Dube, Aman K; Kumar, Maushmi S
... in in vitro condition. We aim to screen the most efficient strain of Cunninghamella sp. among C. elegans, C. echinulata and C. blakesleeana for bromhexine metabolites production. We character- ized th...
Aman K. Dube
Full Text Available Abstract Fungi is a well-known model used to study drug metabolism and its production in in vitro condition. We aim to screen the most efficient strain of Cunninghamella sp. among C. elegans, C. echinulata and C. blakesleeana for bromhexine metabolites production. We characterized the metabolites produced using various analytical tools and compared them with mammalian metabolites in Rat liver microsomes (RLM. The metabolites were collected by two-stage fermentation of bromhexine with different strains of Cunninghamella sp. followed by extraction. Analysis was done by thin layer chromatography, high performance thin layer chromatography, Fourier transform infrared spectroscopy, high performance liquid chromatography and Liquid chromatography–mass spectrometry. The role of Cytochrome P3A4 (CYP3A4 enzymes in bromhexine metabolism was studied. Fungal incubates were spiked with reference standard – clarithromycin to confirm the role of CYP3A4 enzyme in bromhexine metabolism. Three metabolites appeared at 4.7, 5.5 and 6.4 min retention time in HPLC. Metabolites produced by C. elegans and RLM were concluded to be similar based on their retention time, peak area and peak response of 30.05%, 21.06%, 1.34%, and 47.66% of three metabolites and bromhexine in HPLC. The role of CYP3A4 enzyme in metabolism of bromhexine and the presence of these enzymes in Cunninghamella species was confirmed due to absence of peaks at 4.7, 5.4 and 6.7 min when RLM were incubated with a CYP3A4 enzyme inhibitor – clarithromycin.
Full Text Available Background and aims. Xerostomia is one of the most common complications of head and neck radiotherapy. The aim of this study was to evaluate and compare the efficacy of pilocarpine and bromhexine in improving radiotherapy-induced xerostomia and its associated symptoms. Materials and methods. In this single-blind, randomized crossover study, pilocarpine and bromhexine tablets were used by twenty-five patients suffered from xerostomia, with a medical history of head and neck radiotherapy. At step A, the patients were treated with pilocarpine for 2 weeks. In addition, they were asked to take bromhexine for 2 weeks with a oneweek washout period. At step B, the inverse process was conducted (first bromhexine, then pilocarpine. Whole resting saliva was collected from patients before and after receiving each medication by precise measurements. Then, efficacy of the two drugs in the treatment of xerostomia and its related oral complications was evaluated using questionnaires by Dichotomous format. The results were statistically analyzed using t-student and Fisher’s exact and chi-squared tests. Statistical significance was set at P<0.05. Results. The difference between saliva secretion rates before and after medications was not significant for bromhexine users at two steps of the study (P=0.35; however, it was significant for pilocarpine users (P=0.0001. Users of both drugs showed significant differences in improvement of xerostomia, chewing, swallowing, tasting and mouth burning. Conclusion. Pilocarpine is probably more effective in improving xerostomia and its associated problems compared with bromhexine, although the use of the latter was also shown to ease some of the consequences of radiotherapy in the head and neck region.
Dube, Aman K; Kumar, Maushmi S
Fungi is a well-known model used to study drug metabolism and its production in in vitro condition. We aim to screen the most efficient strain of Cunninghamella sp. among C. elegans, C. echinulata and C. blakesleeana for bromhexine metabolites production. We characterized the metabolites produced using various analytical tools and compared them with mammalian metabolites in Rat liver microsomes (RLM). The metabolites were collected by two-stage fermentation of bromhexine with different strains of Cunninghamella sp. followed by extraction. Analysis was done by thin layer chromatography, high performance thin layer chromatography, Fourier transform infrared spectroscopy, high performance liquid chromatography and Liquid chromatography-mass spectrometry. The role of Cytochrome P3A4 (CYP3A4) enzymes in bromhexine metabolism was studied. Fungal incubates were spiked with reference standard - clarithromycin to confirm the role of CYP3A4 enzyme in bromhexine metabolism. Three metabolites appeared at 4.7, 5.5 and 6.4min retention time in HPLC. Metabolites produced by C. elegans and RLM were concluded to be similar based on their retention time, peak area and peak response of 30.05%, 21.06%, 1.34%, and 47.66% of three metabolites and bromhexine in HPLC. The role of CYP3A4 enzyme in metabolism of bromhexine and the presence of these enzymes in Cunninghamella species was confirmed due to absence of peaks at 4.7, 5.4 and 6.7min when RLM were incubated with a CYP3A4 enzyme inhibitor - clarithromycin. Copyright © 2016 Sociedade Brasileira de Microbiologia. Published by Elsevier Editora Ltda. All rights reserved.
Nour T. Abdel-Ghani; Issa, Yousry M.; Ahmed, Howayda M.
Bromhexine hydrochloride ion-selective electrodes (conventional type) based on bromhexinium tetraphenyl borate (I) and bromhexinium-phosphotungstate (II) were prepared. The electrodes exhibited mean slopes of calibration graphs of 59.4 mV and 59.8 mV per decade of bromhexine concentration at 25°C for electrode (I) and (II), respectively. Both electrodes could be used within the concentration range 3.16x10-5-1.00x10-2 M bromhexine within the pH range 2.0-4.5. The standard electrodes potentials...
GOtz, V H
On a possible adjuvant function of a bronchosecretolytic preparation commercially available, N-cyclohexyl-N-methyl-(2-amino-3,5-dibromobenzyl)-amine-hydrochloride (bromhexine, Bisolvon-R), sensibilization tests on 30 rabbits were undertaken. 5 animals received Bisolvon and human albumin as antigen, 5 rabbits human albumin only, 5 rabbits Bisolvon and human lymphocytes, 5 rabbits human lymphocytes only, 5 rabbits Bisolvon alone, and 5 received neither Bisolvon nor any antigen. The techniques in these studies, such as two-dimensional double immunodiffusion in agar gel, lymphocytotoxicity test, mixed lymphocyte culture test, electrophoresis on cellulose-acetate foil were used as well as histologic preparations. It could be ascertained that sensitizing with human albumin and simultaneous application of Bisolvon led to a higher concentration of antibodies against albumin than did sensitizing with human albumin alone. Rabbits sensitized with human lymphocytes showed no obvious difference in their antibody rates whether they had received Bisolvon or not. This applied to cell mediated antibodies as well as to the rate of cytotoxic antibodies against human lymphocytes. Among the histologic findings of spleen, bone marrow showed the morphologic equivalences expected from xenosensitization. Comparing the results of sensitized rabbits with and without Bisolvon there were no positive differences as to intensity and/or type of reactivity to be seen. Liver and kidney showed no considerable pathologic phenomena with the exception of some cases with coccidiosis in the bile ductuli. Concerning the bronchial mucosa, in all rabbits treated with Bisolvon an increase of mucine enriched goblet cells as well as a hypergranulation of different epithelial cell types could be observed. Moreover in all animals, including the controls, an intense lymphatic infilitration in the subepithelial and submucous area was identified. The increased antibody concentration in the sera of animals from
Eichler, V D; Kreuzer, H
After several oral applications of N-cyclohexyl-N-methyl-(2-amino-3,5-dibromobenzyl)-aminehydrochloride (bromhexine, Bisolvon-R) to various calves and pigs the residue behaviour was examined. In animals slaughtered immediately after the final application significant amounts of Bisolvon were found. The substance showed a greater affinity to liver and fat tissue whilst, in general, in the muscle tissue, the lungs and kidneys only very small amounts were traceable. In the liver and lungs 3 different metabolites appeared in small quantities. They were partly in conjugated and partly in free form. Within 2 days the amounts greatly decreased and after 7 days at the latest, no residues were traceable; only in the fat of both animal species and in the kidneys of the calves were small quantities of Bisolvon still to be found. Excretion by the milk following oral and parenteral application was also studied. Only traces of Bisolvon were found, which rapidly decreased. Results of the studies show that, neither at a later date of slaughtering nor immediately after the final application, the residues in the animal tissues and in the milk examined present a danger to the health of the human consumer.
Valenti, S; Marenco, G
237 out-patients suffering from chronic obstructive lung disease (COLD) were selected from 7 Italian clinical centers. They were randomly allocated to either placebo or bromhexine 30 mg b.i.d. p.o., in a double-blind fashion. Sputum volume and quality, facility of expectoration, cough, dyspnea, auscultatory thoracic symptoms, forced expiratory volume, peak expiratory flow rate and residual volume were evaluated. Bromhexine showed a statistically significant therapeutic activity in comparison to placebo. This action was rapid, marked and effective in determining a modulation of bronchial secretions.
Abdel-Ghani, N T; Rizk, M S; Mostafa, M
Simple, rapid, sensitive, precise and accurate spectrophotometeric methods for the determination of ephedrine hydrochloride (E-HCl) and bromhexine hydrochloride (Br-HCl) in bulk samples, dosage form and in spiked urine samples were investigated. The methods are based on the formation of a yellow colored ion-associates due to the interaction between the examined drugs with picric acid (PA), chlorophyllin coppered trisodium salt (CLPH), alizarin red (AR) and ammonium reineckate (Rk) reagents. A buffer solution had been used and the extraction was carried out using organic solvent, the ion associates exhibit absorption maxima at 410, 410, 430 and 530 nm of (Br-HCl)with PA, CLPH, AR and Rk respectively; 410, 410, 435 and 530 of (E-HCl) with PA, CLPH, AR and Rk respectively. (E-HCl) and (Br-HCl) could be determined up to 13, 121, 120 and 160; 25, 200, 92 and 206 μg mL(-1), using PA, CLPH, AR and Rk respectively. The optimum reaction conditions for quantitative analysis were investigated. In addition, the molar absorptivity, Sandell sensitivity were determined for the investigated drug. The correlation coefficient was ≥0.995 (n=6) with a relative standard deviation (RSD) ≤1.15 for five selected concentrations of the reagents. Therefore the concentration of Br-HCl and E-HCl drugs in their pharmaceutical formulations and spiked urine samples had been determined successfully. Copyright © 2013 Elsevier B.V. All rights reserved.
Stojanov, Mladen; Nielsen, Hanne Mørck; Larsen, Kim Lambertsen
Bromhexine hydrochloride (bromhexine) is a mucolytic agent with very low aqueous solubility. However, with addition of cyclodextrins (CD) to the formulation, this disadvantage may be limited and therapeutic doses of bromhexine in solution can be achieved. The interaction of bromhexine with α-, β...
Ottonello, Luciano; Arduino, Nicoletta; Bertolotto, Maria; Dapino, Patrizia; Mancini, Marina; Dallegri, Franco
Neutrophils are major culprits for the protease/antiprotease imbalance during various lung diseases, that is, chronic obstructive pulmonary disease, cystic fibrosis, idiopathic pulmonary fibrosis and adult respiratory distress syndrome. Thus, these cells are presently considered an ideal target for the pharmacologic control of tissue injury during these diseases. This study was planned in order to investigate if ambroxol and its precursor bromhexine are actually capable of preventing alpha-1-antitrypsin (A1AT) inactivation by stimulated neutrophils and possibly to look into the mechanisms underlying this event. Ambroxol inhibited the production of superoxide anion by activated neutrophils, whereas bromhexine had no inhibitory effect. Ambroxol decreased the production of hypochlorous acid (HOCl) from activated neutrophils with high efficiency, whereas bromhexine had a modest activity. Ambroxol and bromhexine were capable of limiting the chlorination of monochlorodimedon by HOCl, displaying the capacity of directly scavenging the oxidant. Ambroxol decreased the release of elastase and myeloperoxidase from activated neutrophils, whereas bromhexine was ineffective. Ambroxol prevented the A1AT inactivation by neutrophils, whereas bromhexine was completely ineffective. Among drugs currently available for in vivo use in humans, ambroxol is unique by virtue of its ability to prevent neutrophil-mediated A1AT inactivation via inhibition of HOCl production as well as HOCl scavenging. Also taking into account its capacity for curbing elastase release, the drug displays the potential to lessen the burden of oxidants/proteases and to increase the antiprotease shield at the site of inflammation. Thus, ambroxol appears to be a good candidate for raising attempts to develop new therapeutic histoprotective approaches to inflammatory bronchopulmonary diseases. PMID:14534155
Gibbs, B F
Ambroxol is a widely used secretolytic agent originally developed from vasicine, a natural alkaloid found in Adhatoda vasica, extracts of which have been used to treat bronchitis, asthma, and rheumatism. We previously reported that ambroxol inhibits IgE-dependent mediator secretion from human mast cells and basophils, key effector cells of allergic inflammation. Here, the mechanisms involved in the inhibitory properties of ambroxol were assessed in comparison to other secretolytic analogues (e.g. vasicine, bromhexine, sputolysin). The results show that, in comparison to ambroxol, which reduced IgE-dependent histamine release from basophils at 10 microM-1 mM, the release of the amine was only moderately reduced by sputolysin and vasicine at 1 mM. In contrast, above 10 microM, bromhexine was found to be toxic to basophils in vitro as evidenced by induction of histamine release and reduced cell viability. In contrast, the inhibitory actions of ambroxol at concentrations below 1 mM were not toxic and entirely reversible. Ambroxol was also more potent than either sputolysin or vasicine in attenuating basophil IL-4 and IL-13 secretions, whereas bromhexine-induced suppression of de novo cytokine synthesis was due to toxic effects. Additionally, ambroxol reduced IgE-dependent p38 MAPK phosphorylation in basophils, unlike bromhexine, sputolysin and vasicine. These results clearly show that ambroxol is both more potent and effective at inhibiting IgE-dependent basophil mediator release and p38 MAPK activity than the other secretolytic analogues employed. The therapeutic potential of ambroxol as an anti-allergic agent is further underlined by these data.
Ottonello, Luciano; Arduino, Nicoletta; Bertolotto, Maria; Dapino, Patrizia; Mancini, Marina; Dallegri, Franco
Neutrophils are major culprits for the protease/antiprotease imbalance during various lung diseases, that is, chronic obstructive pulmonary disease, cystic fibrosis, idiopathic pulmonary fibrosis and adult respiratory distress syndrome. Thus, these cells are presently considered an ideal target for the pharmacologic control of tissue injury during these diseases.This study was planned in order to investigate if ambroxol and its precursor bromhexine are actually capable of preventing alpha-1-a...
Ф. Т. Малыхин; А. А. Визель; И. Ю. Визель
Russia is among the countries where using of mucolytic drugs in clinical practice is widespread. In chronic bronchitis, chronic obstructive pulmonary disease, acute respiratory syndrome with prolonged cough, pneumonia, tuberculosis and many other pathologies using of expectorants and mucoregulating drugs is common. Among the synthetic mucolytics benzyalamine bromhexine has been introduced for a long time in practice; and then its derivative — ambroxol hydrochloride which has better pharmacoki...
Kong, Qingtao; Du, Xue; Huang, Suyang; Yang, Rui; Zhang, Chengzhen; Shen, Yongnian; Liu, Weida; Sang, Hong
The antifungal effects of ambroxol (Amb; the metabolite VIII of bromhexine) against Cryptococcus planktonic cells and mature biofilms were investigated in this study. Amb showed antifungal activity against planktonic cells and mature biofilms. Disk diffusion test similarly showed antifungal profile for planktonic cells. Furthermore, Amb was found to be synergetic with fluconazole against planktonic cells and reduced the adherence of cells to polystyrene. Our results suggest that Amb can inhibit cryptococcal cells and biofilms, indicating its potential role in the prevention and treatment of cryptococcosis. © 2017 APMIS. Published by John Wiley & Sons Ltd.
Ф. Т. Малыхин
Full Text Available Russia is among the countries where using of mucolytic drugs in clinical practice is widespread. In chronic bronchitis, chronic obstructive pulmonary disease, acute respiratory syndrome with prolonged cough, pneumonia, tuberculosis and many other pathologies using of expectorants and mucoregulating drugs is common. Among the synthetic mucolytics benzyalamine bromhexine has been introduced for a long time in practice; and then its derivative — ambroxol hydrochloride which has better pharmacokinetics and pharmacodynamics. Using of ambroxol (Ambrobene in patients with cough, accompanied by difficult expectoration, is useful as it promotes the implementation of the protective cough reflex, providing evacuation of viscous mucus or foreign particles from the respiratory tract.
Full Text Available A simple, accurate, sensitive and reproducible reverse phase high performance liquid chromatographic method has been developed for the quantitative determination of Etoricoxib in pharmaceutical dosage forms. The assay was performed on Hypersil ODS C-18 (250 x 4.6 mm., 5µm particle size column using acetonitrile and potassium dihydrogen phosphate buffer (pH 4.2 (46:54 % v/v as mobile phase with UV detection at 280 nm (flow rate 1.2 ml/min. Bromhexine was used as an internal standard. Quantization was achieved by measurement of the peak area ratio of the drug to the internal standard. The limit of detection (LOD and the limit of quantification (LOQ were 0.0704 µg ml-1 and 0.2134 µg ml-1 respectively. Each analysis required no longer than 10 minutes. The calibration curve was linear over the concentration range from 0.5-85.0 µg ml-1. The retention times of Etoricoxib and Bromhexine were found to be 3.083 and 7.631 minutes respectively. The proposed method was validated according to the ICH guidelines and can be used successfully to analyse marketed formulations.
Tsujimoto, Tatsuhiro; Kawaratani, Hideto; Yoshiji, Hitoshi; Uemura, Masahito; Fukui, Hiroshi
Chronic pancreatitis is a progressive inflammatory condition characterized by repeated attacks of abdominal pain, and the destruction and fibrosis of the pancreatic parenchyma which causes to reduced exocrine and endocrine functions. Alcohol is the most common cause of chronic pancreatitis. Although abstinence is usually considered a prerequisite for successful treatment of alcoholic chronic pancreatitis, we often encounter patients who have repeated attacks from the compensated stage through the transitional stage. In alcoholic chronic pancreatitis, continued alcohol consumption causes changes in the digestive hormones and vagal nerve function that induce the pancreatic acinar cells to oversecrete protein, increasing the protein concentration and viscosity of the pancreatic juice. This induces protein sedimentation from the pancreatic juice and formation of protein plugs within the pancreatic duct, triggering repeated attacks of acute pancreatitis. The treatment of alcoholic chronic pancreatitis includes alleviation of symptoms, particularly abdominal pain, elimination of trigger factors, prevention of recurrence and disease progression, adjuvant therapies for pancreatic exocrine and endocrine failure. Recently, the main constituent proteins in these protein plugs have been identified, enabling trials of several therapies, such as the administration of secretin formulations and endoscopic removal. Bromhexine hydrochloride, a bronchial mucolytic, has an affinity for the pancreatic acinar cells, inducing them to secrete pancreatic juice of low viscosity. In this review, we summarize the most recent thoughts about alcoholic chronic pancreatitis, and the new treatments, and in particular, we present our findings concerning the efficacy of bromhexine hydrochloride in the treatment of this disease.
Ericsson, C H; Juhász, J; Jönsson, E; Mossberg, B
Ambroxol, a metabolite of bromhexine, was investigated in a double-blind, controlled trial using parallel groups. We studied the effects of 60 mg and 120 mg daily versus placebo in subjects with simple chronic bronchitis. Possible therapeutic effects were evaluated by means of interviews on subjective drug effects and current respiratory symptomatology, patient diary cards, and lung function tests. Ninety-seven subjects entered the study and 92 completed satisfactorily. Comparison with the placebo group at the end of the study showed that significantly more subjects in the 120 mg ambroxol group reported improvement in respiratory symptoms, principally improved expectoration. Subjects in the 120 mg group tended to prefer the treatment period when compared to placebo but the diary cards did not indicate significant changes. Lung function values were mainly normal and did not change during treatment. We conclude that the drug had a symptomatic effect and that further studies in more severely affected patients would be worthwhile.
Emmerich, Ilka Ute
In 2016, only one newly developed active pharmaceutical ingredient for horses and food-producing animals was released on the German market for veterinary drug products. The immunomodulator Pegbovigrastim is now available as an injection solution for cattle (Imrestor®). Four established veterinary active pharmaceutical ingredients are available for further species: the ectoparasitic Amitraz (Apitraz®) from the triazapentadiene group was additionally authorized for honeybees, the expectorant Bromhexine (Exflow® Vet) for chickens, turkeys and ducks and the macrolide antibiotic Gamithromycin (Zactran®) for pigs. The dopamine D2 receptor agonist Cabergolin (Velactis®) was released for dairy cattle. However, the authorization was suspended a few months after market introduction because of severe side effects. Additionally, one veterinary drug with a new combination of active ingredients as well as one active substance in mono-preparation have been launched on the market for horses and food producing animals.
Antitussive effect of a fixed combination of Justicia adhatoda, Echinacea purpurea and Eleutherococcus senticosus extracts in patients with acute upper respiratory tract infection: A comparative, randomized, double-blind, placebo-controlled study.
Barth, Anders; Hovhannisyan, Areg; Jamalyan, Kristina; Narimanyan, Mikael
Kan Jang® oral solution (KJ) is a fixed combination of aqueous ethanolic extracts of Justicia adhatoda L. leaf, Echinacea purpurea (L.) Moench root, and Eleutherococcus senticosus (Rupr. & Maxim.) Harms root. It is approved in Scandinavia as an herbal medicinal product for respiratory tract infection treatment. The present clinical trial aimed to compare the antitussive effect of KJ with placebo (PL) and bromhexine (BH) among patients of 18-65 years old with non-complicated upper respiratory infections (URI; i.e., common cold). We performed a parallel-group, randomized, double-blinded, placebo-controlled trial in in 177 patients with acute URI over a 5 day period. We investigated the antitussive effects of a KJ (30 ml/day; 762 mg genuine extracts with standardized contents of 0.2 mg/ml vasicine, 0.8 mg/ml chicoric acid, and 0.03 mg/ml eleutherosides B and E), bromhexine hydrochloride (24 mg/30 ml/day) and PL on cough and blood markers. The primary outcome was cough relief, which was assessed as the change of cough frequency from baseline (cough index). Secondary outcomes were safety with regards to reported adverse events (AEs) and hematological data. Both KJ and BH relieved cough more effectively than placebo. On the third and fourth days of treatment, we observed faster improvement in the group receiving KJ compared to in the groups receiving BH (100%) or PL (100%), indicating a slightly shorter recovery time in the KJ group. KJ showed a good tolerability and safety profile. KJ exerted significant antitussive effects in URI. The present data further support the therapeutic use of KJ in upper respiratory tract infections. Copyright © 2015 The Authors. Published by Elsevier GmbH.. All rights reserved.
Full Text Available Kai-Uwe Kern, Myriam Schwickert Institute of Pain Medicine/Pain Practice, Wiesbaden, Germany Abstract: Fibromyalgia appears to present in subgroups with regard to biological pain induction, with primarily inflammatory, neuropathic/neurodegenerative, sympathetic, oxidative, nitrosative, or muscular factors and/or central sensitization. Recent research has also discussed glial activation or interrupted dopaminergic neurotransmission, as well as increased skin mast cells and mitochondrial dysfunction. Therapy is difficult, and the treatment options used so far mostly just have the potential to address only one of these aspects. As ambroxol addresses all of them in a single substance and furthermore also reduces visceral hypersensitivity, in fibromyalgia existing as irritable bowel syndrome or chronic bladder pain, it should be systematically investigated for this purpose. Encouraged by first clinical observations of two working groups using topical or oral ambroxol for fibromyalgia treatments, the present paper outlines the scientific argument for this approach by looking at each of the aforementioned aspects of this complex disease and summarizes putative modes of action of ambroxol. Nevertheless, at this point the evidence basis for ambroxol is not strong enough for clinical recommendation. Keywords: Nav 1.8, Nav 1.7, bromhexine, hyperalgesia, sympathetically maintained pain, central sensitization, interleukins, neuropathic pain, sodium channels
Rainville, Paul D; Simeone, Jennifer L; Root, Dan S; Mallet, Claude R; Wilson, Ian D; Plumb, Robert S
The emergence of micro sampling techniques holds great potential to improve pharmacokinetic data quality, reduce animal usage, and save costs in safety assessment studies. The analysis of these samples presents new challenges for bioanalytical scientists, both in terms of sample processing and analytical sensitivity. The use of two dimensional LC/MS with, at-column-dilution for the direct analysis of highly organic extracts prepared from biological fluids such as dried blood spots and plasma is demonstrated. This technique negated the need to dry down and reconstitute, or dilute samples with water/aqueous buffer solutions, prior to injection onto a reversed-phase LC system. A mixture of model drugs, including bromhexine, triprolidine, enrofloxacin, and procaine were used to test the feasibility of the method. Finally an LC/MS assay for the probe pharmaceutical rosuvastatin was developed from dried blood spots and protein-precipitated plasma. The assays showed acceptable recovery, accuracy and precision according to US FDA guidelines. The resulting analytical method showed an increase in assay sensitivity of up to forty fold as compared to conventional methods by maximizing the amount loaded onto the system and the MS response for the probe pharmaceutical rosuvastatin from small volume samples.
Zhang, Shui-juan; Jiang, Juan-xia; Ren, Qian-qian; Jia, Yong-liang; Shen, Jian; Shen, Hui-juan; Lin, Xi-xi; Lu, Hong; Xie, Qiang-min
Ambroxol, a metabolite of bromhexine, is shown to exert several pharmacological activities, including secretolytic, anti-inflammatory and antioxidant actions. Oral and intravenous administration of ambroxol is useful for the airway inflammatory diseases. However, little is known about its potential in inhalation therapy for lipopolysaccharide (LPS)-induced mucous hypersecretion and inflammatory response. In the present study, we compared the pharmacological effects of ambroxol by inhalation with intravenous administration and preliminarily explored its mechanism of action. Our results demonstrated that ambroxol administered by inhalation inhibited MUC5AC expression, reduced glycosaminoglycan levels, enhanced the function of mucociliary clearance and promoted sputum excretion, suggesting that ambroxol increases expectoration of sputum by reducing its viscosity. Moreover, ambroxol significantly alleviated LPS-induced the influx of inflammatory cells and the extracellular signal-regulated kinase 1/2 (Erk 1/2) expression in lung tissues, and inhibited increases in the mRNA expression of the pro-inflammatory cytokines tumor necrosis factor (TNF)-α, CCL-2 (monocyte chemotactic protein-1), KC (keratinocyte cell protein) and interleukin (IL)-1β in lung tissues. The secretolytic and anti-inflammatory effects of inhaled ambroxol at a dose of 7.5 mg/ml was comparable to that of ambroxol at 20 mg/ml i.v. and dexamethasone at 0.5 mg/kg i.p. In addition, we found that ambroxol dose-dependently inhibited LPS-induced increases in the mRNA expression of MUC5AC, TNF-α, and IL-1β in human bronchial epithelial cell (NCI-H292) by inhibiting the Erk signaling pathway. These results demonstrate the beneficial effects of ambroxol in inhalation therapy for the airway inflammatory diseases. Copyright © 2016 Elsevier B.V. All rights reserved.
Zhang, Yunhui; Fu, Yakun; Yu, Jialin; Ai, Qing; Li, Junshuai; Peng, Ningning; Song, Sijie; He, Yu; Wang, Zhengli
Central venous catheters are widely used in neonatal intensive care units (NICUs) nowadays. The commonest cause of catheter-related bloodstream infections (CRBSIs) is coagulase-negative staphylococci (CoNS). Ambroxol, an active metabolite of bromhexine, exhibits antimicrobial activity against strains producing biofilm and enhances the bactericidal effect of some antibiotic by breaking the structure of biofilm. In this study, we aimed to determine the effect of ambroxol with vancomycin on the biofilm of Staphylococcus epidermidis (S. epidermidis) in vitro and in vivo. In the in vitro study, the biofilm of S. epidermidis was assessed by XTT reduction assay and analysed by confocal laser scanning microscopy (CLSM). In the in vivo study, a rabbit model of CRBSIs was created by intravenous intubation with a tube covered with S. epidermidis biofilm. The rabbits received one of the following four treatments by means of antibiotic lock therapy: normal heparin, ambroxol, vancomycin, or vancomycin plus ambroxol each for 3 days. The microstructure of the biofilm was assessed by scanning electron microscopy (SEM). The number of bacterial colonies in the organs (liver, heart, and kidney) and on the intravenous tubes was measured on agar plates. Pathological changes in the organs (liver, heart, and kidney) were observed with Hematoxylin-Eosin staining. The ambroxol exhibits significant efficacy to potentiate the bactericidal effect of vancomycin on S. epidermidis biofilm both in vitro and in vivo. The antibiotic lock therapy using a combination of ambroxol and vancomycin reveals a high ability to eradicate S. epidermidis biofilms in vivo. These results provide the basis of a useful anti-infection strategy for the treatment of CRBSIs. Copyright © 2015 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Kogi, K; Saito, T; Kasé, Y; Hitoshi, T
The following three experiments were performed to determine the effects of N-acetyl-L-cysteine (NAC) on the quantity and quality of respiratory tract fluid (RTF) and sputum. All drugs used were administered into the stomach through a gastric tube. 1) Indirect measurement of bronchial secretion in rats, which was expressed by the amounts of dye excreted into the respiratory tract, was carried out according the the Sakuno's method, with some modification. Some expectorants of the secretomotor type, such as bromhexine and pilocarpine, significantly increased the secretion, even at low doses. On the other hand, mucolytic agents such as NAC augmented the secretion only in doses of 500 to 1500 mg/kg. 2)As a direct method of measurements, Kasé's modification of Perry and Boyd's method was used to collect RTF, quantitatively, from rabbits. The RTF of healthy rabbits was colorless and watery. The administration of NAC in doses of 500 to 1500 mg/kg augmented the output volume and RTF became slightly turbid, probably due to an increase in the viscous mucus. 3) Rabbits with subacute bronchitis were prepared by long-term exposure to air contaminated with SO2 gas and sputa were collected before and after administration of NAC, respectively, according to the Kase's method. The sputa were opalescent and viscous gel included nodular masses. The administration of NAC, 1000 and 1500 mg/kg resulted in a dose dependent decrease in the relative viscosity. The percent-decreased in viscosity with NAC was statistically correlated with that in amounts of dry matter, those in protein and polysaccharide in the sputa. From the results described above, it was concluded that NAC given into the stomach can liquefy sputum by splitting mucoprotein disulphide linkages, that is, altering the rheological characteristics of sputum to facilitate expectoration.
Korany, Mohamed A; Maher, Hadir M; Galal, Shereen M; Fahmy, Ossama T; Ragab, Marwa A A
This manuscript discusses the application of chemometrics to the handling of HPLC response data using the internal standard method (ISM). This was performed on a model mixture containing terbutaline sulphate, guaiphenesin, bromhexine HCl, sodium benzoate and propylparaben as an internal standard. Derivative treatment of chromatographic response data of analyte and internal standard was followed by convolution of the resulting derivative curves using 8-points sin x(i) polynomials (discrete Fourier functions). The response of each analyte signal, its corresponding derivative and convoluted derivative data were divided by that of the internal standard to obtain the corresponding ratio data. This was found beneficial in eliminating different types of interferences. It was successfully applied to handle some of the most common chromatographic problems and non-ideal conditions, namely: overlapping chromatographic peaks and very low analyte concentrations. For example, a significant change in the correlation coefficient of sodium benzoate, in case of overlapping peaks, went from 0.9975 to 0.9998 on applying normal conventional peak area and first derivative under Fourier functions methods, respectively. Also a significant improvement in the precision and accuracy for the determination of synthetic mixtures and dosage forms in non-ideal cases was achieved. For example, in the case of overlapping peaks guaiphenesin mean recovery% and RSD% went from 91.57, 9.83 to 100.04, 0.78 on applying normal conventional peak area and first derivative under Fourier functions methods, respectively. This work also compares the application of Theil's method, a non-parametric regression method, in handling the response ratio data, with the least squares parametric regression method, which is considered the de facto standard method used for regression. Theil's method was found to be superior to the method of least squares as it assumes that errors could occur in both x- and y-directions and
Welsh, Emma J; Evans, David J; Fowler, Stephen J; Spencer, Sally
overview included 40 or fewer participants. The total number of participants included in reviews ranged from 40 to 1040. The age range of adult participants was from 36 to 73 years and children ranged from six to 16 years. The proportion of male participants ranged from 21% to 72%. Where reported, mean baseline forced expiratory volume in one second (FEV1) ranged from 1.17 L to 1.66 L and from 47% to 88% predicted. Most of the reviews had search dates older than two years.We have summarised the published evidence as outlined in Cochrane reviews, but it was not possible to draw definitive conclusions. There was inconclusive evidence on the use of long-term antibiotics and nebulised hypertonic saline for reducing exacerbation frequency and evidence that human deoxyribonuclease (RhDNase) increases exacerbation frequency. Improvements in lung function were reported for inhaled corticosteroids (ICS) though this was small and not clinically relevant. Evidence of benefit for hyperosmolar agents and mucolytics was inconclusive. There was limited evidence of improvements in quality of life with airway clearance techniques and physical therapy but evidence of benefit for hyperosmolar agents was inconclusive. Secondary outcomes were not clearly reported in all trials in the included reviews. Improvements in dyspnoea, wheeze and cough-free days were reported for small trials of ICS and LABA (long-acting beta2-agonsts)/ICS and cough reduction was also reported for a small bromhexine trial. Reduction in sputum production was reported for long-term antibiotics and airway clearance techniques but evidence of benefit for hyperosmolar agents was inconclusive.Adverse events were included as outcomes in seven reviews. The review of long-term (four weeks to one year) prophylactic courses of antibiotics reported significantly more cases of wheeze (Peto odd ratio (OR) 8.56, 95% confidence intervals (CI) 1.63 to 44.93), dyspnoea (12 versus three, P value = 0.01) and chest pain (seven versus zero