of medazonamid on cough in an experiment]. / Vozdeistvie medazonamida na kashel' v éksperimente.

The anti-cough effect of medazonamide was studied on 40 nonanesthetized cats. The cough was induced by mechanical irritation of the laryngopharyngeal and tracheobronchial mucous of the respiratory tract. It was shown that the intraabdominal administration of medazonamide in 5, 10 and 20 mg/kg doses has less anti-cough effect than codeine in the given conditions.