Transferability of cephalothin to the alveolar cavity in thoroughbreds. (1/26)

Five Thoroughbreds were classified into 4 groups according to the administration method used for saline solution (saline), ambroxol, and cephalothin sodium (cephalothin). In group A, cephalothin was injected intravenously after oral administration of ambroxol. In group B, cephalothin was injected intravenously after oral administration of saline. Groups C and D were used as control groups. The dose of cephalothin or ambroxol was clinically administrated. Venous blood and bronchoalveolar lavage fluid (BALF) were sampled from each group. In groups A and B, cephalothin concentrations in plasma reached their maximum level 5 min after cephalothin administration and then declined over time. In plasma obtained from groups A and B, there were no significant differences in pharmacokinetic parameters (T1/2, Kel, Vd). By contrast, cephalothin concentrations in BALF reached their peak at 180 min after cephalothin administration in both groups A and B and maintained a relatively high level even after 300 min. These findings indicate that cephalothin requires a relatively long period of time to move from the blood stream to the alveolar cavity, but once transferred to the alveolar cavity, it is preserved for a long time. In groups A and B, cephalothin concentrations in BALF were approximately at the same level. However, in group A, total protein in BALF was lower at 60, 180, and 300 min than the other groups. Then, cephalothin concentration was adjusted to total protein in BALF. After adjustment to total protein in BALF, group A showed a concentration level of cephalothin approximately 1.5-fold higher than that of group B. This suggests that the transferability of cephalothin to the alveolar cavity improves as a result of the oral administration of ambroxol.  (+info)

Effect of early ambroxol treatment on lung functions in mechanically ventilated preterm newborns who subsequently developed a bronchopulmonary dysplasia (BPD). (2/26)

In a randomized trial in 102 preterm newborns with respiratory distress syndrome (RDS) it has been shown that early Ambroxol treatment (30 mg kg(-1) over the first 5 days) significantly reduces the incidence of RDS-associated complications [bronchopulmonary dysplasia (BPD), intraventricular haemorrhage, post-natal acquired pneumonia]. The aim of the present analysis was to investigate the effect of Ambroxol treatment on lung function in newborns who developed BPD. Respiratory function testing (RFT) was performed immediately after extubation and at day 28. Tidal volume (VT) and respiratory frequency (f) were measured during tidal breathing using the deadspace free flow-through technique. The lung mechanic parameter VT/maxPes was determined by measuring the maximal oesophageal pressure changes, maxPes, with a catheter tip pressure transducer. In the placebo group 36/50 infants were extubated within the first 28 days of life and 13/36 (36%) developed BPD. In the Ambroxol group 44/52 were extubated and 9/44 (20%) developed BPD. After extubation, RFT showed (i) no statistically significant difference in the ventilatory parameters of either treatment group, (ii) improved (P<0.05) lung mechanics (VT/maxPes) in Ambroxol group compared to controls (94+/-27 ml kPa(-1) vs. 8.1+/-2.6 ml kPa(-1)) and (iii) no statistically significant difference in lung function between infants with and without BPD. At day 28 we found (i) no effect of early Ambroxol treatment on lung functions, (ii) significantly (P < 0.05) higher f (58.5+/-11.7 min(-1) vs. 49.7+/-10.1 min(-1)) and significantly (P<0.01) lower V(T) (9.6+/-1.9 ml vs. 12.3+/-2.7 ml) and V(T)/maxPes (8.9+/-2.6 ml kPa(-1)] vs. 12.0+/-2.9 ml kPa(-1)) in infants with BPD compared to infants without and (iii) these differences are not influenced by early Ambroxol treatment. If the process of BPD development is induced, early Ambroxol treatment has no influence on impaired lung function at day 28.  (+info)

Effects of N-acetylcysteine and ambroxol on the production of IL-12 and IL-10 in human alveolar macrophages. (3/26)

BACKGROUND: N-acetylcysteine (NAC) and ambroxol (AMB) have recently been proposed as possible therapeutic agents in the treatment of pulmonary disorders. IL-12 plays an important role in host resistance to infection and the development of Th-1 cells. In contrast, IL-10 is involved in anti-inflammatory and immunoregulatory mechanisms. OBJECTIVE: We investigated the effects of NAC and AMB on secretions of IL-12 and IL-10 from human alveolar macrophages. METHODS: Alveolar macrophages were obtained from 7 healthy nonsmokers by bronchoalveolar lavage. The cells were first incubated with either NAC or AMB for 2 h and then cultured in lipopolysaccharide (LPS) solution for 24 h. IL-12 and IL-10 secretions were measured by ELISA. RESULT: Both NAC and AMB enhanced LPS-induced secretion of IL-12. NAC also enhanced LPS-induced IL-10 secretion, while AMB did not. The ratio IL-12/IL-10 secretion was increased by AMB, but NAC did not affect it. CONCLUSIONS: The results suggest that NAC enhances inflammatory and immune responses and prevents excessive responses reciprocally, through keeping local balance of IL-12 and IL-10 production in alveolar macrophages at inflammatory sites of bacterial pneumonia. AMB appears to strengthen inflammatory responses and cell-mediated immunity, facilitating the development of Th-1 cells, through shifting the local balance to IL-12 dominance.  (+info)

Depressant effect of ambroxol on stimulated functional responses and cell death in rat alveolar macrophages exposed to silica in vitro. (4/26)

The present study examined the effect of ambroxol on free radical production, granule enzyme release, and cell death in silica-activated rat alveolar macrophages. The action of ambroxol was assayed by measuring changes in the activities of protein kinase C (PKC) and tyrosine kinase (PTK) and in the intracellular calcium level. Ambroxol attenuated the production of superoxide, hydrogen peroxide, and nitric oxide and the release of acid phosphatase and lysozyme in macrophages activated by silica. Staurosporine, genistein, EGTA, and trifluoperazine inhibited the silica-induced free radical production and granule enzyme release. Silica induced the increase in PKC and PTK activities and the elevation of intracellular calcium level in macrophages, which was decreased by ambroxol. Silica induced a cell death and increased the caspase-3 activity in macrophages in a concentration-dependent manner. Ambroxol decreased the silica-induced cell viability loss in macrophages. The results show that ambroxol decreases the stimulated responses and cell death in rat alveolar macrophages exposed to silica, which may be accomplished by inhibition of activation processes, protein kinases, and calcium transport. The inhibitory effect of ambroxol on silica-induced cell death appears to provide the protective effect on pulmonary tissues against the toxic action of silica.  (+info)

Ambroxol suppresses influenza-virus proliferation in the mouse airway by increasing antiviral factor levels. (5/26)

The protective effect of ambroxol, a mucolytic agent which has antioxidant properties and stimulates the release of pulmonary surfactant, against influenza-virus proliferation in the airway was investigated in mice. Ambroxol or the vehicle was administered intraperitoneally twice a day for 5-7 days to mice shortly after intranasal infection with a lethal dose of influenza A/Aichi/68 (H3N2) virus, and the survival rate, virus titre and levels of factors regulating virus proliferation in the airway fluid were analysed. Ambroxol significantly suppressed virus multiplication and improved the survival rate of mice. The effect of ambroxol reached a peak at 10 mg x kg(-1) x day(-1), higher doses being less effective. Ambroxol stimulated the release of suppressors of influenza-virus multiplication, such as pulmonary surfactant, mucus protease inhibitor, immunoglobulin (Ig)-A and IgG, although it stimulated the release of a trypsin-type protease that potentiates virus proliferation. In addition, ambroxol transiently suppressed release of the cytokines, tumour necrosis factor-alpha, interferon-gamma and interleukin-12, into airway fluid. Although ambroxol had several negative effects on the host defence system, overall it strikingly increased the concentrations of suppressors of influenza-virus multiplication in the airway.  (+info)

Inhibition of tetrodotoxin (TTX)-resistant and TTX-sensitive neuronal Na(+) channels by the secretolytic ambroxol. (6/26)

Ambroxol has a long history for the treatment of airway diseases because of its beneficial effects on surfactant synthesis and mucus-modifying properties. Some findings, however, point to an additional effect on neuronal signal transduction: ambroxol can suppress reflexes such as the cough or the corneal reflex. The airways and the cornea are innervated by C-fibers, which express voltage-gated Na(+) channels with and without sensitivity to tetrodotoxin (TTX). In this study, we performed voltage-clamp experiments to investigate whether ambroxol affects these channel types. In rat dorsal root ganglia, TTX-resistant Na(+) currents were suppressed in a concentration-dependent manner with IC(50) values of 35.2 and 22.5 microM for tonic and phasic block, respectively. Depolarizing prepulses increased the potency of ambroxol, and steady-state inhibition curves were shifted to more negative values. The inhibition was not frequency-dependent. TTX-sensitive currents were inhibited with lower potency (approximately 50% inhibition with 100 microM). Recombinant rat brain IIA channels in Chinese hamster ovary cells were blocked with IC(50) values of 111.5 and 57.6 microM for tonic and phasic block, respectively; in contrast to TTX-resistant channels the block was frequency-dependent. Thus, ambroxol indeed blocks neuronal voltage-gated Na(+) channels, and TTX-resistant channels in sensory neurons were more sensitive than TTX-sensitive. Compared with known local anesthetics (e.g., lidocaine or benzocaine), the potency for Na(+) channel block was relatively high. A recent clinical trial has further confirmed that ambroxol relieved pain and was beneficial in patients who suffered from sore throat.  (+info)

Pulmonary alveolar proteinosis successfully treated with ambroxol. (7/26)

A 79-year-old woman was admitted to hospital due to a four-month history of a cough and dyspnea on exertion. Chest CT scans revealed ground glass opacity with thickened interlobular septa in both lungs. Bronchoalveolar lavage fluid (BALF) had milky appearance and revealed large acellular eosinophilic amorphous bodies positively stained with periodic acid-Schiff (PAS). Autoantibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF) were present in sera and BALF from the patient. Ambroxol was started in a daily dose of 45 mg orally. Her oxygen saturation improved and abnormal shadows in CT scan disappeared 6 months after beginning the therapy.  (+info)

In vitro inhibition of human neutrophil histotoxicity by ambroxol: evidence for a multistep mechanism. (8/26)

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.  (+info)

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