Biomedical subjects

M Molimard

Publications and source records attributed to M Molimard.

53 records · Page 3Linked to original sources

PubMed1995

Furosemide inhibits bradykinin-induced contraction of human bronchi: role of thromboxane A2 receptor antagonism.

Bradykinin contracts human isolated small bronchi through prostanoid release and subsequent TP receptor stimulation. Furosemide 10(-4) to 10(-3) M concentration dependently inhibited bradykinin- and the stable TP receptor agonist U-46619-induced contraction of human isolated small airways. The inhibitory effect of furosemide on U-46619-induced contraction involves competitive antagonism at TP receptors. Such an inhibition of TP receptors could a least partly explain the inhibitory effect of furosemide on bradykinin-induced contraction, and could be one of the mechanisms of the protective effect of furosemide in asthma.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1995

Role of thromboxane A2 in bradykinin-induced human isolated small bronchi contraction.

We previously demonstrated that the bradykinin-induced contraction of human isolated small bronchi is inhibited by indomethacin, capsaicin (N-methyl-N-6-nonenamide) and ruthenium red but not by tachykinin receptor antagonists. The thromboxane A2 receptor (TP receptor) antagonist GR32191 ((1R-(1 alpha(Z),2 beta,3 beta,5 alpha))-(+)-7-(5-(((1,1'-biphenyl)-4-yl)- methoxy)-3-hydroxy-2-(1-piperidinyl)cyclopentyl)-4-heptenoic acid, hydrochloride) (10(-10) to 10(-8) M) dose dependently inhibited the effect of bradykinin, suggesting the mediation of the TP receptor in the action of bradykinin. With higher concentrations of GR32191 (10(-7) and 10(-6) M) bradykinin induced a relaxation which was inhibited by indomethacin and by the bradykinin B2 receptor antagonist Hoe 140 (D-Arg0[Hyp3,Thi-5,D-Tic7,Oic8]bradykinin). The thromboxane A2 synthase inhibitor dazoxiben (4-(-2-(1H-imidazol-1-yl)ethoxy) benzoic acid hydrochloride) 10(-6) M inhibited the bradykinin-induced contraction, suggesting that thromboxane A2 was involved in TP receptor stimulation. The thromboxane A2 mimetic U-46619 (9,11-dideoxy-11 alpha,9 alpha-epoxy-methano-prostaglandin F2 alpha)-induced contraction of human distal bronchi was not inhibited by capsaicin and ruthenium red. Our data suggest that bradykinin contracts human isolated small bronchi through thromboxane A2 release. The inhibitory effect of ruthenium red and capsaicin on the bradykinin response may be due to inhibition of thromboxane A2 release or arachidonic mobilisation.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1995

In vitro effects of HOE 140 in human bronchial and vascular tissue.

Bradykinin is a potent inflammatory mediator which may be involved in various airway diseases. A selective and potent antagonist of the bradykinin B2 receptor has recently been discovered (HOE 140: D-Arg-[Hyp3,Thi5,D-Tic7,Oic8]bradykinin). The purpose of this study was to evaluate the potency of this compound in isolated human tissue (bronchus, pulmonary artery endothelium, umbilical artery and vein smooth muscle). Bradykinin induced contractions of the isolated human bronchus and umbilical artery and vein (the umbilical vessels were pretreated with indomethacin and L-nitro-arginine to inhibit prostaglandin and nitric oxide synthesis). It provoked an endothelium-dependent relaxation in the human pulmonary artery. HOE 140 was a non-competitive antagonist in human bronchial tissue (pKB: 8.19 +/- 0.30) and a competitive one in vascular tissue (pA2: 7.97 +/- 0.12, 8.16 +/- 0.16 and 8.00 +/- 0.11 in human pulmonary artery, umbilical artery and vein respectively). The effect of HOE 140 was selective as it did not influence the umbilical vein contractile response to serotonin and histamine. HOE 140 up to 3 x 10(-6) M was devoid of residual agonistic activity in the various human preparations studied. Furthermore, although the effects of HOE 140 were fully reversible, in isolated bronchial airways and umbilical veins, HOE 140 (10(-6) M) still possessed activity 1 h after being washed out in both tissues. Our results indicate that HOE 140 is a potent and potentially long-acting antagonist of the human bradykinin B2 receptor.

Binding Sites↗

PubMed1995

Analysis of the immunological humoral response to Mycobacterium tuberculosis glycolipid antigens (DAT, PGLTb1) for diagnosis of tuberculosis in HIV-seropositive and -seronegative patients.

Using an enzyme immunoassay (EIA) test, the concentrations of IgG antibodies against 2,3 diacyl trehalose (DAT) and phenolic glycolipid Tb1 (PGLTb1) were measured in the sera of 153 patients with active tuberculosis, 50 of whom were coinfected with HIV, and in the sera of 152 healthy blood donors, 149 asymptomatic HIV-seropositive patients, 12 HIV-seronegative patients with conditions simulating tuberculosis, 23 HIV-seropositive patients with disseminated infection caused by mycobacteria other than tuberculosis and 24 HIV-seropositive patients with pulmonary disease from whom mycobacteria was not isolated in culture. A slightly lower percentage (74%) of the HIV-seropositive than the HIV-seronegative (77%) tuberculosis patients were positive for anti-DAT and anti-PGLTb1 IgG antibodies, with a specificity ranging from 91 to 95%. There was no significant difference between EIA sensitivity in smear-positive and smear-negative patients with pulmonary tuberculosis for all HIV immune statuses and sites of disease (pulmonary vs. extrapulmonary). In HIV-seropositive patients, however, sensitivity was always lower for disseminated tuberculosis than for localized tuberculosis. Combining data for both the smear test and the EIA maximized sensitivity. The main value of the EIA test could be to provide early complementary information by antibody detection in patients with tuberculosis, particularly those with a negative smear test.

Adult↗

PubMed1994

Contractile effects of bradykinin on the isolated human small bronchus.

Bradykinin (Bk) induced a contraction in all small bronchi samples (diameter, 0.5 to 1 mm) from 20 patients. pD2 was 7.7 +/- 0.1 (pD2 = -log EC50) and maximal effect (Emax) was 36.2 +/- 4.7% of the maximal response to acetylcholine. The B2 agonist [Hyp3TyrMe8]Bk contracted airway smooth muscle with a pD2 of 7.8 +/- 0.2 and an Emax of 39 +/- 9%. The B1 agonist [Sar1dPhe8desArg9]Bk induced only a weak contraction at 10(-6) M. The effect of Bk was abolished by the B2 (Hoe 140) but not by the B1 [Leu8desArg9]Bk receptor antagonist. Indomethacin 10(-6) M abolished Bk-induced contraction, suggesting that cyclooxygenase products are involved in Bk action. Capsaicin 10(-5) M, which selectively depletes C fibers from airway mediators through the ruthenium red pathway, and ruthenium red 10(-5) M significantly inhibited the concentration-response curves to Bk. However, tetrodotoxin (+/-)-CP-96,345, SR 48968, and atropine did not significantly affect Bk concentration-response curves, suggesting that nerve conduction, substance P (SP), neurokinin A (NKA), and acetylcholine release are not involved in Bk action. Our data indicate that Bk contracts human distal airway smooth muscle through the Bk B2 receptor and a cyclooxygenase pathway. This effect appears to involve capsaicin and ruthenium red pathways but neither acetylcholine nor NKA and SP release.

Acetylcholine↗

PubMed1994

Effect of furosemide on prostaglandin synthesis by human nasal and bronchial epithelial cells in culture.

Inhaled furosemide protects asthmatic subjects against bronchial obstruction caused by indirect provocants. We have attempted to correlate the protective effect of furosemide with its ability to alter prostaglandin (PG) synthesis by the airway epithelium. Human epithelial cells from nasal polyps and bronchi were cultured in DME-Ham's F12 medium with 10% fetal calf serum. Confluent cells (days 6 through 8) were incubated for 30 min in fresh medium, and the PGs in the supernatant were measured by radioimmunoassay. Spontaneous output (ng.ml-1.mg-1 cell protein) was as follows (mean +/- SEM): PGE2 = 7.74 +/- 2.10 (n = 12), PGF2 alpha = 1.66 +/- 0.12 (n = 15), 6-keto-PGF1 alpha = 4.32 +/- 1.37 (n = 11), PGD2 = 0.73 +/- 0.16 (n = 11) for bronchial cells and PGE2 = 7.24 +/- 0.80 (n = 32), PGF2 alpha = 1.38 +/- 0.12 (n = 17), 6-keto-PGF1 alpha = 6.79 +/- 2.50 (n = 15), PGD2 = 0.42 +/- 0.07 (n = 17) for nasal cells. Incubation with arachidonic acid (25 micrograms/ml) for 30 min significantly increased the amounts of the four PGs. Incubation with furosemide (10(-4) M) for 30 min caused a marked reduction in both basal and arachidonic acid-stimulated production of PGE2 and PGF2 alpha but did not reduce production of 6-keto-PGF1 alpha and PGD2. Incubation with bumetanide (10(-4) M) for 30 min did not modify the PGE2 synthesis by nasal epithelial cells.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗

PubMed1994

Rolipram, but not siguazodan or zaprinast, inhibits the excitatory noncholinergic neurotransmission in guinea-pig bronchi.

Theophylline has been reported to inhibit excitatory noncholinergic but not cholinergic-neurotransmission in guinea-pig bronchi. As theophylline might exert this effect through an inhibition of phosphodiesterases (PDE), and since many types of PDE have now been described, the aim of this study was to investigate the effects of three specific inhibitors of PDE on the electrical field stimulation (EFS) of the guinea-pig isolated main bronchus in vitro. The drugs used were siguazodan, rolipram and zaprinast, which specifically inhibit PDE types, III, IV and V, respectively. Guinea-pig bronchi were stimulated transmurally with biphasic pulses (16 Hz, 1 ms, 320 mA for 10 s) in the presence of indomethacin 10(-6) M and propranolol 10(-6) M. Two successive contractile responses were observed: a rapid cholinergic contraction, followed by a long-lasting contraction due to a local release of neuropeptides from C-fibre endings. Rolipram (10(-9) to 10(-6) M) but not siguazodan or zaprinast, inhibited the peptidergic contraction in a concentration-dependent manner. Conversely, the cholinergic response was unaffected. Contractile responses induced by exogenous acetylcholine (10(-8) to 10(-3) M) or [Nle10]NKA(4-10) (10(-10) to 10(-6) M) were also unaffected by rolipram, siguazodan and zaprinast (10(-7) M). These results demonstrate that concentrations of rolipram, similar to those which inhibit PDE, reduce the release of sensory neuropeptides from C-fibre endings, and suggest that the cyclic adenosine monophosphate (AMP) PDE type IV is specifically involved in this effect, as in other anti-inflammatory effects.

Animals↗

PubMed1993

Effect of frusemide on bradykinin- and capsaicin-induced contraction of the guinea-pig trachea.

Frusemide, a loop diuretic, inhibits the bronchial response to various bronchoconstrictor stimuli in asthmatic subjects. The underlying mechanisms remain unclear. In order to determine whether frusemide inhibits pharmacologically induced C-fibre stimulation, we investigated the effect of frusemide on bradykinin-, capsaicin-, neurokinin A-, and substance P-induced contraction of the guinea-pig isolated trachea. Frusemide 10(-5) and 10(-4) M produced a significant inhibition of concentration-response curves to bradykinin, which was markedly reduced by indomethacin 10(-6) M. Frusemide significantly reduced capsaicin-induced contraction only in the presence of indomethacin 10(-6) M. Neurokinin A- and substance P-induced contractions were not affected by frusemide and/or indomethacin. Our data suggest that a cyclo-oxygenase pathway is involved in the inhibition by frusemide of the bradykinin-induced contraction, but not in the inhibition of the capsaicin-induced contraction.

Animals↗

PubMed1993

[Novelties and perspectives in asthma medicines].

Numerous works are devoted to the search for new classes of medication with the goal of promoting more efficacious and better tolerated drugs. Besides long-acting beta-2-adrenergic stimulants which are undergoing commercial development and whose indications are yet to be defined, one can distinguish several therapeutic classes which are undergoing research and development. Specific phosphodiesterase inhibitors of smooth bronchial muscle would have similar effects to theophylline with reduced side-effects. The potassium channel openers have a very powerful broncho-dilator action but the molecules studied are not specific for the bronchi and still have too many side-effects. Antagonists of tachykinins open research avenues in physiopathology and may have a therapeutic application. Anti-leukotrienes by their anti-inflammatory effect, would have a steroid sparing effect.

Adrenergic beta-Agonists↗

PubMed1992

Formoterol and salbutamol inhibit bradykinin- and histamine-induced airway microvascular leakage in guinea-pig.

1. The effects of the beta 2-adrenoceptor agonists, salbutamol and formoterol, on the increase of microvascular permeability induced by histamine or bradykinin in guinea-pig airways have been studied in vivo. Extravasation of intravenously injected Evans blue dye was used as an index of permeability. The effects of salbutamol and formoterol on the increase in pulmonary airway resistance induced by histamine or bradykinin have also been studied. 2. The increase in pulmonary airway resistance induced by histamine or bradykinin was totally inhibited by salbutamol and formoterol. The ED50 of the two mediators were 0.59 +/- 0.21 (n = 5) and 0.20 +/- 0.14 (n = 5) micrograms kg-1 respectively for salbutamol, and 0.13 +/- 0.12 (n = 6) and 0.02 +/- 0.01 (n = 6) micrograms kg-1 respectively for formoterol. 3. Salbutamol (10 and 30 micrograms kg-1) and formoterol (1 and 10 micrograms kg-1) inhibited the increase of microvascular permeability induced by histamine (30 micrograms kg-1) in the guinea-pig airways. The inhibitory effect was predominant in the trachea and the main bronchi, with a maximum inhibition of 20 to 50%. The two drugs had little or no inhibitory effect on the other structures studied, viz. nasal mucosa, larynx, proximal and distal intrapulmonary airways. 4. Salbutamol and formoterol (1 and 10 micrograms kg-1) abolished the increase in microvascular permeability induced by bradykinin (0.3 micrograms kg-1). This inhibitory effect of two beta-adrenoceptor stimulants was predominant in the trachea and the nasal mucosa where it was observed with 1 microgram kg-1 of the beta-adrenoceptor agonists.In the main bronchi, and in the proximal and distal intrapulmonary airways, the effects of bradykinin were abolished by 10 pg kg- of formoterol and salbutamol.5. The effects of bradykinin, but not those of histamine, were significantly reduced (nasal mucosa, main bronchi and distal intrapulmonary airways) or abolished (trachea, proximal intrapulmonary airways) by morphine 10mgkg-1, i.v. These results suggest that an indirect effect, through non-adrenergic noncholinergic (NANC) nerves is involved in the action of bradykinin on the microvascular permeability.6. In conclusion, intravenously injected beta-adrenoceptor stimulants can inhibit, partially or totally, the increase of airways microvascular permeability induced by intravenous histamine or bradykinin. However, these effects require doses that are higher than those that inhibit the increase in pulmonary airway resistance induced by these mediators. As suggested by the results obtained with morphine, the higher efficacy of beta2-adrenoceptor agonists versus bradykinin may occur through activation of presynaptic receptors of the non-adrenergic non-cholinergic (NANC) nerves preventing release of inflammatory neuropeptides such as substance P and neurokinin A.

Adrenergic beta-Agonists↗

PubMed1992

[Occurrence of an epidermoid bronchial carcinoma 8 years after a small cell carcinoma treated with only 3 courses of chemotherapy].

A case of squamous cell bronchial carcinoma developed 8 years after treatment of a small cell carcinoma is reported. Three hypotheses may be put forward to explain this sequence of events: either a squamous cell line was selected from within an initially mixed tumour, or the small cell carcinoma differentiated into a squamous cell carcinoma, or a second primary tumour developed independently. All this is purely speculative, but the long doubling time implied by the first two hypotheses would be in favour of a second primary tumour.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1990

[Methods of stopping smoking].

The majority of smokers who stop smoking do it alone. The methods of stopping are aimed at helping those who cannot achieve this. The different methods used include psycho-therapy (individual-group), medication, and in the first place is nicotine chewing-gum (but also clonidine which opens a new perspective), aversive behaviour and reinforcement methods, hypnosis and acupuncture. The inadequacy of validated controlled trials by biological measurements makes it difficult to compare different methods. The levels of cessation evaluated varies as a function of recruitment, the relationship between the patient and the therapist, and between the association of the different methods. An important factor in the success resides in the motivation of the subjects explaining that the bias of recruitment readily lead to differences in the results which are superior to the action of the therapy itself. Associated to psychotherapy is the use of nicotine chewing-gum in pharmacologically dependent smokers, and seems to give good enough results. Behavioural methods have an important early success level but these are somewhat deceiving in the long-term and are not totally without risk. Acupuncture, hypnosis and the progressive reduction in nicotine levels (nicotine fading) requires controlled studies to judge their own efficacy. The frequency of failure in the first year remains the major current problem in the methods of stopping. It is convenient not only to develop maintenance strategies but also at the sociological level to diminish the environmental pressures inciting people to smoke.

Acupuncture Therapy↗

PubMedDate not supplied

[Approach to bronchial hyperreactivity in vitro].

The isolated human bronchus model is interesting for the study of drug-receptor interactions in 'normal' preparations. Several attempts have been made to prepare in vitro models of airway hyperresponsiveness close to the pathophysiology of asthma. In this paper, we shall present some results obtained with LPS and interleukin 1 beta (IL-1 beta). LPS (100 ng/ml, for 3 to 6 h) or IL-1 beta potentiated bradykinin and the tachykinin NK-1 selective receptor agonist [Sar9, Met-O2] SP -induced human isolated bronchi contraction in vitro (IL-1 beta 3 10(-10) M, at 37 degrees C for 1 to 3 h for bradykinin or at 21 degrees C for 15 h for [Sar9, Met-O2] SP in Krebs-Henseleit solution). As in control bronchi, the effects of bradykinin and of [Sar9, Met-O2] SP after interleukin 1 beta pre-treatment were abolished by indomethacin (10(-6) M), the thromboxane A2 receptor antagonist GR 32191 suggesting that prostanoids remain involved under these experimental conditions. Although bradykinin and [Sar9, Met-O2] SP -induced contractions were mediated by thromboxane receptor stimulation, the thromboxane A2 (TxA2) mimetic U46619 induced contraction of human bronchi was not enhanced by IL-1 beta pre-treatment. The cyclooxygenase 2 (cox 2) inhibitor GGP 28238 (10(-6) M) inhibited IL-1 beta-induced potentiation of [Sar9, Met-O2] SP but not of bradykinin effect. Bradykinin and [Sar9, Met-O2] SP induced a release of TxB2, the stable metabolite of TxA2, in the organ bath and this release was increased by IL-1 beta pre-treatment. Bradykinin-induced release of 6 keto prostaglandin F1 alpha (the stable metabolite of prostaglandin I2) was not enhanced by IL-1 beta. Taken together, our results suggest that IL-1 beta is able to potentiate the effect of bradykinin or tachykinin receptor agonists on the human isolated bronchus. Several mechanisms might be involved, including an increase of thromboxane synthase synthesis and/or activity in the case of bradykinin and of short term incubation (3 h, 37 degrees C) or an increase of synthesis and/or activity of cox-2 for tachykinin and for long-term incubation (15 h, 21 degrees C).

Asthma↗

PubMedDate not supplied

[Research on inflammatory mediators in asthma: new therapeutic approaches].

During the National Meeting of Clinical Pharmacology (Giens 1998), the working group exchanged information and examined the new therapeutic approaches to inflammation in asthma. The group performed a state of the art review of the current research on mediators of bronchial inflammation to determine new pharmacological targets of therapeutic interest. An update on the development of potential drugs acting on these targets was established. Specificities related to asthma in terms of evaluation and development of anti-inflammatory drugs were discussed. The place of pharmaco-economy in the development of anti-asthmatic drugs was specified.

Anti-Asthmatic Agents↗

PubMedDate not supplied

[Plasmatic dosage of antiretroviral drugs by high performance liquid chromathography ].

A high-performance liquid chromatographic method has been developed for the determination of eight antiretroviral drugs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, efavirenz and nevirapine) in a single run. After a liquid-liquid extraction with diethylether, the antiretroviral drugs are separated on a Stability RP18 column eluted with a gradient of acetonitrile and phosphate buffer (50 mM pH 5.65). A sequential ultraviolet detection allowed for simultaneous quantitation of antiretroviral drugs (240, 215, 260 nm). Calibration curves were linear in the range 100-10,000 ng/ml. The limit of quantitation was 50 ng/ml for all drugs except for nevirapine (100 ng/ml). The accuracies ranged from 88.2% to 110.9% and both inter- and intra-day coefficients of variation were lower than 11%. The extraction recoveries were higher than 62%. This method is simple and shows good specificity with respect to commonly coprescribed drugs.

Anti-HIV Agents↗

PubMedDate not supplied

[Tuberculosis: a new priority].

Tuberculosis is one of the most widespread diseases affecting more than 8 million subjects. The death toll has been estimated at 3 million persons annually. In France, the incidence in 1991 was 15 per 100,000 inhabitants with wide regional variation (37 per 100,000 in Paris and surrounding areas). It is difficult to interpret variations in incidence which would appear to be on the rise since 1993. (The increase may be a real rise in incidence or simply due to better registration as a result of reports of HIV infection.) In industrialized countries, economic factors, movements in populations, restrictive policies in antituberculosis health care and HIV infection are all factors leading to an increased incidence in tuberculosis. These observations strongly suggest the need for reorganizing our health care policy in the fight against tuberculosis, improving modern techniques in bacteriological identification and imagining new modalities of prevention and treatment. Special emphasis must be placed on research still required before this curable disease can be eradicated.

AIDS-Related Opportunistic Infections↗

PubMedDate not supplied

Use of formoterol dry powder administered for three months via a single-dose inhaler in 1,380 asthmatic patients.

Formoterol is a long-acting beta 2-adrenoceptor agonist available in a single-dose breath-actuated device (Foradil) for asthma treatment. Since efficacy and ease of use are key factors for compliance to therapy, the aim of this study was to assess correct use, efficacy and safety of Foradil in a 3-month, open, uncontrolled, multicenter trial. This study was performed on 1,380 patients with moderate or severe persistent asthma treated with inhaled corticosteroid (age: 48.4 +/- 16.2 years; FEV1: 65.4 +/- 19.4% of normal). During the study, compliance was over 90%. More than 90% of the patients used the inhaler correctly and found it easy or very easy to use. The mean increase in peak expiratory flow rate (PEFR), 30 to 60 min after inhalation, was 52.3 and 36.7 l/min for the morning and the evening respectively (p = 0.0001). This increase was already significant 5 min after inhalation, confirming the fast onset of action of formoterol. Mean predose PEFR and daytime/nocturnal symptom scores improved during the length of the study. Rescue short-acting beta 2-agonist consumption was more than three times reduced. At study completion, formoterol dosage was 12 micrograms and 24 micrograms twice daily for 71.5% and 28.5% of the patients respectively. Physicians judged the overall efficacy as good or very good in 87.1% of the patients, and they estimated the tolerability as very good or good in 92.6%. Drug-related adverse events were similar to those of other beta 2-agonists. In conclusion, this study demonstrated the ease of use of this formoterol single-dose dry powder inhaler, and confirmed the good efficacy and safety profile of this long-acting bronchodilator in asthma.

Administration, Inhalation↗