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J Mallol

Publications and source records attributed to J Mallol.

At least 19 recordsLinked to original sources
PubMed2006

Receptor-receptor interactions involving adenosine A1 or dopamine D1 receptors and accessory proteins.

The molecular basis for the known intramembrane receptor-receptor interactions among heptahelical receptors (G protein coupled receptors, GPCR) was postulated to be heteromerization based on receptor subtype specific interactions between different types of homomers of GPCR. Adenosine and dopamine receptors in the basal ganglia have been fundamental to demonstrate the existence of receptor heteromers and the functional consequences of such molecular interactions. The heterodimer is only one type of heteromeric complex and the evidence is equally compatible with the existence of higher order heteromeric complexes, where also adapter proteins such as homer proteins and scaffolding proteins can exist, assisting in the process of linking the GPCR and ion channel receptors together in a receptor mosaic that may have special integrative value and may constitute the molecular basis for learning and memory. Heteromerization of D(2) dopamine and A(2A) adenosine receptors is reviewed by Fuxe in another article in this special issue. Here, heteromerization between D(1) dopamine and A(1) adenosine receptors is reviewed. Heteromers formed by dopamine D(1) and D(2) receptors and by adenosine A(1) and A(2A) receptors also occur in striatal cells and open new perspectives to understand why two receptors with apparently opposite effects are expressed in the same neuron and in the nerve terminals. The role of accessory proteins also capable of interacting with receptor-receptor heteromers in regulating the traffic and the molecular physiology of these receptors is also discussed. Overall, the knowledge of the reason why such complex networks of receptor-receptor and receptor-protein interactions occur in striatal cells is crucial to develop new strategies to combat neurological and neuropsychiatric diseases.

Animals↗
PubMed2005

CD26, adenosine deaminase, and adenosine receptors mediate costimulatory signals in the immunological synapse.

Adenosine deaminase (ADA), a protein whose deficit leads to severe combined immunodeficiency, binds to the cell surface by means of either CD26, A(1) adenosine receptors, or A(2B) adenosine receptors. The physiological role of these interactions is not well understood. Our results show that by a 3-fold reduction in the EC(50) for the antigen, ADA potentiated T cell proliferation in autologous cocultures with antigen-pulsed immature or mature dendritic cells. Costimulation was not due to the enzymatic activity but to the interaction of ADA-CD26 complexes in T cells with an ADA-anchoring protein in dendritic cells. From colocalization studies, it is deduced that ADA colocalizing with adenosine receptors on dendritic cells interact with CD26 expressed on lymphocytes. This costimulatory signal in the immunological synapse leads to a marked increase (3- to 34-fold) in the production of the T helper 1 and proimmflamatory cytokines IFN-gamma, TNF-alpha, and IL-6.

Adenosine Deaminase↗
PubMed2003

Aluminum-induced pro-oxidant effects in rats: protective role of exogenous melatonin.

In recent years, it has been suggested that oxidative stress is a feature of Alzheimer's disease in which aluminum (Al) could exacerbate oxidative events. The goal of the present study was to assess in rats the pro-oxidant effects induced by Al exposure, as well as the protective role of exogenous melatonin. Two groups of male rats were intraperitoneally injected with Al only or melatonin only, at doses of 5 and 10 mg/kg/day, respectively for 8 wk. During this period, a third group of animals received Al (5 mg/kg/day) and melatonin (10 mg/kg/day). At the end of the treatment period, rats were anesthesized and arterial blood was obtained. Thereafter, animals were killed and liver and brain (cortex, hippocampus and cerebellum) were removed. These tissues were processed to examine oxidative stress markers: glutathione transferase (GST), reduced glutathione (GSH), oxidized glutathione (GSSG), superoxide dismutase (SOD), glutathione reductase (GR), glutathione peroxidase (GPx), catalase (CAT), thiobarbituric acid reactive substances (TBARS), as well as protein content. Samples of these tissues were also used to determine Al, Fe, Mn, Cu and Zn concentrations. The results show that Al exposure promotes oxidative stress in different neural areas, including those in which Al concentrations were not significantly increased. The biochemical changes observed in neural tissues show that Al acts as pro-oxidant, while melatonin exerts an antioxidant action in Al-treated animals. The protective effects of melatonin against cellular damage caused by Al-induced oxidative stress, together with its low toxicity, make melatonin worthy of investigation as a potential supplement to be included in the treatment of neurological disorders in which the oxidative effects must be minimized.

Aluminum↗
PubMed2003

Agreement between written and video questions for comparing asthma symptoms in ISAAC.

Phase One of the International Study of Asthma and Allergies in Childhood (ISAAC) has reported the prevalence of asthma, rhinitis and eczema symptoms in children. In 99 centres from 40 countries, a total of just under 317,000 13-14-yr-old children also completed a video questionnaire, showing the symptoms and signs of asthma. This first video sequence has been compared to the ISAAC written question asking about current wheezing to explore variations in agreement and the contribution of each questionnaire to wheezing prevalence between centres, by region and language groups. In general, responses to the video questionnaire gave a lower prevalence than the siritten questionnaire and responses were closely correlated. The overall proportion of agreement was high, mean 0.89. but unbalanced, with good negative agreement but poor positive agreement. Chance corrected agreement using Cohen's kappa coefficient, was generally low, with onl 20 centres with kappa >0.4. The contribution of each questionnaire to wheezing prevalence also varied between centres and suggests that written questions about wheezing are variably understood and interpreted by 13-14 yr olds. International comparisons of wheezing and its audiovisual presentation suggest that adolescents interpret a written question about wheezing differently from its audiovisual presentation and that this interpretation shows variation between centres. This relationship and the interpretation of both written and audiovisual presentation of symptoms requires further study in order to better predict asthma.

Adolescent↗
PubMed2002

Parameters related to oxygen free radicals in erythrocytes, plasma and epidermis of the hairless rat.

The following parameters related to oxygen free radicals (OFR) were determined in erythrocytes and the epidermis of hairless rats: catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), reduced (GSH) and oxidized (GSSG) glutathione, glutathione S-transferase (GST), superoxide dismutase (SOD) and thiobarbituric acid reactive substances (TBARS). GSH, GSSG and TBARS were also analyzed in plasma. In erythrocytes, the Pearson correlation coefficients (r) were significant (p < 0.001) between glutathione and other parameters as follows: GSH correlated negatively with GSSG (r = -0.665) and TBARS (r = -0.669); GSSG correlated positively with SOD (r = 0.709) and TBARS (r = 0.752). Plasma GSSG correlated negatively with erythrocytic thermostable GST activity (r = -0.608; p=0.001) and with erythrocytic total GST activity (r = -0.677; p < 0.001). In epidermis (p < 0.001 in all cases), GSH content correlated with GSSG (r = 0.682) and with GPx (r = 0.663); GSSG correlated with GPx (r = 0.731) and with GR (r = 0.794). By multiple linear regression analysis some predictor variables (R(2)) were found: in erythrocytes, thermostable GST was predicted by total GST activity and GSSG, GSSG content was predicted by GSH and by the GSH/GSSG ratio and GPx activity was predicted by GST, CAT and SOD activities; in epidermis, GSSG was predicted by GR and SOD activities and GR was predicted by GSSG, TBARS and GPx. It is concluded that the hairless rat is a good model for studying OFR-related parameters simultaneously in blood and skin, and that it may provide valuable information about other animals under oxidative stress.

Animals↗
PubMed2001

Metabotropic glutamate 1alpha and adenosine A1 receptors assemble into functionally interacting complexes.

Recently, evidence has emerged that seven transmembrane G protein-coupled receptors may be present as homo- and heteromers in the plasma membrane. Here we describe a new molecular and functional interaction between two functionally unrelated types of G protein-coupled receptors, namely the metabotropic glutamate type 1alpha (mGlu(1alpha) receptor) and the adenosine A1 receptors in cerebellum, primary cortical neurons, and heterologous transfected cells. Co-immunoprecipitation experiments showed a close and subtype-specific interaction between mGlu(1alpha) and A1 receptors in both rat cerebellar synaptosomes and co-transfected HEK-293 cells. By using transiently transfected HEK-293 cells a synergy between mGlu(1alpha) and A1 receptors in receptor-evoked [Ca(2+)](i) signaling has been shown. In primary cultures of cortical neurons we observed a high degree of co-localization of the two receptors, and excitotoxicity experiments in these cultures also indicate that mGlu(1alpha) and A1 receptors are functionally related. Our results provide a molecular basis for adenosine/glutamate receptors cross-talk and open new perspectives for the development of novel agents to treat neuropsychiatric disorders in which abnormal glutamatergic neurotransmission is involved.

Animals↗
PubMed2001

Comodulation of CXCR4 and CD26 in human lymphocytes.

We provide convergent and multiple evidence for a CD26/CXCR4 interaction. Thus, CD26 codistributes with CXCR4, and both coimmunoprecipitate from membranes of T (CD4(+)) and B (CD4(-)) cell lines. Upon induction with stromal cell-derived factor 1alpha (SDF-1alpha), CD26 is cointernalized with CXCR4. CXCR4-mediated down-regulation of CD26 is not induced by antagonists or human immunodeficiency virus (HIV)-1 gp120. SDF-1alpha-mediated down-regulation of CD26 is not blocked by pertussis toxin but does not occur in cells expressing mutant CXCR4 receptors unable to internalize. Codistribution and cointernalization also occurs in peripheral blood lymphocytes. Since CD26 is a cell surface endopeptidase that has the capacity to cleave SDF-1alpha, the CXCR4.CD26 complex is likely a functional unit in which CD26 may directly modulate SDF-1alpha-induced chemotaxis and antiviral capacity. CD26 anchors adenosine deaminase (ADA) to the lymphocyte cell surface, and this interaction is blocked by HIV-1 gp120. Here we demonstrate that gp120 interacts with CD26 and that gp120-mediated disruption of ADA/CD26 interaction is a consequence of a first interaction of gp120 with a domain different from the ADA binding site. SDF-1alpha and gp120 induce the appearance of pseudopodia in which CD26 and CXCR4 colocalize and in which ADA is not present. The physical association of CXCR4 and CD26, direct or part of a supramolecular structure, suggests a role on the function of the immune system and the pathophysiology of HIV infection.

Adenosine Deaminase↗
PubMed2001

Therapeutic equivalence of three metered-dose inhalers containing salbutamol (Albuterol) in protecting against methacholine-induced bronchoconstriction in children with asthma.

Many pharmaceutical companies sell salbutamol in metered-dose inhalers (MDI) for the treatment of asthma. However, the therapeutic equivalence of the more recently released generic products has not been compared with the original patented product in children. Twenty children with mild to moderate asthma, presently asymptomatic and with normal lung function, were randomly allocated to receive 200 microg of inhaled salbutamol (Albuterol) from three MDIs prepared by different manufacturers: the original Glaxo product and two generic products. The three drug formulations and placebo were given 10 min before a methacholine challenge test to determine the degree of protection provided against methacholine-induced bronchoconstriction (MIB) by each salbutamol aerosol. Tests were performed on 4 consecutive days. Doubling concentrations of methacholine were inhaled until the forced expired volume in 1 sec (FEV(1)) decreased by 20% from its baseline value. Compared to placebo, all patients increased significantly the provocation concentration that decreased FEV(1) by 20% (PC(20)) by more than one doubling concentration after inhaling each of the three salbutamol aerosols. The effectiveness was not significantly different between medications (P = 0.8). There was a small but significant difference among MDIs in aerosol particle size and total and fine-particle dose released per actuation. However, no relation was found between aerosol particle size or released dose and the protective effect. This study shows that the three tested brands of salbutamol MDI protected asthmatic children equally from MIB. When prescribing these salbutamol MDIs to prevent symptoms triggered by nonspecific stimuli in asthmatic children, the selection may be based on cost-benefit criteria.

Adolescent↗
PubMed2001

Adenosine A2B receptors behave as an alternative anchoring protein for cell surface adenosine deaminase in lymphocytes and cultured cells.

Adenosine deaminase (ADA) is an enzyme of the purine metabolism that has been largely considered to be cytosolic. Recently, it has been demonstrated that the enzyme appears on the surface of lymphocytes where it interacts with the T-cell activation antigen CD26. ADA also appears on the surface of nonlymphoid cells anchored to adenosine A1 receptors. Here it is demonstrated that cell surface ADA in ADA+/CD26- T lymphocytes anchors to adenosine receptors of the A2B subtype (A2BR). An interaction between A2BR and cell surface ADA has been demonstrated in transfected Chinese hamster ovary cells and Jurkat J32 T lymphocytes. This has been proved by coimmunoprecipitation, binding of exogenous ADA to A2BR+ cells, and coimmunolocalization. The specificity of the interaction has also been demonstrated by the lack of interaction with other members of the G protein-coupled receptor superfamily. Binding of ADA to A2BR increases the affinity of the agonist 5'-N-ethylcarboxamidoadenosine and cAMP production. This effect occurs even when ADA devoid of enzyme activity is used. Therefore, in lymphocytes, cell surface ADA, apart from degrading extracellular adenosine, regulates those actions of adenosine that are mediated via adenosine receptors of the A2B subtype.

Adenosine Deaminase↗
PubMed2001

Involvement of caveolin in ligand-induced recruitment and internalization of A(1) adenosine receptor and adenosine deaminase in an epithelial cell line.

Chronic exposure of A(1) adenosine receptors (A(1)R) to A(1)R agonists leads to activation, phosphorylation, desensitization, and internalization to intracellular compartments of the receptor. Desensitization and internalization of A(1)R is modulated by adenosine deaminase (ADA), an enzyme that regulates the extracellular concentration of adenosine. ADA interacts with A(1)R on the cell surface of the smooth muscle cell line DDT1 MF-2, and both proteins are internalized following agonist stimulation of the receptor. The mechanism involved in A(1)R and ADA internalization upon agonist exposure is poorly understood in epithelial cells. In this report, we show that A(1)R and ADA interact in LLC-PK(1) epithelial cells. Exposure of LLC-PK(1) cells to A(1)R agonists induces aggregation of A(1)R and ADA on the cell surface and their translocation to intracellular compartments. Biochemical and cell biology assays were used to characterize the intracellular vesicles containing both proteins after agonist treatment. A(1)R and ADA colocalized together with the rafts marker protein caveolin. Filipin, a sterol-binding agent that disrupts rafts (small microdomains of the plasma membrane), was able to inhibit A(1)R internalization. In contrast, acid treatment of the cells, which disrupts internalization via clathrin-coated vesicles, did not inhibit agonist-stimulated A(1)R internalization. We demonstrated that A(1)R agonist N(6)-(R)-phenylisopropyl adenosine promotes the translocation of A(1)R into low-density gradient fractions containing caveolin. Furthermore, a direct interaction of the C-terminal domain of A(1)R with caveolin-1 was demonstrated by pull down experiments. These results indicate that A(1)R and ADA form a stable complex in the cell surface of LLC-PK(1) cells and that agonist-induced internalization of the A(1) adenosine receptor and ADA is mediated by clathrin-independent endocytosis.

Adenosine Deaminase↗
PubMed2001

International Study of Asthma and Allergies in Childhood (ISAAC): prevalence of asthma and asthma-related symptoms among Brazilian schoolchildren.

We have studied the prevalence of asthma and its symptoms using a standard written questionnaire (WQ) designed for the International Study of Asthma and Allergies in Children (ISAAC). The WQ (questions 1 through 8 related to asthma) was applied to 13,604 children aged 6-7 years from six Brazilian cities: Porto Alegre (South, N = 2,976), Curitiba (South, N = 1,664), São Paulo (Southeast, N = 3,005), Uberlândia (Southeast, N = 3,002), Itabira (Southeast, N = 1,551) and Recife (Northeast, N = 1,406). At the age of 13-14 years the WQ was applied to 20,554 schoolchildren living in Porto Alegre (South, N = 3,198), Curitiba (South, N = 3,008), São Paulo (Southeast, N = 3,008), Uberlândia (Southeast, N = 3,001), Itabira (Southeast, N = 2,134), Salvador (Northeast, N = 3,119) and Recife (Northeast, N = 3,086). The parents of the younger children answered the WQ, whereas the adolescents answered the questionnaire themselves. The response rates were 72% and 93% for the 6-7-year-old children and for the 13-14-year-old children, respectively. There was a slight predominance of male children in the population studied. In the group of 6-7-year-olds, the prevalence of physician diagnosed asthma was 7.3% for boys and 4.9% for girls: in the group of 13-14-year-olds the rates were 9.8% and 10.2%, respectively. Asthma severity was similar for both age groups, and wheezing following exercise was more frequent among the adolescents. In keeping with studies from other parts of the world, comparison between reported symptoms and diagnosed asthma revealed a significantly lower frequency of diagnosed asthma, suggesting that in the study population, asthma is underdiagnosed.

Adolescent↗
PubMed2000

Prevalence of asthma symptoms in Latin America: the International Study of Asthma and Allergies in Childhood (ISAAC).

The prevalence of respiratory symptoms indicative of asthma in children from Latin America has been largely ignored. As part of the International Study of Asthma and Allergies in Childhood (ISAAC), 17 centers in 9 different Latin American countries participated in the study, and data from 52,549 written questionnaires (WQ) in children aged 13-14 years and from 36,264 WQ in 6-7 year olds are described here. In children aged 13-14 years, the prevalence of asthma ever ranged from 5.5-28%, and the prevalence of wheezing in the last 12 months from 6.6-27%. In children aged 6-7 years, the prevalence of asthma ever ranged from 4.1-26.9%, and the prevalence of wheezing in the last 12 months ranged from 8.6-32.1%. The lower prevalence in centers with higher levels of atmospheric pollution suggests that chronic inhalation of polluted air in children does not contribute to asthma. Furthermore, the high figures for asthma in a region with a high level of gastrointestinal parasite infestation, and a high burden of acute respiratory infections occurring early in life, suggest that these factors, considered as protective in other regions, do not have the same effect in this region. The present study indicates that the prevalence of asthma and related symptoms in Latin America is as high and variable as described in industrialized or developed regions of the world.

Adolescent↗
PubMed2000

The heat shock cognate protein hsc73 assembles with A(1) adenosine receptors to form functional modules in the cell membrane.

A(1) adenosine receptors (A(1)Rs) are G protein-coupled heptaspanning receptors that interact at the outer face of the plasma membrane with cell surface ecto-adenosine deaminase (ecto-ADA). By affinity chromatography the heat shock cognate protein hsc73 was identified as a cytosolic component able to interact with the third intracellular loop of the receptor. As demonstrated by surface plasmon resonance, purified A(1)Rs interact specifically with hsc73 with a dissociation constant in the nanomolar range (0.5 +/- 0.1 nM). The interaction between hsc73 and A(1)R led to a marked reduction in the binding of the ligands and prevented activation of G proteins, as deduced from (35)S-labeled guanosine-5'-O-(3-thio)triphosphate binding assays. Interestingly this effect was stronger than that exerted by guanine nucleotide analogs, which uncouple receptors from G proteins, and was completely prevented by ADA. As assessed by immunoprecipitation a high percentage of A(1)Rs in cell lysates are coupled to hsc73. A relatively high level of colocalization between A(1)R and hsc73 was detected in DDT(1)MF-2 cells by means of confocal microscopy, and no similar results were obtained for other G protein-coupled receptors. Colocalization between hsc73 and A(1)R was detected in specific regions of rat cerebellum and in the body of cortical neurons but not in dendrites or synapses. Remarkably, agonist-induced receptor internalization leads to the endocytosis of A(1)Rs by two qualitatively different vesicle types, one in which A(1)R and hsc73 colocalize and another in which hsc73 is absent. These results open the interesting possibility that signaling via G protein-coupled receptors may be regulated by heat shock proteins.

Adenosine Deaminase↗
PubMed2000

[Prevalence of asthma in Chilean students. Descriptive study of 24,470 children. ISAAC-Chile].

BACKGROUND: There is little information about the prevalence of asthma in Latin American children. AIM: To determine the prevalence of asthma among Chilean school age children. SUBJECTS AND METHODS: The prevalence of respiratory symptoms related to asthma in schoolchildren aged 7 and 13 years, coming from South Santiago, Central Santiago, Valdivia and Punta Arenas, was determined using the methodology of the International Study on Asthma and Allergies in Childhood (ISMC). A random sample of school children aged 6-7 and 13-14 years from each locality was selected. This resulted in 24)470 surveyed children (11,723 aged 6-7 years and 12,747 aged 13-14 years). RESULTS: The current prevalence of wheezing ("wheezing in the last 12 months") ranged from 16.5% to 20.0% in children aged 67 years, and from 6.8% to 11.7% in children aged 13-14 years. The cumulative prevalence of asthma ("asthma ever"), ranged from 9.7% and 16.5% in the 6-7 years group and from 7.3% to 12.4% in those aged 13-14 years. CONCLUSIONS: This study found much higher figures for prevalence of respiratory symptoms related to asthma in school children than those previously reported in this country, with a significant variability between centers (p < 0.05). The prevalence of asthma in Chilean schoolchildren is as high and variable as that reported in industrialized countries.

Adolescent↗
PubMed1999

Epidermal growth factor (EGF)-induced up-regulation and agonist- and antagonist-induced desensitization and internalization of A1 adenosine receptors in a pituitary-derived cell line.

This report concerns the study of homologous and heterologous regulation of cell surface A1 adenosine receptors (A1R) in a pituitary-derived cell line. This has been possible by the use of the recently developed anti-A1R antibodies in immunocytochemical assays. Functional desensitization and internalization of A1R in GH4 cells occurred after treatment with agonist but also with antagonist. Epidermal growth factor (EGF) treatment led to the up-regulation of cell surface A1R in GH4 cells. Confocal analysis evidenced an EGF-induced increase of A1R present in intracellular clathrin-coated vesicles. The up-regulation was blocked by actinomycin D thus suggesting the involvement of protein synthesis in the effect induced by the growth factor. These results constitute the first example of adenosine receptor regulation by EGF and one of the few examples of antagonist-induced desensitization and internalization among G-protein-coupled receptors.

Adenosine↗
PubMed1999

Early effects of inhaled steroids on airway hyperreactivity and pulmonary function in asthma.

While inhaled steroids (IS) are increasingly recognized as having a more rapid onset of action than was once thought, little is known about the early changes in objective measures of respiratory function that follow the inhalation of repeated doses. These early effects were examined in a randomized, double-blind, placebo-controlled, crossover study of 20 children aged 10-16 years with stable mild asthma. Beclomethasone dipropionate (BDP) 2,000 mcg, fluticasone propionate (FP) 400 mcg, and placebo were given twice daily for three doses. Airway hyperreactivity (AHR) to methacholine (PC20), pulmonary function tests (PFT: FVC, FEV1, FEF25-75%), and the rate of recovery from methacholine-induced bronchospasm following administration of salbutamol were determined at 8 h (after 1 dose) and at 32 h (after three doses). At 8 h, minor improvements in AHR were demonstrated, averaging 0.32 doubling doses in PC20. At 32 h, significant improvements in AHR and PFTs were present, averaging 0.92 doubling doses in PC20, 3.96% of predicted values in FEV1, and 7.74% of predicted values in FEF25-75%. No significant changes occurred in FVC. There were no significant differences between the effects of BDP and FP. Inhaled steroids were associated with a slower response to salbutamol following methacholine challenge testing at 32 h. We conclude that IS, given in repeated high doses, result in significant improvements within 32 h in both AHR and PFTs, along with changes in response to beta2 agonists. These effects are likely to be the result of the topical activity of IS.

Administration, Inhalation↗
PubMed1999

Effect of different inhaled bronchodilators on recovery from methacholine-induced bronchoconstriction in asthmatic children.

Two hundred fourteen children with mild to moderate asthma were studied to determine bronchodilator effects 5 min after administration of five different metered dose inhaler (MDI) aerosol formulations available in our country, and results were compared to placebo. Methacholine bronchial challenge was performed by the tidal breathing method, using increasing concentrations until a fall in forced expired volume in 1 s (FEV(1)) >/=20% was achieved (PC20). Immediately after FEV(1) had fallen 20% or more, children were randomly allocated into 1 of 6 groups to receive: salbutamol 200 microg (S), fenoterol 200 microg (F), salbutamol 200 microg + beclomethasone 100 microg (S + B), fenoterol 200 microg + ipratropium bromide 80 microg (F + IB), salmeterol 50 microg (SM), and placebo (P). The bronchodilator effect was determined by measuring FEV(1) 5 min after inhalation of medications. Nonparametric tests were used for statistical analysis. The six groups were similar in anthropometric and in respiratory characteristics. All five inhaled aerosols containing beta-agonists caused a significant bronchodilator effect as compared to placebo. However, the effect was significantly greater in the groups treated with F or F + IB (P < 0.05) compared to other formulations. We conclude that the five types of aerosols used in this study are able to reverse methacholine-induced bronchoconstriction 5 min after inhalation of a bronchodilator.

Administration, Inhalation↗