Genetic deletion of the Tas2r143/Tas2r135/Tas2r126 cluster reveals that TAS2Rs may not mediate bitter tastant-induced bronchodilation.

Bitter taste receptors (TAS2Rs) and their signaling elements are detected throughout the body, and bitter tastants induce a wide variety of biological responses in tissues and organs outside the mouth. However, the roles of TAS2Rs in these responses remain to be tested and established genetically. Here, we employed the CRISPR/Cas9 gene-editing technique to delete three bitter taste receptors-Tas2r143/Tas2r135/Tas2r126 (i.e., Tas2r triple knockout [TKO]) in mice. The fidelity and effectiveness of the Tas2r deletions were validated genetically at DNA and messenger RNA levels and functionally based on the tasting of TAS2R135 and TAS2R126 agonists. Bitter tastants are known to relax airways completely. However, TAS2R135 or TAS2R126 agonists either failed to induce relaxation of pre-contracted airways in wild-type mice and Tas2r TKO mice or relaxed them dose-dependently, but to the same extent in both types of mice. These results indicate that TAS2Rs are not required for bitter tastant-induced bronchodilation. The Tas2r TKO mice also provide a valuable model to resolve whether TAS2Rs mediate bitter tastant-induced responses in many other extraoral tissues.

Pharmacological targeting of histamine H4 receptor in periodontal disease.

OBJECTIVE: The objective of this study was to investigate whether histamine H4 receptor (H4 R) antagonists could prevent experimental periodontitis (EP)-induced histological, functional and inflammatory alterations in submandibular gland (SMG), periodontal bone and gingiva. METHODS: Bilateral EP was induced for 2 weeks in anaesthetized male rats. The effect of systemic and local administration of H4 R antagonists (JNJ7777120, JNJ10191584) on histopathology and functionality of SMG, bone loss and gingival inflammation was evaluated. RESULTS: The subcutaneous administration of JNJ7777120 prevented periodontitis-induced SMG histological injury, reducing vacuolization and apoptosis and additionally reversed the increased prostaglandin E2 (PGE2) levels in SMG while it partially reversed the methacholine-induced salivation reduction produced by periodontitis. JNJ7777120 attenuated bone loss and the increased PGE2 levels and inflammatory infiltration in gingival tissue of rats with periodontitis. Finally, local administration of JNJ7777120 and JNJ10191584 was also beneficial for improving periodontal parameters. CONCLUSIONS: H4 receptor antagonists are able to ameliorate periodontitis-induced injury on SMG, gingival tissue and bone structure, suggesting that pharmacological targeting of H4 R could be an attractive strategy to improve periodontal health.

Angiogenesis and airway reactivity in asthmatic Brown Norway rats.

Expanded and aberrant bronchial vascularity, a prominent feature of the chronic asthmatic airway, might explain persistent airway wall edema and sustained leukocyte recruitment. Since it is well established that there are causal relationships between exposure to house dust mite (HDM) and the development of asthma, determining the effects of HDM in rats, mammals with a bronchial vasculature similar to humans, provides an opportunity to study the effects of bronchial angiogenesis on airway function directly. We studied rats exposed bi-weekly to HDM (Der p 1; 50 µg/challenge by intranasal aspiration, 1, 2, 3 weeks) and measured the time course of appearance of increased blood vessels within the airway wall. Results demonstrated that within 3 weeks of HDM exposure, the number of vessels counted within airway walls of bronchial airways (0.5-3 mm perimeter) increased significantly. These vascular changes were accompanied by increased airway responsiveness to methacholine. A shorter exposure regimen (2 weeks of bi-weekly exposure) was insufficient to cause a significant increase in functional vessels or reactivity. Yet, 19F/1H MR imaging at 3T following αvß3-targeted perfluorocarbon nanoparticle infusion revealed a significant increase in 19F signal in rat airways after 2 weeks of bi-weekly HDM, suggesting earlier activation of the process of neovascularization. Although many antigen-induced mouse models exist, mice lack a bronchial vasculature and consequently lack the requisite human parallels to study bronchial edema. Overall, our results provide an important new model to study the impact of bronchial angiogenesis on chronic inflammation and airways hyperreactivity.

Relationship of mannitol challenge to methacholine challenge and inflammatory markers in persistent asthmatics receiving inhaled corticosteroids.

BACKGROUND: Mannitol is a novel osmotic indirect bronchial challenge agent used to aid asthma diagnosis and management and is thought to reflect underlying inflammatory processes in asthma. Our objective was to evaluate relationships between mannitol airway hyperresponsiveness (AHR) and other measures of airway inflammation as well as direct-acting methacholine challenge in persistent asthmatics receiving inhaled corticosteroids. METHODS: We analysed screening data of mild to moderate persistent asthmatics, all receiving inhaled corticosteroids (ICS), who had mannitol and/or methacholine challenges, fractional exhaled nitric oxide (FeNO), and salivary eosinophilic cationic protein (ECP) performed as part of the same screen. Mannitol AHR was grouped by PD(10) (cumulative provocative dose required to produce a 10 % fall in FEV(1)): mild (315-635 mg), moderate (75-315 mg), and severe (0-75 mg). FeNO groups were low (<25 ppb), medium (25-50 ppb), and high (> 50 ppb) and methacholine PC(20) (provocative concentration of methacholine required to cause a 20 % fall in FEV(1)) groups were mild (2-8 mg/ml), moderate (0.5-2 mg/ml), and severe (0-0.5 mg/ml). RESULTS: Mannitol PD(10) groups were significantly different overall for FeNO (p = 0.023): 43 % higher in the severe vs. the mild group. There was a significant overall difference for methacholine PC(20) (p = 0.006): a 2.1 doubling dilution difference between severe vs. mild mannitol groups. FeNO groups were significantly different overall for mannitol PD(10) (p = 0.01) and methacholine PC(20) (p = 0.029). Methacholine PC(20) groups were significantly different overall for mannitol PD(10) (p < 0.001) and FeNO (p = 0.005). No significant differences were found across any groups for salivary ECP, FEV(1) % predicted, or ICS dose. Mannitol PD(10), methacholine PC(20), and FeNO as continuous variables all correlated with each other. CONCLUSIONS: Mannitol challenge reflects underlying inflammation using FeNO and direct AHR using methacholine. Thus, mannitol may be a useful screening tool for the assessment of asthmatic patients receiving inhaled corticosteroids.

Atypical antipsychotics--effects of amisulpride on salivary secretion and on clozapine-induced sialorrhea.

OBJECTIVE: Amisulpride is suggested for treatment of clozapine-induced sialorrhea. However, objective measurements of its effectiveness are lacking and, preclinically, amisulpride has no effect. We currently hypothesise that amisulpride acts by reducing the nervous- rather than the clozapine-driven salivary secretion. MATERIAL AND METHODS: Effects of intravenous amisulpride (as well as of clozapine and raclopride, a dopamine D2/D3 antagonist) were investigated in rats, including those subjected to chronic preganglionic parasympathetic denervation (submandibular glands) or combined postganglionic parasympathetic and sympathetic denervation (parotid glands). In duct-cannulated glands, secretion was evoked reflexly, at low and maximum flow rates, and by electrical stimulation of the parasympathetic and sympathetic innervations, and administration of autonomimetics (including substance P). RESULTS: Unlike clozapine, amisulpride had no effect on the reflexly evoked secretion at maximum rate. With respect to reflex secretion at low rate and to the secretion evoked by muscarinic, α-adrenergic, ß-adrenergic and substance P receptors, amisulpride (in contrast to raclopride) dose dependently potentiated the responses. Amisulpride had no effect on gland blood flow. CONCLUSIONS: No support for any inhibitory influence of amisulpride was found. Conversely, amisulpride universally enhanced secretion, suggesting that amisulpride is a potential drug for dry-mouth treatment. The mechanism behind the potentiation is currently unknown.

Vaccine-induced CD8+ T cell-dependent suppression of airway hyperresponsiveness and inflammation.

Suppressing the abnormalities associated with asthma has been difficult to accomplish using immunotherapy or vaccination once the disease is established. The effector cells necessary for effective immunization/vaccination and immunotherapy of asthma are also not well understood. Therefore, we vaccinated allergen (OVA)-sensitized mice to determine whether therapeutic immunization could suppress airway hyperresponsiveness (AHR) and inflammation and to identify key immune effector cells and cytokines. Mice were immunized with a vaccine comprised of Ag and cationic liposome-DNA complexes (CLDC), a vaccine which has previously been shown to elicit strong CD4(+) and CD8(+) T cell responses and activation of Th1 immunity. We showed that immunization with the OVA-CLDC vaccine significantly suppressed AHR, eosinophilia, goblet cell metaplasia, and Th2 cytokine production. In contrast, immunization with CLDC alone suppressed eosinophilia and Th2 cytokine production, but failed to suppress AHR and goblet cell changes. Using adoptive transfer experiments, we found that suppression of AHR was mediated by Ag-specific CD8(+) T cells and was dependent on IFN-gamma production by the transferred T cells. Thus, we conclude that generation of strong, allergen-specific CD8(+) T cell responses by immunization may be capable of suppressing AHR and allergic airway inflammation, even in previously sensitized and challenged mice.

Clozapine-induced salivation: interaction with N-desmethylclozapine and amisulpride in an experimental rat model.

Many drugs (e.g. amisulpride) have been used to treat troublesome clozapine-induced salivation; however, varying success has been achieved in this respect, probably because, until recently, the salivatory action of clozapine has been largely unexplained. In the rat, clozapine and its main metabolite, N-desmethylclozapine, were found to exert mixed secretory actions: excitatory, through muscarinic acetylcholine M1-receptors giving rise to a long-lasting, low-level flow of saliva; and inhibitory, through muscarinic M3-receptors and α(1) -adrenoceptors reducing the parasympathetically and sympathetically nerve-evoked flow of saliva. The aim of the present study was to define the interactions between clozapine and N-desmethylclozapine, and clozapine and amisulpride, with respect to the excitatory response. Submandibular glands, sensitized by chronic parasympathetic preganglionic denervation, were studied in pentobarbitone-anaesthetized rats. To prevent clozapine from being metabolized to N-desmethylclozapine by hepatic enzymes, the liver was, under terminal anaesthesia, excluded from the circulation. The weak receptor-stimulating clozapine prevented the strong receptor-stimulating N-desmethylclozapine, at specific ratios in humans and in rats, from exerting its full agonistic action. In conclusion, the contribution of N-desmethylclozapine to the clozapine-induced sialorrhoea was, at most, only partly additive. Furthermore, the present experimental set-up failed to demonstrate any anti-salivatory action of amisulpride on the clozapine-induced flow of saliva.

Sequential sensitization to different occupational compounds in a young woman.

BACKGROUND: Very few authors have reported sensitization to two or more different occupational sensitizers in a single patient. OBJECTIVE: To describe a subject with occupational asthma caused by sensitization to two different agents, exposure to which occurred in dierent time periods. METHODS: We studied a young woman with asthma-like symptoms predominantly in relationship to a sequential occupational exposure, first to methylene diisocyanate (MDI) and later to flour dust. In the first and second periods of occupational exposure, the patient was subjected to metbacholine challenge test (MCT), sputum analysis, and specific challenge test (SCT). RESULTS: At the first observation, MCT (PD20FEV1: 0.109 mg) and SCT with MDI were positive and induced sputum analysis showed a high percentage of eosinophils (32%). The patient reduced exposure to MDI but symptoms worsened with continuing occupational exposure. After one year, she started another job exposed to flour dust. After four years, asthma symptoms persisted despite treatment with inhaled corticosteroids and bronchodilators, and bronchial byperreactivity and sputum eosinophbilia were still present (PD2OFEV1: 0.067 mg; sputum eosinophils: 5.3%). The patient also developed rhinitis symptoms associated with dermatitis. A SCT with flour dust showed an immediate response (deltaFEV1: 33%). The subject left work and a year later was still symptomatic:pulmonary function was within normal limits under regular therapy and induced sputum showed absence of eosinophilia. CONCLUSIONS: This was an unusual case of double sensitization to different occupational compounds to which the patient was exposed in different time periodsj suggesting the role of a pre-existing occupational aSthma in the development and/or worsening of sensitization to other occupational agents.

Role of the endocannabinoid system in ethanol-induced inhibition of salivary secretion.

AIM: The aim of the present study was to determine whether the endocannabinoid system could be involved in the ethanol-induced inhibition of salivation in adult male Wistar rats. METHODS: Salivary secretion induced by different concentrations of methacholine, a cholinergic agonist, and the endocannabinoid arachidonoyl ethanolamide (anandamide, AEA) production in the submandibular gland (SMG) were determined in rats after ethanol (3 g/kg) administration by gastric gavage. To study the participation of cannabinod receptors in ethanol action, we evaluated methacholine-induced salivary secretion after ethanol administration when CB1 or CB2 receptors were blocked by intra-SMG injections of their selective antagonists AM251 and AM630, respectively. Additionally, we evaluated the in vitro effect of ethanol (0.1 M) on SMG production of cAMP, alone or combined with AM251 or AM630. RESULTS: Acute ethanol administration increased AEA production in SMG and also inhibited the methacholine-induced saliva secretion that was partially restored by intraglandular injection of AM251 or AM630. In addition, ethanol significantly reduced the forskolin-induced increase in cAMP content in SMG in vitro while treatment with AM251 blocked this response. CONCLUSION: We conclude that the inhibitory effect produced by ethanol on submandibular gland salivary secretion is mediated, at least in part, by the endocannabinoid system.

Saliva production and surface tension: influences on patency of the passive upper airway.

Pharyngeal patency is influenced by the surface tension (gamma) of the upper airway lining liquid (UAL), of which saliva is a major component. We investigated the influences of saliva production on gamma of the UAL, and upper airway re-opening and closing pressures. In 10 supine, male, anaesthetized, tracheostomised, mechanically ventilated New Zealand White rabbits, we measured re-opening and closing of the passive isolated upper airway at baseline and following graded (cumulative) doses of methacholine or atropine. Upper airway liquid volume index (UALVI) was assessed using a standardized suction procedure (secretion weight obtained per second) expressed as the natural logarithm (LnUALVI). The gamma of UAL samples were measured using the 'pull-off' force technique. Across all animals, baseline values were: LnUALVI -6.2 (-8.6 to -5.4) median (interquartile range), gamma of UAL 58.9 (56.6-59.9) mN m(-1), re-opening 8.6 (6.9-11.1) cmH(2)O, and closing pressures 3.2 (1.8-5.7) cmH(2)O. LnUALVI increased by approximately 0.17 per microg kg(-1) methacholine and decreased by approximately 0.14 per 100 microg kg(-1) atropine (both P < 0.03, linear mixed effects modelling). Surface tension was unchanged by methacholine but increased by approximately 0.6 mN m(-1) per 100 microg kg(-1) atropine (P < 0.004). When data were analysed across all animals, both re-opening and closing pressures increased as surface tension increased (by approximately 0.4 cmH(2)O mN(-1) and by approximately 0.7 cmH(2)O mN(-1), respectively; both P < 0.05). We conclude that saliva production influences upper airway mechanical properties partly via alterations in gamma of UAL. We speculate that in obstructive sleep apnoea, altered autonomic activity may reduce saliva production and increase surface tension of the upper airway lining liquid, thus increasing the likelihood of upper airway obstruction.

Differences in the response to methacholine between the tidal breathing and dosimeter methods: influence of the dose of bronchoconstrictor agent delivered to the mouth.

BACKGROUND: It has been postulated that differences in provocative concentration of methacholine causing a 20% fall in FEV1 (PC20) values between the dosimeter method and tidal breathing method might be due to differences in the dose of agonist delivered to the mouth. The aim of the present study was to determine the influence of the dose of aerosol delivered to the mouth on differences in the response obtained with each challenge method. METHODS: This study measured airway responsiveness to methacholine by dosimeter method and tidal breathing method in 27 subjects with suspected asthma. The dosimeter was modified to deliver an identical volume to that obtained with the tidal breathing method. Concentration-response curves were characterized by the PC20. RESULTS: The dosimeter method PC20 was significantly higher than the tidal breathing method PC20, with geometric mean values of 4.03 (95% confidence interval [CI], 1.86 to 8.78 mg/mL) and 2.19 (95% CI, 1.32 to 3.64 mg/mL; p = 0.04), respectively. The mean difference in the PC20 value detected with each method was similar in subjects with tidal breathing method PC20 values > or = 2 mg/mL (0.77 doubling concentrations) and in those with PC20 values < 2 mg/mL (0.96 doubling concentrations; p = 0.83). CONCLUSIONS: The tidal breathing method produces PC20 values significantly lower than a modified dosimeter method, which delivers the same volume of aerosol. These results suggest that the discordant PC20 values obtained with the two methods are not due to differences in the dose of agonist delivered to the mouth.

Exercise-induced asthma may be associated with diminished sweat secretion rates in humans.

BACKGROUND: Muscarinic receptor agonists increase water secretion from the acinar cells of respiratory, sweat, salivary, and lacrimal glands. Mice lacking the gene for aqueous water channel aquaporin (Aqp) 5 exhibit methacholine-induced bronchiolar hyperreactivity when compared to normal mice. Individuals with asthma also have enhanced airway responsiveness to methacholine and diminished airway hydration. Because Aqp5 in humans is also expressed in respiratory, sweat, salivary, and lacrimal glands, we hypothesized that those individuals with exercise-induced asthma and excessive bronchiolar reactivity should also have decreased muscarinic receptor-dependent sweat, salivary, and tear gland secretions. METHODS: Healthy, athletic subjects who are suspected of having exercise-induced bronchospasm were recruited, and FEV(1) values were determined following provocative airway challenges with methacholine. Measurements of pilocarpine-induced sweat secretion were taken in 56 volunteers, and some additional subjects also had timed collections of saliva and tear production. RESULTS: Subjects manifesting excessive airway reactivity demonstrated by exaggerated methacholine-induced reductions in FEV(1) also had diminished values for pilocarpine-induced sweat secretion (n = 56; r = - 0.59; p < 0.0001). The rate of pilocarpine-stimulated sweat secretion in our subjects correlated highly with salivary flow rate (r = 0.69; p < 0.0001) and tearing rate (r = 0.86; p < 0.001). CONCLUSION: Hyperhidrosis, sialorrhea, and excessive tearing are traits that may indicate a phenotype that predicts resistance to hyperactive airway diseases such as exercise-induced asthma in humans.

Melatonin-evoked in vivo secretion of protein and amylase from the parotid gland of the anaesthetised rat.

The intravenous infusion of melatonin (5 and 25 mg/kg over 10 min) evoked a dose-dependent output of protein and amylase but no overt fluid secretion from the parotid gland of the pentobarbitone-anaesthetised rat, as revealed by increased concentrations of protein and amylase activity in a subsequent wash-out flow of saliva in response to an intravenous bolus injection of methacholine (5 microg/kg) 10 min later. The secretory responses to melatonin occurred in the presence of alpha- and beta-adrenoceptor antagonists. They were not affected by the cholecystokinin A-receptor antagonist, lorglumide, and they were reproduced in eviscerated animals acutely subjected to postganglionic sympathetic and parasympathetic denervation of the gland. The responses to melatonin were partially dependent on nitric oxide generation, through the activity of nitric oxide synthase of the neuronal type. Immunoblotting showed both melatonin receptors of type 1 and type 2 to be expressed in parotid gland tissue. The relative specific melatonin 2-receptor antagonist luzindole prevented the expected secretory effects of melatonin. The results favour a direct action by melatonin on melatonin receptors of parotid secretory cells and suggest a potential physiological role for melatonin in the regulation of salivary glandular activities.

Methacholine dry powder inhaler as a new tool for bronchial challenge test.

BACKGROUND: The methacholine (MCH) challenge test is performed to detect bronchial hyperresponsiveness in subjects suffering from asthma. It is conducted by inhaling spasmogen substances at increasing doses and measuring FEV1-PD20 variation following the bronchoconstriction evoked. AIM: This paper describes a new method for MCH challenge test using pre-metered respirable powders of MCH at different doses for facilitating test execution. The availability of a series of pre-metered doses gives higher control over aerosolized dose and fine particle fraction (respirable dose), improving the accuracy and repeatability of the test. Dosimetric tests with MCH solution and pre-dosed powder challenge tests were clinically compared. METHODS AND MATERIALS: The inhalation powders were prepared by spray drying of solutions of methacholine, mannitol and hydroxypropylmethylcellulose in which different concentrations of MCH were included. The methacholine powders prepared were carefully characterized in terms of aerodynamic properties. RESULTS: Inhalation powders containing methacholine from 12.5 to 200 microg per metered dose, having a fine particle fraction between 40 and 60%, were prepared using mannitol and cellulose polymer. Eighteen subjects (12 hyperresponsive and six normal) were subjected to both the MCH solution and powder tests in random sequence. No significant differences in FEV1 and PD20 values were found between the challenge tests performed with liquid and powder formulations of methacholine. CONCLUSIONS: Powders of MCH having high respirability of the delivered doses can be prepared by spray drying. They allow for the performance of a challenge test using a dry powder inhaler. The powder dose series can be an alternative to the current dosimetric test with MCH solutions.

Acute salivary gland hypofunction in the duct ligation model in the absence of inflammation.

OBJECTIVE: The commonly associated aetiology of salivary gland inflammation and salivary hypofunction has led to the widely held belief that inflammation causes salivary gland hypofunction. Indeed, our own recent study seemed to support this contention. Here, we tested the hypothesis that, in an acute duct ligation model, eliminating inflammation the submandibular gland would recover normal function. MATERIALS AND METHODS: Ligation of the rat submandibular gland excretory duct for 24 h was used to induce inflammation and salivary gland hypofunction. A group of duct ligated rats was compared with a second group given dexamethasone, on the day of duct ligation. Twenty-four hours later salivary gland function was assessed and salivary glands were collected. RESULTS: Histology and myeloperoxidase activity assay revealed a profound decrease in inflammatory cell infiltration of ligated glands from rats given dexamethasone, compared with ligated glands in the absence of dexamethasone. Salivary flow rate evoked by methacholine was decreased (P < 0.01) by approximately 56% (ligated vs control, 79 +/- 9 microl min(-1) g(-1)vs 177 +/- 11 microl min(-1) g(-1)) and salivary flow from ligated dexamethasone-treated and ligated glands was similar. CONCLUSION: Despite eliminating the inflammatory reaction in the ligated gland, salivary hypofunction was not reversed, suggesting that other mechanisms must be at work in the ligation-induced salivary hypofunction.

Inhibition of salivary secretion by activation of cannabinoid receptors.

It is known that marijuana use decreases saliva secretion. Therefore, we hypothesized that cannabinoid receptors (CBs) are located in salivary glands to mediate that effect. In these experiments, we used the submandibular gland (SMG) of male rats, which is one of the major salivary glands. Mammalian tissues contain at least two types of CBs, CB1 and CB2, mainly located in the nervous system and peripheral tissues, respectively. Both receptors are coupled to Gi protein and respond by inhibiting the activity of adenylyl cyclase. We demonstrated that both CB1 and CB2 are present in the SMG, each showing specific localizations. The best-known endocannabinoid is anandamide (AEA), which binds with high affinity to CB1 and CB2. We showed that AEA markedly reduced forskolin-induced increase of cAMP content in vitro. This effect was blocked by AM251 and AM630 (CB1 and CB2 antagonists, respectively), indicating that both receptors are implicated in SMG physiology. In addition, we showed that AEA injected intraglandularly to anesthetized rats inhibited norepinephrine (NE)- and methacholine (MC)-stimulated saliva secretion in vivo and that both AM251 or AM630 prevented the inhibitory action of AEA. Also, the intraglandular injection of AM251 increased saliva secretion induced by lower doses of NE or MC. This increase was synergized after coinjection with AM630. Therefore, we concluded that AEA decreases saliva secretion in the SMG acting through CB1 and CB2 receptors.

Peak inspiratory flow rate after methacholine challenge in asthmatic patients and its impact on the effect of formoterol via different inhalers.

The goal of the present study was to investigate the bronchodilating effects of 6 and 12 microg formoterol delivered by the Turbuhaler, in comparison to salbutamol 200 microg (metered dose inhaler) and to controls without treatment. After inducing acute and severe bronchial obstruction by means of methacholine challenge, peak inspiratory mouth flow (PIMF) was measured through a stenosis, simulating the internal resistance of the Turbuhaler, with the in-check device. In addition the relationship was studied between PIMF and clinical response in the 3 treatment groups. In the 176 patients methacholine caused a mean fall in FEV(1) of 37.1 +/- 6.9% compared to baseline. Ten minutes after bronchodilator inhalation, FEV(1) improved significantly in all three treatment groups. At 30 minutes after bronchodilator administration, only the salbutamol 200 microg and the formoterol 12 microg groups had a significantly greater increase in FEV1 than controls (0.69 +/- 0.43 l and 0.66 +/- 0.37 l vs 0.38 +/- 0.32 l, p < 0.0005), whereas the formoterol 6 microg group showed no significant improvement (0.41 +/- 0.38 l, p = 0.74). Thirteen patients (7.4%) did not reach a minimal PIMF of 30 l/min through the in-check device after challenge. In the four patients in the formoterol 6 microg group with a PIMF below 30 l/min inhalation did not cause bronchodilation. In conclusion, the results demonstrate that 6 microg formoterol via Turbuhaler leads to less and slower onset of bronchodilation compared to the other groups in our setting. If patients fail to generate a PIMF of 30 l/min, 6 microg formoterol via Turbuhaler may provide inadequate relief in a severe asthma attack.

In vivo studies of effects of antidepressants on parotid salivary secretion in the rat.

Tricyclic antidepressants (TCA) are well-known xerogenic drugs, while antidepressants such as selective serotonin reuptake inhibitors (SSRI) are considered less xerogenic. The antimuscarinic effect of the TCAs has been considered to be the principal mechanism causing a dry mouth. Although the muscarinic receptor is commonly targeted by xerogenic pharmaceuticals, the salivation reflex arc may be affected at other levels as well. We currently wondered whether or not antidepressants exert an inhibition of the salivary reflex not only at the glandular level but at a central level as well. In this study, the effects of a TCA (clomipramine), a SSRI (citalopram) and a serotonin-noradrenaline reuptake inhibitor (SNRI; venlafaxine) were examined on reflex- (0.5M citric acid applied on the tongue) and methacholine-evoked salivary secretion. While all three compounds inhibited citric acid-evoked secretion (-40 to -60% at 5mg/kg i.v. of the antidepressants), only clomipramine inhibited methacholine-evoked secretion (-30% at 5mg/kg i.v.). On the contrary, both citalopram and venlafaxine increased the methacholine-evoked secretion (+44 to 49%). This was particularly obvious for the salivary protein output (>200%). In the presence of α- and ß-adrenoceptor antagonists, the citalopram- and venlafaxine-induced increases were reduced. Thus, antidepressants irrespective of type may exert xerogenic effects by inhibiting the salivary reflex in the central nervous system. However, while TCAs may also hamper the secretory response by antimuscarinic effects, the SSRI and the SNRI groups of pharmaceuticals seem to lack this additional xerogenic mechanism indicating a better therapeutic profile and better opportunities for pharmacological treatment of drug-induced xerostomia.

The use of sterically stabilized liposomes to treat asthma.

Asthma is characterized by airway hyperresponsiveness, chronic inflammation, and airway remodeling, which may lead to progressive, irreversible lung damage. Liposomes have been used for the delivery of aerosolized asthma medications into the lungs. This method could facilitate sustained action of steroids while using only a fraction of the dosage and a less frequent dosing interval than conventional therapy. We describe the evaluation of the effect of budesonide encapsulated in sterically stabilized liposomes on lung inflammation and airway hyperreactivity in a mouse model of asthma. We outline the determination of markers implicated in the progression of asthma, including histopathology, eosinophil peroxidase activity in bronchoalveolar lavage, and airway hyperresponsiveness to methacholine. Weekly administration of budesonide in sterically stabilized liposomes results in a significant reduction in the total lung inflammation score, peripheral blood eosinophil counts, and the total serum IgE level, similar to that obtained with daily budesonide. Airway hyperresponsiveness to methacholine challenge decreases significantly in the group treated with weekly budesonide in sterically stabilized liposomes, while it does not decrease in the daily budesonide group.