Lacrimal secretion stimulants: sigma receptors and drug implications.

3H-DTG (1.3-di(2-[5-3H]tolyl)guanidine) or 3H-haloperidol was added to sigma-receptors (25 nM) in the presence of 25 nM spiperone and incubated with increasing concentrations of bromhexine derivatives (phenylalkylamines; 10(-9) to 10(-2)M) in membrane homogenate suspensions. IC50 values for two derivatives ranged from 3.2 to 8.8 nM for both radioligands. A preferred derivative, 7A (N,N'-dimethyl-2-phenyl-ethylamine), yielded an IC50 of 7.8 nM for 3H-haloperidol but showed much less affinity in displacing 3H-DTG (IC50 = 900 nM). Applying the technic of Bromberg [Exp. Eye Res., 40:313-320, 1985], in vitro protein secretion rates were measured following stimulation of either lacrimal gland slices or isolated, intact lacrimocytes with the compounds. In vitro protein secretion rates exhibit a dose-response relationship with increases in protein release up to a concentration of 10(-8) to 10(-4) M for various derivatives of bromhexine and 10(-4) M for carbachol. By means of Schirmer strips, tear fluid was collected over a five minute period at 10 and 60 minutes post-dosing following the topical application (50 microliters) to the right eye of New Zealand white rabbits (n = 20-24) of 7A at various concentrations. Incubation of lacrimocytes with 7A alone (10(-4) M), with haloperidol (10(-4) M) alone or in combination show that 7A is acting as an agonist to stimulate protein release, whereas haloperidol is acting as an antagonist to inhibit release. In vivo protein secretion rates also show a dose-response curve (at both 10 and 60 minutes post-dosing) for 7A that reach a statistically significant maximum in the dosed eye at a concentration of 0.15% w/v. Analysis of protein extracts using size exclusion HPLC shows an increase in secretory proteins, particularly tear-specific prealbumin.

[Ambroxol versus betamethasone for the promotion of antepartum lung maturity in pathological pregnancies]. / Ambroxol versus Betamethason zur Förderung der antepartalen Lungenreife bei pathologischen Schwangerschaften.

Although glucocorticoids have been universally implemented to stimulate fetal lung maturity, their effectiveness and side effects are still widely contested. In search of alternative drugs a double-blind study was conducted between June 1981 and June 1984 comparing betamethasone, a conventional corticoid, and ambroxol, a bromhexine metabolite for efficacy and tolerance in prenatal prevention of the respiratory distress syndrome (RDS) in premature infants and full-term neonates. The therapeutic efficacies of betamethasone and ambroxol for this indication proved to be comparable. Since the possible risks of corticoid therapy in abnormal pregnancies are repeatedly discussed in the literature and in daily clinical practice. 137 patients with EPH gestosis, placental insufficiency, diabetes mellitus, and premature rupture of the membranes were selected from the original group of 308 patients. Only minor side effects (e.g. nausea) were present in a few of the 137 cases undergoing treatment with the 2 test substances. No side effects were observed in the neonates. The incidence of fetal RDS was comparable in both groups (2.9% with ambroxol, 2.2% with betamethasone). Transient and mild RDS cases were slightly more frequent in the ambroxol group than in the betamethasone group. To date, contraindications to ambroxol treatment in abnormal pregnancies are unknown and since generally the rate of potential side effects is considered to be lower in comparison with corticoid treatment, the use of ambroxol especially in abnormal pregnancies corresponding indication can be recommended.

[Combination of oral bacterial vaccines and antibiotics in acute recurrent respiratory infections]. / Sull'associazione vaccino batterico orale e antibiotici in corso di infezioni respiratorie acute ricorrenti.

The authors treated 34 patients with acute bronchopulmonary disease or flare-ups of chronic ones with equal doses of ambroxol and ceftriaxone considering the homogeneity of the morbid processes. Patients were divided into two groups of 17 subjects each: group A was given a polyvalent oral bacterial vaccine, group B a placebo. Relevant differences were found between the experimental and control groups concerning cough (score: A = 108, B = 119), duration of expectoration (A = 5.3 days, B = 6.4 days), duration of antibiotic therapy (A = 8.0 days, B = 8.8 days), and length of hospitalization (A = 10.9 days, B = 12.0 days). Differences were slight as far as duration of fever, characteristics of cough and objective findings on the chest were concerned.

[Prophylaxis and treatment of bronchopulmonary complications with ambroxol administered by infusion in elderly patients undergoing surgery]. / Prevenzione e trattamento delle complicanze broncopolmonari con ambroxol per infusione negli operandi anziani.

The Authors consider the high number of patients who are affected with chronic obstructive bronchitis due to various factors (cigarettes smoking, infections, pollution, reduced immune response). These patients, when submitted to middle-high abdominal surgery in total anaesthesia of middle-long duration, are at increased risk due to pulmonary complications. Therefore, an adequate respiratory protection is necessary; actually it is possible with high dose of Ambroxol (1 g). Two groups, both of 35 patients, were compared; the first group was treated with Ambroxol 1 g the second one with aminophilline, bromexine, B2 adrenergic agonists, corticosteroids. The results show the efficacy of respiratory protection by using Ambroxol 1g.

Steady-state bioavailability and pharmacokinetics of ambroxol and clenbuterol administered alone and combined in a new oral formulation.

Ambroxol and clenbuterol are two drugs with potential pharmacological synergy. The objective of this study was to compare the apparent bioavailabilities at steady-state of these two compounds administered alone or in combination (CHF-023). Nine healthy male volunteers participated in the study. They received 30 mg of ambroxol alone (one Fluibron tablet), or 20 micrograms of clenbuterol alone (one Spiropent tablet), or 30 mg of ambroxol plus 20 micrograms of clenbuterol in combination (one CHF-023 tablet), every 12 hours for 7 days on three separate occasions. Ambroxol and clenbuterol concentrations were measured in plasma by appropriate GC/MS methods. Pharmacokinetic parameters were calculated by non-compartmental methods and submitted to statistical comparisons. Compartmental analysis was also performed on data provided by CHF-023 treatment. It was concluded that apparent bioavailabilities of ambroxol and clenbuterol are almost identical in Fluibron and CHF-023 tablets, and in Spiropent and CHF-023 tablets, respectively, with no statistically significant differences between pharmacokinetic parameters calculated for these two drugs during different treatments, except for peak concentration of ambroxol.

The effects of Oradexone and Ambroxol pretreatment of the oxidative sensitivity of the red blood cells in preterm infants.

The antioxidant enzyme activities and lipid peroxidation in the red blood cells of cord blood were investigated and compared at different gestation times in preterm and full-term neonates, with and without pretreatment of the pregnant mothers with Oradexone (Dexamethasone) or Ambroxol. Administration of the two drugs not only stimulated the lung surfactant system, but also exerted favourable effects on the antioxidant enzyme activities while the lipid peroxidation was decreased.

[Effect of ambroxol on surfactant lipids in patients after resection of pulmonary tissue]. / Wplyw ambroxolu na lipidy surfaktantu u chorych po wycieciu miazszu plucnego.

Effect of Ambroxol on phospholipids and higher fatty acids of pulmonary surfactant was studied in patients with lung cancer undergoing pulmonary resection. Intravenous administration of Ambroxol was carried out for 8 days in a dose 1000 mg per day before pulmonary resection. It produced elevation of disaturated phosphatidylcholine and the general level of phosphatidylcholine. Also increase of palmitic acid and saturated fatty acids of the phospholipid fraction was found. The results of this study show that Ambroxol on a short time elevates levels of active substances of pulmonary surfactant and decreases the destructive processes of pulmonary parenchyma.

Ambroxol for prevention and treatment of hyaline membrane disease.

To estimate the efficacy of ambroxol for clinical use in prenatal prevention and postnatal therapy of hyaline membrane disease (HMD) all available experimental and clinical data were reviewed. The administration of ambroxol in animals has a certain promoting influence on lung maturation, a high specificity to lung tissue and a favourable relationship between intended action and negative adverse effects. In clinical studies concerning the prevention of HMD, ambroxol increases the values of amniotic fluid parameters used for estimation of lung maturity and reduces the incidence of HMD at least as effectively as corticosteroids. The number of infants at less than 33 gestational weeks in these reports is small, and further studies will have to confirm the results. Ambroxol applied postnatally has beneficial effects on the course of severe HMD by increasing survival rate, by decreasing duration of oxygen need and artificial ventilation and by improving compliance. Pharmacological studies in preterm HMD-infants showed no influence of ambroxol on blood pressure and heart rate. In 3 of 8 newborns a transient increase of transcutaneous oxygen tension was seen during infusion of ambroxol. Ambroxol is quickly bound to tissue receptors which release it continuously indicating that repeated applications are as effective as continuous infusion.

[A controlled study on the action of a new formulation of ambroxol in asthmatiform bronchitis in children]. / Studio clinico controllato sull'attività di una nuova formulazione di ambroxol nella bronchite asmatiforme del bambino.

A comparison between the action of Ambroxol and Acetylcysteine was carried out in 28 children aged 2 to 13 (mean 7 years 3 months) affected with spastic bronchitis. 14 patients were treated daily for 10 days by the oral route with 30 mg of Ambroxol (2 sachets) and 14 with 200-300 mg of Acetylcysteine (2-3 sachets). Quantity and quality of sputum, difficulty in expectorating, cough, dyspnea, bronchial bruits, were assessed before the treatment, 5 days into it and at the end. Both drugs were effective and well tolerated, but Ambroxol proved to be more rapid in achieving a satisfactory improvement than Acetylcysteine.

[Comparison of the effect of Lasolvan and betamethasone on lung maturity of fetal rabbits]. / Der Vergleich des Einflusses von Lasolvan und von Betamethason auf die Lungenreife fetaler Kaninchen.

8 rabbits received Lasolvan i.v. on day 25, 26 and 27 of pregnancy. 8 rabbits received betamethasone i.m. on 26th and 27th day of pregnancy. The control group received 0.9% NaCl. On day 28 of pregnancy the caesarean section was carried out, the newborn rabbits killed after 45 minutes. In their lungs the lecithin contents was significantly higher in the Lasolvan group than in the betamethasone group and control group, but in the betamethasone group not significantly higher than in the control group. Betamethasone caused in the fetuses the lowering of the body weight, of the wet weight of lungs, of the dry weight lungs and the increase of the pulmonary fluid contents. Lasolvan had no such undiserable effect.

Failure of ambroxol to influence the allergen induced bronchial constriction in sensitized guinea pigs.

The action of ambroxol was tested in an in vivo guinea pig asthma model. Ambroxol, a compound with antiallergic properties effects the mediator releasing cells in vitro and surfactant secretion from alveolar type II cells. This paper deals with the action of ambroxol in an in vivo asthma model in guinea pigs. Ovalbumin sensitized guinea pigs were artificially ventilated by negative chest wall pressure, using a tank respirator. Breathing parameters were measured pneumotachographically. The experimental animals were treated with 50 mg/kg ambroxol i.p. for 5 days; control animals received saline only. The results indicate that pretreatment with ambroxol had no significant effect on the allergic bronchial constriction, while in vitro ambroxol effects on mediator releasing cells and surfactant production point to antiallergic properties. An explanation of the failure of allergenic preventing effects of ambroxol in vivo may be its insufficient concentration in the tissue.

Clinical trial of ambroxol (Mucosolvan) in Sjögren's syndrome.

A clinical trial is described in which twelve patients with Sjögren's Syndrome (SS) were given a dose of 135 mg ambroxol (Mucosolvan) daily for eight weeks. Nine of the patients completed the trial. Three patients dropped out because they developed side effects (generalized rashes in two patients and stomatitis in one). The side effects, however, were mild and cleared off after cessation of treatment. Ambroxol improved sicca symptoms, especially ocular symptoms, in the SS patients, although lacrimal and salivary gland functions measured by Schirmer test or gum test were not changed. Furthermore, the treatment did not alter any chemical findings determined in the stimulated tear and saliva. Our results suggest that ambroxol is useful for the management of sicca symptoms in some patients with SS.

Effect of ambroxol of neutrophil chemotaxis in vitro.

Ambroxol hydrochloride has been shown to protect the lung from damage by polymorphonuclear leucocyte (PMN). In view of this observation we have studied the effect of Ambroxol on PMN chemotaxis using a variety of chemoattractants. The PMN response was inhibited 50-80% by preincubating the cells with concentrations of 10(-4) M Ambroxol. There was no evidence of PMN killing by the drug at concentration of 10(-3) M. The results suggest that Ambroxol my have a role in the management of patients whose chronic lung damage is due to excess PMN recruitment.

[Modification of mucociliary clearance by a combination of theophylline with ambroxol and of ambroxol in monotherapy]. / Beeinflussung der mukoziliaren Clearance durch die Kombination Theophyllin mit Ambroxol sowie durch Ambroxol in einer Monotherapie.

Influence on Mucociliary Clearance by a Theophylline-Ambroxol Combination and by Ambroxol in Monotherapy. In a controlled randomised double-blind study the influence of theophylline + ambroxol (TA) and ambroxol (A) on lung function and mucociliary clearance was investigated. 19 patients with chronic obstructive lung disease were treated after a 5-day wash-out period for 5 days with TA (700 mg theophylline, 60 mg ambroxol/d) or A (60 mg ambroxol/d), respectively. Measurements were done on the 5th and 10th day. Under the treatment with TA a marked improvement of lung function was observed. The mucociliary clearance improved under treatment with TA and A, with TA being significantly better compared with treatment group A.