Cough and Arabinogalactan Polysaccharide from the Bark of Terminalia Arjuna.

In this work we investigated the antitussive activity of the medicinal tree Terminalia arjuna. We used the stem bark for extraction and preparation of water extracted isolate and its two fractions: acetone-soluble (TA-S) and acetone precipitated (TA-P) fraction. The presence of a pectic arabinogalactan was confirmed in TA-P fraction by chromatographic and spectroscopic analysis. The antitussive activity of samples was assessed after oral administration in a dose of 50 mg.kg(-1) in healthy guinea pigs, in which cough was elicited by inhalation of citric acid (0.3 mol/L) in body plethysmograph. The water extracted isolate showed a significant ability to decrease the number of cough efforts by 64.2 %; the antitussive activity on par with that of codeine phosphate. The TA-P fraction showed the antitussive activity of 54.8 %. In contrast, TA-S fraction had only a mild antitussive activity. No changes in in vivo airway resistance were noted. We conclude that arabinogalactan is an essential component of Terminalia arjuna that underlies its antitussive action.

Structural Elements and Cough Suppressing Activity of Polysaccharides from Zingiber officinale Rhizome.

Zingiber officinale is used for the management of fever, bronchial asthma and cough for thousands of years. While the link to a particular indication has been established in human, the active principle of the formulation remains unknown. Herein, we have investigated a water extracted polysaccharides (WEP) containing fraction from its rhizome. Utilizing a traditional aqueous extraction protocol and using chemical, chromatographic and spectroscopic methods a fraction containing a branched glucan and polygalaturonan in a ratio of 59:1 was characterized. This glucan, which has a molecular mass of 36 kDa, is made up of terminal-, (1,4)- and (1,4,6)-linked α-Glcp residues. Oral administration of WEP in doses of 25 and 50 mg/kg body weight significantly inhibited the number of citric acid-induced cough efforts in guinea pigs. It does not alter the specific airway smooth muscle reactivity significantly. Thus, traditional aqueous extraction method provides molecular entities, which induces antitussive activity without addiction.

Polyphenols and their components in experimental allergic asthma.

The aim of the study was to investigate the potential anti-inflammatory effects in -experimental allergic asthma of natural polyphenolic compounds or their single major components. The experiment was performed after 21-days sensitization of guinea pigs with ovalbumin suspension. Changes in airway reactivity after the long-term treatment with the polyphenolic compounds Provinol and Flavin-7 and their single major components quercetin and resveratrol during were assessed using a whole body plethysmography. Reactivity of tracheal smooth muscle was studied in vitro in response to cumulative doses of the bronchoconstrictive mediators histamine and acetylcholine. Furthermore, concentrations of the inflammatory cytokines IL-4 and IL-5 were measured in bronchoalveolar lavage fluid. The results demonstrate significant anti-inflammatory effects of Provinol and Flavin-7 exerted in the airways. In contrast, chronic treatment with quercetin and resveratrol, single components of the two polyphenols, did not show such activity. We conclude that polyphenolic compounds are more effective in the anti-inflammatory effects in the airways than their separate components.

Antioxidant activity of herbal polysaccharides and cough reflex.

The extraction of Fallopia sachalinensis leaves resulted in two fractions (FS-1 and FS-2). Chemical and spectral analyses of samples revealed the prevalence of pectic polysaccharides with high galacturonic acid, arabinose, galactose, and rhamnose content. Arabinogalactan with a higher content of phenolic prevailed in the FS-1, whereas rhamnogalacturonan predominated in the FS-2 fraction. Both polysaccharides showed significant antioxidant activity according to DPPH and FRAP assays. Evaluation of antitussive activity in healthy adult conscious guinea pigs after oral application of 50 and 75 mg/kg of the FS-2 polysaccharide extracts showed a significant suppression of cough reflex, without an influence on specific airway resistance. The suppression of cough was comparable with that of codeine.

The influence of the PDE inhibitors on cough reflex in guinea pigs.

In this study the effects of non-selective PDE inhibitors (theophylline and theobromine) and selective inhibitors of PDE 1, 3, 4 and 5 on cough, induced by citric acid, were evaluated. Inhalation of citric acid aerosol was used for cough provocation in healthy and ovalbumin-sensitized guinea pigs and the number of cough efforts was registered after visual and acoustic control by a skilled observer, with subsequent evaluation of airflow changes in a double chamber whole body plethysmograph. The pre-treatment with theophylline and theobromine (10 mg/kg b.w. intraperitoneally) decreased the number of cough efforts evoked by inhalation of citric acid aerosol (0.6 mol/l) in both healthy and ovalbumin-sensitized animals. The selective inhibitors (all 1 mg/kg b.w. intraperitoneally) of PDE1 (vinpocetin), PDE3 (cilostazol), and PDE4 (citalopram) showed antitussive effects in healthy guinea pigs. Conversely, the antitussive potential of PDE1 (vinpocetin), PDE4 (citalopram), and PDE5 (zaprinast) was observed in ovalbumin-sensitized animals. We conclude that the administration of non-selective PDE inhibitors influenced the citric acid-induced cough both in healthy and ovalbumin-sensitized guinea pigs, indicating the participation of a bronchodilating action and suppression of airway hyperreactivity in the cough suppression. With selective inhibitors, PDE4 inhibition seems to be the most effective in cough suppression, confirming its positive effects tested in chronic airway inflammatory diseases associated with bronchoconstriction and cough (Fig. 6, Ref. 27).

Metabolic risk in selected second-generation antipsychotics.

BACKGROUND: Many studies have reported higher incidence of metabolic abnormalities in patients receiving antipsychotic medications than in general population. OBJECTIVES: The objective of our study was to determine the prevalence of metabolic syndrome in a group of patients receiving long-lasting antipsychotic treatment and also whether the cardiovascular risk among different second-generation antipsychotics varies. METHODS: Our study group consisted of 71 patients who were on antipsychotic monotherapy for at least 12 months. In each patient, fasting plasma glucose, HDL cholesterol, triglycerides, liver enzymes, bilirubin and plasma immunoreactive insulin levels were examined. We measured body weight, height, body mass index, waist circumference and body fat percentage together with blood pressure and heart rate. We assessed metabolic syndrome prevalence in the study group and correlations among its components as well as between them and other variables. The data were processed by statistics programme STATISTICA 8.0. For detection of correlations Spearman's rank correlation test was used. RESULTS: The prevalence of metabolic syndrome in our sample reached 41%. The highest prevalence rate of 50% was detected in the olanzapine subgroup. Identical prevalence of 40% was observed in quetiapine and risperidone subgroups. The lowest prevalence of 25% and 31% was observed in sertindol and amisulpirid subgroup, respectively. The prevalence rate of metabolic syndrome in men was 51% compared to 34% in women. CONCLUSION: According to metabolic syndrome prevalence rates olanzapine appears to be associated with the highest cardiovascular risk, amisulpirid and sertindol appear to be much safer (Tab. 2, Ref. 13).

Side effects of anastrozole in the experimental pre-menopausal mammary carcinogenesis.

UNLABELLED: The aim of this study was to assess side effects of aromatase inhibitor anastrozole in the prevention of N-methyl-N-nitrosourea - induced pre-menopausal mammary carcinogenesis in female Sprague-Dawley rats. This model mimicked situation in healthy, but from the point of view of the development of breast cancer, high-risk pre-menopausal women.

Aromatase inhibitor anastrozole was used as a chemopreventive agent taken by the animals in the food during the whole period of time of the experiment. Group 1 - the control group had taken food without anastrozole, the groups 2 and 3 with anastrozole in various concentrations - 0.05 mg/1 kg of food (ANA 0.05) and 0.5 mg/1 kg of food (ANA 0.5).

In anastrozole-treated animals in comparison with untreated animals, macroscopic changes of uterus and vagina were not found. The values of absolute and relative wet weight of uterus and vagina in the groups ANA 0.05 and ANA 0.5 were comparable with the control. Histological examination did not show atrophic changes in endometrium of uterus and in epithelium of vagina in anastrozole-treated animals. In the group ANA 0.5 myometrium was significantly grosser than in the group ANA 0.05 (P<0.05). Anastrozole neither affects parameters of plasma lipid metabolism (triacylglycerols, total cholesterol, low - density lipoprotein cholesterol and high - density lipoprotein cholesterol) nor serum levels of sex hormones (estradiol, testosterone, dehydroepiandrosterone). Compact bone thickness in the groups with anastrozole was significantly increased in comparison with untreated animals (P<0.001). A significant increase in body weight was found in the group ANA 0.5 compared with the control group (P<0.01). The significant increase in body weight gain was not attended by the significant increase in food intake.

The side effects of aromatase inhibitor anastrozole in the prevention of N-methyl-N-nitrosourea - induced pre-menopausal mammary carcinogenesis in female Sprague-Dawley rats on myometrium, compact bone thickness and body weight gain were observed.

A beneficial influence of provinol on the reduction of allergen induced hyperreactivity in guinea pigs.

BACKGROUND: The anti-inflammatory, anti-allergic, antioxidant properties of flavonoids are known in the respiratory tract. We are interested in the role of Provinol during an allergic inflammation of the airway. OBJECTIVES: The aim of this study was to examine the influence of an acute administration of Provinol on tracheal smooth muscle reactivity in guinea pigs and to assess the involvement of nitric oxide in the mechanism of Provinol action. METHODS: This experiment was performed 14 days after the sensitization of animals by ovalbumin. In vivo, the specific airway conductance, as a tracheal smooth muscle reactivity parameter in response to bronchoconstrictor histamine, was evaluated after peroral administration of Provinol alone or together with L-NAME (N(omega)-nitro-L-arginine methyl ester). In vitro, Provinol alone or in combination with L-NAME were added into an organ baths before the supplement of direct bronchoconstrictor histamine, acetylcholine and the allergen ovalbumin in rising concentrations. The amplitude of the tracheal smooth muscle contraction, as a tracheal smooth muscle reactivity parameter in response to histamine, acetylcholine and ovalbumin was evaluated. RESULTS: Our results showed that a Provinol has significant bronchodilatory activities both in vivo and in vitro. CONCLUSION: Provinol alleviated the contraction of tracheal smooth muscle in guinea pigs sumin. Nitric oxide plays an important role in the mechanism of Provinol action (Fig. 2, Ref. 28n.(Fig. 2, Ref. 28).

Preventive effects of letrozole in the model of premenopausal mammary carcinogenesis.

Single - agent therapy with aromatase inhibitors has no established role in premenopausal women with breast cancer. In this study, tumor suppressive effects of letrozole in the prevention of N-methyl-N-nitrosourea - induced mammary carcinogenesis in female Sprague-Dawley rats were evaluated. Letrozole was dietary administered in two concentrations - 1 mg/1 kg (LETRO 1), and 10 mg/1 kg (LETRO 10). Letrozole suppressed incidence of mammary gland cancer by 93 % (P<0.00002) in the group LETRO 1 in comparison with control animals. Total suppression of mammary carcinogenesis was observed in the group LETRO 10. In the groups with letrozole, uterine and vaginal atrophy was found at the end of experiment. In letrozole - treated animals in comparison with untreated animals, increased plasmatic triacylglycerol concentrations (P<0.0001) were observed, but total cholesterol and cholesterol of low- and high- density lipoprotein fractions were not significantly changed. An increase in body weight gain and food intake was found in the groups LETRO 1 and LETRO 10 compared with the control group (P<0.0001). The present study points to high tumor suppressive effects of letrozole in premenopausal model of mammary carcinogenesis in female rats.

Neoplastic effects of exemestane in premenopausal breast cancer model.

Aromatase inhibitor exemestane as a single - agent has no established role in the treatment of premenopausal breast cancer women. The aim of this study was to evaluate preventive effects of exemestane in the model of premenopausal Nmethyl- N-nitrosourea - induced mammary carcinogenesis in female rats. Exemestane treatment begun 7 days prior to carcinogen administration and continued next 12 weeks - till the end of experiment. Exemestane was dietary administered in two concentrations of 1 mg / 1kg (EXE 1), or 10 mg/1 kg (EXE 10), respectively. Exemestane increased the tumor frequency by 80.5 % (P=0.034) in the group EXE 1 and by 61.5 % (P=0.045) in the group EXE 10 in comparison with control animals. In the group EXE 10, the incidence of mammary tumors was increased by 11.5 % (P=0.31) and tumor volume by 41.5 % (P=0.23), also the latency was shortened by 8 days (P=0.078) compared with controls. In the groups with exemestane, changes in weights and histology of uterus and vagina were not found at the end of experiment. Exemestane did not alter serum concentrations of estradiol, testosterone and dehydroepiandrosterone. In the group EXE 10 in comparison with untreated animals, exemestane decreased serum concentrations of triacylglycerols by 9 % (P=0.032), total cholesterol by 19.5 % (P=0.0002) and cholesterol of low - density and high - density lipoprotein fractions by 41 % (P<0.0001), or 21.5 % (P=0.0002), respectively. In the group EXE 1, the decrease in cholesterol of low-density lipoprotein fraction by 22.5 % (P=0.0005) was recorded. An increase in food intake (P=0.023) and body weight gain (P=0.036) was found in the group EXE 10 compared with the control group (P<0.05). The present study points to apparent tumor - promoting effects of dietary administered exemestane in the model of premenopausal mammary carcinogenesis in female rats. Exemestane as a steroidal agent indicated androgenic effects on rat lipid metabolism in this experiment.

Relation of L-arginine to airway hyperreactivity.

The deficiency or the decrease in the bioavailability in basic substrate for nitric oxide synthesis - L-arginine can be one of factors contributing to the airway hyperreactivity. We studied the influence of L-arginine supplementation on the experimental airway hyperreactivity induced in guinea pigs by exposure to toluene vapours. L-arginine was administered before exposure in a dose of 300 mg/kg b.w. intraperitoneally during 3 or 17 days. After that the airway reactivity changes to histamine or acetylcholine were studied in in vitro conditions. In addition to that the tissue strips from exposed animals were incubated with L-arginine in concentration 10(-4) mol/l. The administration of L-arginine during 3 days decreased the airway reactivity increased by irritant exposure. We recorded the decrease in the airway reactivity in animals with bronchial hyperreactivity after incubation of tissue strips with L-arginine, too. The pre-treatment of animals with L-arginine during 17 days did not affect the airway smooth muscle reactivity in larger extent. The exogenous administration of L-arginine resulted in a protective effect under the conditions of experimental airway hyperreactivity. The effect of supplementation was different depending on airway level and pre-treatment duration. The results refer to the importance of optimal L-arginine level for the control of bronchomotoric tone.

In vitro reactivity of urinary bladder smooth muscle in rabbits influenced by xanthine derivatives.

INTRODUCTION: The contractions of urinary bladder smooth muscle are evoked by parasympathetic nervous system, with its main mediator acetylcholine. These contractions can be inhibited by two basic mechanisms--inhibition of contraction (anticholinergic drugs) or inducing the relaxation (sympathomimetics, calcium channel blockers). In this study, we investigated the effect of caffeine and theophylline--both are nonselective inhibitors of phosphodiesterase--on urinary bladder smooth muscle contractions evoked by acetylcholine. METHODS: The reactivity of the urinary bladder smooth muscle was estimated by in vitro method using organ chambers. RESULTS: Caffeine and theophylline caused decrease of urinary bladder smooth muscle reactivity to acetylcholine. This decrease was statistically significant only in concentrations of 10(-4) and 10(-3) mol.l(-1) of caffeine and theophylline. CONCLUSIONS: Caffeine and theophylline significantly influenced the reactivity of urinary bladder smooth muscle in guinea pigs to acetylcholine. By comparing the influence of aminophylline we can conclude, that caffeine as well as theophylline caused significantly stronger decrease of the reactivity to acetylcholine than aminophylline only in lower concentration (Fig. 4, Ref. 30). Full Text (Free, PDF) www.bmj.sk.

Effect of NO-synthase and arginase inhibition in airway hyperreactivity.

BACKGROUND: The decreased L-arginine bioavailability, the basic substrate for nitric oxide synthesis, can be one of the factors contributing to the airways hyperreactivity. OBJECTIVES: We investigated the effect of various inhibitors of the enzyme activities utilizing L-arginine in a guinea pig model of experimental ovalbumin-induced airway hyperreactivity. METHODS: We used the in vivo pre-treatment with non-specific inhibitor of NO synthase No-nitro-L-arginine metylester (L-NAME) and relatively specific inhibitor of inducible NO synthase--aminoguanidine. Inhibitors were administered in one-shot (on the 14th day, 30 minutes before the inhalation of ovalbumin) or in a long-time regime (during the whole period of sensibilization by ovalbumin--14 days). We administered the inhibitor of arginase Nomega-hydroxy-L-arginine (NOHA) to the tracheal and lung tissue smooth muscle strips from sensibilized animals. RESULTS: We observed an increase in the tracheal smooth muscle response to histamine in animals that received an inhalation dose of L-NAME (40 mg/kg b.w.) or aminoguanidine (50 mg/kg b.w.) 30 minutes before the inhalation of ovalbumin but did not evoke any significant difference in the reactivity of lung tissue smooth muscle. Tracheal smooth muscle responded with enhanced contraction amplitude to histamine after chronic pre-treatment with L-NAME or aminoguanidine. The inhibition of arginase with NOHA in vitro decreased the tracheal and lung tissue smooth muscle reactivity to histamine. CONCLUSION: The results suggest that NO-synthase isoforms as well as arginase are involved in the production of NO and in the control of bronchomotoric tonus (Fig. 4, Tab. 2, Ref. 31). Full Text (Free, PDF) www.bmj.sk.

Evaluation of the cough reflex and airway reactivity in toluene- and ovalbumin-induced airway hyperresponsiveness.

Stimulation of mechanoceptors is considered to be the major mechanism of cough. Our aim in this study was to evaluate the relationship between in vivo and in vitro airway reactivity (AR) in chemically- and antigen-induced airway hyperresponsiveness (AHR). AHR was induced chemically (toluene vapors) or via antigen (ovalbumin) in healthy guinea pigs. While toluene inhalation did not cause a significant difference in the number of cough efforts during citric acid nebulization, a significant increase in specific airway resistance after inhalation of histamine was observed, as measured in double chamber body plethysmograph. In contrast, ovalbumin led to a significant increase in both the number of cough efforts and in vivo AR. The in vitro tests confirmed the presence of increased reactivity of tracheal and lung tissue strips to histamine. However, no clear correlation between bronchoconstriction and cough reflex was found in the experimental model used for this study.

Effects of meconium on airway reactivity to histamine and acetylcholine in vitro.

To better understand the mechanisms contributing to altered airway reactivity in the meconium aspiration syndrome, in this study we investigated whether there could be a meconium dose-dependent response of tracheal smooth muscle and lung tissue reactivity to histamine and acetylcholine in vitro. Tracheal and lung tissue strips from healthy guinea pigs were incubated for 1 hour in organ chambers with three different concentrations of meconium (1, 2, and 5 mg/ml) or in Krebs-Henseleit solution. Thereafter, the contractile responses to histamine and acetylcholine were recorded. Cumulative doses of histamine and acetylcholine increased reactivity of the strips in all groups. Tracheal smooth muscle reactivity to histamine and acetylcholine (10(-5)-10(-3) mol/l) was highest with the highest meconium concentration. In contrast, lung tissue reactivity tended to decrease with increasing meconium concentration. The mechanisms influencing the airway smooth muscle contractile response to meconium require further studies.

The role of potassium ion channels in cough and other reflexes of the airways.

In this study we investigated whether openers of potassium channels, K+ATP--pinacidil and BK+Ca--NS1619, modulate cough reflex and airway smooth muscle (ASM) reactivity in in vivo and in vitro conditions in guinea pigs. The cough reflex was induced by 0.3 M citric acid aerosol given for 3 min during which time a total number of coughs was counted. ASM reactivity in vivo was expressed as the values of specific airway resistance calculated by Pennock. Changes in ASM reactivity in vitro were tested by a tissue bath method. We found that both openers of potassium channels inhibit the citric acid-induced cough. ASM reactivity in vivo was significantly abolished by pinacidil and NS1619, which corresponded with the results of in vitro measurements. Pretreatment by selective blockers, K+ATP--glibenclamide and BK+Ca-tetraethylammonium prevented the above mentioned effects. The results indicate an important role of K+ATP and BK+Ca ion channels in defense reflexes of airways.

Age-dependent changes of airway obstruction parameters.

The study was aimed at the assessment of the physiological range of phi and Tme/Te indices in children of up to 24 months of age, as based on noncalibrated respiratory inductive plethysmography performed in the supine position. We also examined the dependence of these indices on children's age and sex. The study was carried out in 127 healthy children. The results of the study indicate a significant decrease of phi in children aged 7-24 months in comparison with children of up to 6 months of age (P<0.001). Similarly, values of Tme/Te were found significantly higher in the group of older children (P<0.05). We did not find any appreciable sex differences in both measured parameters. The results of this study suggest that the Tme/Te index might be more stable, less age-dependent parameter of the Respitrace measurement than the phase angle j, but further research and analysis to achieve a correct verdict are warranted.

Aromatase inhibitors in the breast cancer therapy and their potential using in the prevention setting.

Long term exposure to estradiol is associated with an increased risk of breast cancer. Aromatase inhibitors, suppressing tumour and plasma estrogen levels by blocking conversion of testosteron to estrogen, have been proven to provide the most effective endocrine therapy in metastatic and adjuvant setting in postmenopausal women. Questions remains about the long term side effects and safety profile of aromatase inhibitors. The effectiveness and safety of aromatase inhibitors therapy in premenopausal breast cancer patients is unknown, this needs to be further investigated. Although tamoxifen represents the gold standard for prevention therapy at present, results of ongoing studies may indicate a role of aromatase inhibitors in prevention of breast cancer (Tab. 2, Ref. 22).

The antitussive activity of polysaccharides from Althaea officinalis l., var. Robusta, Arctium lappa L., var. Herkules, and Prunus persica L., Batsch.

BACKGROUND: The therapy of pathological type of cough presents serious medical problem. OBJECTIVES: The aim of experiments was to investigate polysaccacharide influence on experimentally induced cough. METHODS: The purified and/or modified polysaccharides from the flowers and plants, characterized by chemical composition and molecular properties were subjected to tests for antitussive activity on cough, induced mechanically in conscious cats of both sexes. RESULTS: The results revealed that the tested polysaccharides exhibited statistically significant cough-suppressing activity, which was noticeably higher than that of the non-narcotic drug used in clinical practice to treat coughing. The most expressive antitussive activity was observed with the polysaccharide from marsh mallow, containing the highest proportion of the uronic acid constituent. Negative influence of the tested compounds on expectoration was negligible when compared to that of codeine. CONCLUSION: Antitussive activity of various plant polysaccharides was confirmed. These results allow ranging them among prospective antitussive agents (Tab. 2, Fig. 6, Ref. 15) Full Text (Free, PDF) www.bmj.sk.

In vitro contractile response of human myometrium to oxytocin, PGF2alpha, bradykinin and ET-1.

BACKGROUND: The imbalance in the sex hormones levels is the limited factor which induces disturbances in the uterus function and elevates uterine contractile activity. OBJECTIVES: The aim of our study was to evaluate and compare the direct contractile responsiveness of myometrium to the effects of uterotonic agents--oxytocin, PG2alpha, ET-1, and bradykinin--in the strips of human non-pregnant myometrium during different phases of menstrual cycle. METHODS: Reactivity of human myometrial strips, obtained from the pre-menopausal woman undergoing total hysterectomy for benign gynaecological indications such as leiomyomas, was evaluated in vitro. RESULTS: Our results showed an increased reactivity of myometrium to contractile mediators during follicular phase of the cycle. Our findings support the idea that estrogens might have a positive influence on the expression of various types of receptors (FP, OTR, BK2R and ET(A)R) and thus promote the contractility in response to uterotonic agents. On the contrary, minimal myometrial response to oxytocin, PG2alpha, ET-1, and bradykinin were observed during luteal phase when progesterone levels are increased. CONCLUSION: Our results indicate that the contractile activity of myometrium is mostly influenced by changes in sex steroid hormones during menstrual cycle. In future, this experimental model can be used for the study of mechanism regulating myometrial smooth muscle reactivity and its pharmacological modulation (Fig. 4, Ref. 20). Full Text (Free, PDF) www.bmj.sk.