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Biomedical subjects

D Morin

Publications and source records attributed to D Morin.

At least 145 records · Page 8Linked to original sources
PubMed1990

Variations of airway responsiveness to methacholine and exercise in asthmatic and normal subjects over a 12-month period.

This study looked at seasonal fluctuations of airway responsiveness (AR) to methacholine and exercise in ten mild asthmatic and seven normal subjects. Each subject had a monthly methacholine inhalation test. An exercise challenge with measurement of expiratory flows was performed initially in the fall (F), then in winter (W), and in summer (S). Throughout the study, the subjects were asked to record on a diary card twice daily peak flow rates and respiratory symptoms, one week a month. Airway responsiveness to exercise and methacholine remained generally stable throughout the year, although an increase in respiratory symptoms occurred during fall and winter. The overall AR to methacholine was not significantly different during the different seasons (F, W, S and Spring) with the methacholine concentration producing a 20% fall in FEV1, PC20 (mg/ml) values, respectively, of 1.7 +/- 1.2 mg/ml, 1.8 +/- 1.1, 2.1 +/- 1.2, and 2.0 +/- 1.9 for asthmatics and 79.0 +/- 1.2 mg/ml, 66.8 +/- 1.0, 87.3 +/- 1.0, and 73.1 +/- 1.0 for normals. However, short term variations in AR were associated to exposure to antigens and cold weather. Mean daily peak expiratory flows remained generally stable through the seasons. On the three exercise tests, the VO2 max and the mean % fall in FEV1 after maximal exercise showed large variations; these, however, were not significantly different (mean fall: 16.2% (F), 16.6% (W), and 14.7% (S) in asthmatics). In conclusion, although it may increase transiently, overall airway responsiveness to methacholine and exercise remains generally stable in asthmatic and normal subjects throughout the year.

Adult↗
PubMed1990

Metabolic activation and bronchiolar Clara cell necrosis from naphthalene in the isolated perfused mouse lung.

A method for isolation and maintenance of the mouse lung ex vivo suitable for the study of the relationship between metabolism and toxicity is described. Physical, biochemical and morphological evaluations revealed that the lung is viable for up to 5 hr. No significant alterations in the architecture of the bronchiolar epithelium were observed by light or electron microscopy, despite evidence of interstitial and peribronchial edema. Although increases in pulmonary arterial pressure were noted at 5 hr, lung wet/dry weight was elevated only minimally (11%). Glutathione levels remained stable for the first 3 hr but fell to 57 +/- 14% of control at 5 hr. Naphthalene monooxygenase activity was not altered significantly during 5 hr of perfusion. Perfusion of the lung with naphthalene resulted in swelling and vacuolation of Clara cells followed by concentration-dependent losses of this cell type from the bronchiolar epithelium. Clara cells comprised 63% of the epithelial cells in terminal airways of control mice; 10 mumol of naphthalene decreased this number to 30%. Perfusion with naphthalene resulted in concentration-dependent decreases in pulmonary glutathione. Reactive metabolites were bound covalently to protein in the lung and in the perfusate. This study is the first to provide unambiguous evidence that naphthalene-induced Clara cell necrosis can be mediated entirely by processes resident in the lung. In addition, this work validates the use of the isolated perfused mouse lung for studying the role of reactive metabolites produced in situ vs. those entering the lung via the circulation.

Animals↗
PubMed1989

Isolated phrenic nerve injury after apparently atraumatic puncture of the internal jugular vein.

Vascular lesions due to subclavian and internal jugular vein puncture may result in hematomas, which are usually clinically evident. While mostly benign, some of these hematomas can cause compression of the surrounding structures. When the hematoma is obvious, straightforward correlation can be made between the symptoms, for instance nerve compression, and the clinical signs. We present a case where we missed the diagnosis of phrenic nerve paralysis, which occurred after an unsuccessful, but apparently atraumatic attempt to puncture the internal jugular vein, prior to cardiac surgery. At the time the diagnosis was made (8 days post-op), the radiographic appearance of the neck was normal, and further investigation (i.e., CT-scan) had become pointless. A retrospective study of serial chest X-rays disclosed a space occupying lesion in the right lateral neck that displaced the nasogastric tube. This abnormality could only be seen on the first film and disappeared on the following. Since phrenic nerve paralysis is extremely rare in our institution, even after cardiac surgery, and as there was no clinical evidence of hematoma, our attention was not been drawn to the only definite sign that could have led to an early diagnosis.

Adult↗
PubMed1989

Glutathione depletion and cytotoxicity by naphthalene 1,2-oxide in isolated hepatocytes.

The ability of naphthalene 1,2-oxide to diffuse across intact cellular membranes, the subsequent biotransformation of this epoxide and its potential to produce losses in cellular viability have been examined in incubations of isolated hepatocytes. Addition of 1R,2S- or 1S,2R-naphthalene oxide enantiomers (15, 30 and 60 microM) to isolated hepatocytes resulted in a rapid depletion of intracellular glutathione. Depletion of glutathione was concentration dependent and maximal at 5-15 min. Addition of either of the enantiomeric oxides at 60 microM resulted in the loss of more than 20 nmol glutathione/10(6) cells (1 ml cells); thus more than a third of the added epoxide was available for conjugation with intracellular glutathione. The time course and concentration dependence of glutathione depletion corresponded to the rapid, concentration-dependent formation of naphthalene oxide glutathione conjugates. The levels of glutathione adduct were highest 1 min after addition of naphthalene oxide and declined to 25% of this level after 30 min. Loss of glutathione conjugates from incubations correlated with the formation of N-acetylcysteine adducts. In contrast, the levels of glutathione adducts added exogenously to hepatocytes were relatively stable over a 120-min incubation suggesting that although further metabolism of naphthalene oxide glutathione adducts formed intracellularly is possible, extracellular glutathione adducts cannot penetrate the hepatocellular membrane. Small amounts of radiolabel from [3H]naphthalene 1,2-oxide were bound covalently to macromolecules in hepatocytes; the rate of this binding slowed rapidly after the first minute of incubation. Severe blebbing of the surface of the hepatocytes was noted in cells incubated for 30 min with 480 microM naphthalene oxide. Many of the cells were vacuolated at 60 min and progressed to frank necrosis with pyknotic nuclei and inability to exclude trypan blue. Cells incubated with 1-naphthol responded in a qualitatively similar fashion to those cells incubated with epoxide; however, hepatocytes incubated with 1-naphthol progressed to frank cellular necrosis at a slower rate. In hepatocytes partially depleted of glutathione by pretreatment with buthionine sulfoximine, addition of 1S,2R-naphthalene oxide at a rate of 1 nmol/min/10(6) cells resulted in significant losses in cell viability. In contrast, no losses in cell viability were observed with the enantiomer, 1R,2S-naphthalene oxide. Both epoxides produced similar losses in cellular glutathione levels.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1989

Pharmacological profile of binedaline, a new antidepressant drug.

The interactions of binedaline (binodaline), a new antidepressant drug, and its main metabolites with neurotransmitter receptors and monoamine uptake sites were studied. In receptor binding assays, binedaline was compared to amitriptyline, imipramine, maprotiline and mianserin. Unlike these drugs binedaline did not show any significant affinity for an alpha adrenergic, muscarinic cholinergic, histamine H1 or serotonin2 (5-HT2) receptors. Binedaline and desmethylbinedaline were potent inhibitors of the uptake of norepinephrine in synaptosomes from rat cerebral cortex (Ki = 25 and 29 nM, respectively). Binedaline also inhibited 5-HT uptake with a weak affinity (Ki = 847 nM) but was inactive as an inhibitor of dopamine uptake in synaptosomes from rat striatum (Ki greater than 2 microM). No specific binding was found using [3H]binedaline. After 2 weeks of daily administration of binedaline (20 mg/kg i.p.), the number of beta adrenergic recognition sites labeled with [3H]CGP 12177 remained constant in rat forebrain, as did 5-HT2 receptors and benzodiazepine receptors. In contrast a prolonged treatment with maprotiline (20 mg/kg i.p.) increased the apparent Kd value of [3H]CGP 12177 by 43% and the apparent maximal binding value of [3H]RO 15-1788 by 20% as compared to control. Our results indicate that binedaline is comparable to a tricyclic antidepressant drug in inhibiting the norepinephrine uptake but, however, it is devoid of affinity for neurotransmitter receptors. This probably explains why this drug does not induce the classical side effects of tricyclic antidepressant drugs. These results also suggest that a reduction in beta adrenergic, 5-HT2 or benzodiazepine receptors is not always related to an antidepressant chronic treatment.

Aged↗
PubMed1989

Bronchial responsiveness increases after seasonal antigen exposure in non-asthmatic subjects with pollen-induced rhinitis.

This study looked at the effects of natural antigenic exposure on non-specific airway responsiveness (NSAR) in pollen-sensitized non-asthmatic subjects with seasonal rhinitis. Eight subjects had daily recordings of their respiratory symptoms and peak flow rates during and out of the pollen season. Airway response to methacholine was measured at 1-week to 2-week intervals. Pre-season spirometry and NSAR were normal in all subjects. Their PC20 methacholine ranged from 64 to greater than 256 mg/mL. During natural pollen exposure, all subjects had symptoms of rhinoconjunctivitis. The only chest symptom observed was coughing. No significant change in peak flow rates was observed throughout the study. A significant increase in bronchial responsiveness to methacholine occurred in five subjects although it did not reach the asthmatic range (less than 16 mg/mL). This change in NSAR was reproduced after antigen (tree pollen) challenge in the laboratory in one of the subjects. A significant increase in blood eosinophils was observed during seasonal pollen exposure. This study shows that following natural antigenic exposure, NSAR can increase in non-asthmatic subjects with allergic rhinitis, although it may not reach the "hyperresponsive range," and is associated with the development of a cough. These data suggest that natural exposure in non-asthmatic atopics may induce an inflammatory reaction in the airways to a degree that may increase NSAR.

Adult↗
PubMed1989

Effect of alpha-1-acid glycoprotein, albumin and palmitic acid on the brain and salivary gland extraction of warfarin in rats.

The effect of plasma protein binding of warfarin on its transfer into the brain and salivary gland was investigated using alpha-1-acid glycoprotein and human serum albumin (HSA) in combination or not with palmitic acid. The tissue extraction of [14C] warfarin relative to [3H]water was determined by intracarotid injection technique in male Wistar rats. The tissue extraction of warfarin varied inversely with the concentration of added serum protein, (HSA and alpha-1-acid glycoprotein), and addition of palmitic acid to HSA diminished the extraction. The fraction of drug uptaked by tissue (tissue available fraction) was always dramatically greater than the in vitro free drug fraction, and this was interpreted as an enhanced in vivo drug dissociation from the binding protein. The fraction of drug uptake by salivary gland was closer to the in vitro free fraction than the fraction of drug uptake by brain tissue. The addition of palmitic acid to HSA induced parallel changes in the in vitro free fraction of warfarin and in the brain tissue or salivary gland extraction of warfarin. These data indicate that a part of protein-bound warfarin (as determined in vitro) is available for tissue extraction via an enhanced in vivo dissociation of the drug-protein complex in the tissue microcirculation. The in vitro data were fitted to a saturable model of binding whereas the in vivo data could satisfactorily fit a model dealing with a nonsaturable model of binding, and this is probably the result of the several-fold increase in the in vivo dissociation constant.

Animals↗
PubMed1988

[Incidence and treatment of coronary restenosis in spite of the implantation of an endoprosthesis].

Between April 1986 and February 1988, 72 endoprosthesis implantations were carried out in the coronary arteries of 65 patients. The indication for implantation was either abrupt closure post angioplasty or prevention of restenosis. The first 3 cases of restenosis within the stented segment are reported. Two were treated by repeat balloon angioplasty, with temporary improvement. The possible mechanisms underlying this particular form of restenosis are discussed.

Angioplasty, Balloon↗
PubMed1988

Serum binding of indapamide in health and disease: primary role of alpha 1-acid glycoprotein.

The serum concentrations of alpha-1-acid glycoprotein (AAG), albumin (HSA), and non-esterified fatty acids (NEFA), and the serum binding of indapamide were measured in four groups of individuals: control (healthy) subjects (N = 24), patients with inflammatory syndrome (N = 28), with hepatic (N = 20) and renal (N = 27) insufficiency. Indapamide serum binding was increased in patients with inflammatory syndrome (82.2 +/- 3.4%, P less than .001), decreased in patients with hepatic insufficiency (72.3 +/- 5.9%, P less than .001) and unchanged in patients with renal insufficiency (77.7 +/- 2.8%) as compared with controls (78.2 +/- 3.1%). A multivariate analysis indicated that these changes were mainly related to concomitant changes in AAG concentration (that explained 63% of intersubject variability in bound/free binding ratio), and to a lesser extent to HSA (that explained only 4% of the variability in the binding). These data show that the free fraction of the acidic drug indapamide in serum is affected by pathologic conditions in which changes in AAG concentration occur and that, unexpectedly, HSA plays a negligible role in the binding.

Adolescent↗
PubMed1988

Variation in serum binding of tertatolol mediated by disease-induced modification of alpha-acid glycoprotein concentration.

The serum concentrations of alpha 1-acid glycoprotein (AAG), albumin (HSA) and non-esterified fatty acids, and the serum binding of tertatolol were measured in four groups of individuals: healthy control subjects (n = 24), and patients with inflammation (n = 28), and hepatic (n = 20) and renal (n = 27) insufficiency. Serum binding of tertatolol was increased in patients with inflammation (94.6%), decreased in patients with hepatic insufficiency (88.8%) and it was unchanged in patients with renal insufficiency (92.8%) as compared to controls (92.7%). Multivariate analysis indicated that the changes were mainly related to concomitant changes in AAG concentration, which could account for 57% of intersubject variability in the bound/free ratio, and to a lesser extent in HSA, which accounted for only 4% of the variability in the binding. The data show that the free fraction of the basic drug tertatolol in serum is affected by pathological conditions that cause changes in AAG concentration.

Adolescent↗
PubMed1988

Cicletanine binding to human plasma proteins and erythrocytes, a particular HSA-drug interaction.

The binding of cicletanine to human serum, isolated proteins and red blood cells was studied in vitro by equilibrium dialysis. Our results show this drug is highly bound to serum (97.3%) at therapeutic levels. No saturation to the binding sites was seen. Human serum albumin was shown to mainly responsible for this binding (93.5%) with a saturable process characterized by one binding site with a moderate affinity (K = 75800 M-1) and a non saturable process with a low total affinity (nK = 6400 M-1). Like many basic lipophilic drugs, cicletanine showed a saturable binding to alpha-1-acid glycoprotein with one site and a moderate affinity (K = 38,800 M-1). Its binding to lipoproteins and red blood cells was weak and non saturable. Over the range of therapeutic concentrations, the unbound fraction in blood remains constant (3.6%). Moreover, interactions were studied using bilirubin and non esterified fatty acids at pathological concentrations and these endogenous compounds did not alter cicletanine binding human serum or to human serum albumin likewise cicletanine shared the diazepam-site on HSA but no inhibition could take place between cicletanine and the drugs sharing the same binding site in serum at therapeutic levels.

Anti-Arrhythmia Agents↗
PubMed1988

Blood binding and tissue uptake of drugs. Recent advances and perspectives.

The free drug hypothesis, which states that only the unbound moiety of drug in blood is available for tissue diffusion, is discussed according to recent investigations. In some experimental conditions, it must be assumed that part of the protein-bound drug in plasma is extracted during a single passage through the organ studied. The mechanisms underlying these observations are not unequivocal and remain hypothetical. In the liver, high-affinity binding sites for serum albumin have been demonstrated, and they would explain the high extraction by liver of endogenous and exogenous compounds. However, these experiments measure the unidirectional transfer of a drug from the vascular to the extravascular space in non-steady-state conditions. Hence, in steady-state conditions, the free drug hypothesis cannot be ruled out because it is supported by numerous pharmacokinetic studies.

Animals↗
PubMed1988

[Congenital heart diseases and urinary malformations].

The purpose of this study was to evaluate the advisability of a systematic search for uropathy in patients with malformative heart disease. Thirty-three cases of urinary tract malformation associated with congenital cardiopathy are reported. These cases represent 2.8 p. 100 of all cardiac patients seen during the same period. The congenital heart diseases were varied, with a predominance of ventricular septal defect (48 p. 100) followed by dextrocardia, single ventricle and coarctation of the aorta. UT abnormalities included vesico-ureteral reflux (36 p. 100), renal agenesis (5 cases), renal dysplasia or hypoplasia (4 cases), upper UT obstruction (4 cases), hypospadias (3 cases), renal ectopia (3 cases), lower UT obstruction (2 cases), polycystic kidney, megaloureter, horseshoe kidney and supernumerary kidney (1 case each). A study of the literature showed that the two uropathies with a risk of associated cardiopathy are renal agenesis and horseshoe kidney. The cardiopathy-uropathy association was found in isolation (11 cases) or combined with cryptorchidism (2 cases) or with multiple malformations (20 cases). The malformations were diverse, the most frequent being neurosensorial malformations (70 p. 100), followed by skeletal malformations (55 p. 100) equally divided between apine and limbs, genital malformations (35 p. 100) and digestive tract malformations (25 p. 100). A study of the cardiopathy-uropathy concordances failed to elicit any predominant association; in the literature, ventricular septal defect is usually associated with horseshoe kidney.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormalities, Multiple↗
PubMed1987

Determination of clomipramine and its hydroxylated and demethylated metabolites in plasma and urine by liquid chromatography with electrochemical detection.

A procedure for the determination of clomipramine and its 8-hydroxy, demethyl, 8-hydroxydemethyl and didemethyl metabolites in plasma and urine by high-performance liquid chromatography with electrochemical detection is described. A 1-ml plasma or urine sample is made alkaline with a carbonate buffer (pH 9.8) and extracted with 20% ethyl acetate in n-heptane. After back-extraction into an acid phosphate buffer (pH 2.4), an aliquot is injected into a 5-microns ion-paired reversed-phase column and eluted with a mobile phase containing a phosphate buffer with tetramethylammonium chloride-acetonitrile (57:43). The detection is coulometric with a first cell at +0.40 V, a second at +0.73 V and a guard cell set at 0.75 V for oxidation of the mobile phase. The method provides recoveries in the general range of 80-110% and a day-to-day precision of 3.7-8.8%, depending on the compound. The minimum quantifiable level for all compounds was 0.2 ng/ml with a 20-microliters injection. Steady-state plasma concentration data and urinary levels are reported for 24 depressed patients receiving daily either 75-150 mg orally or 50-75 mg by infusion.

Chromatography, High Pressure Liquid↗
PubMed1987

Interactions of phenylalkylamines with human lung membrane and microsome preparation.

Lipophilic amines are recognized as important tracers for brain imaging. Their pulmonary accumulation was a drawback for optimal concentration in the brain. We used IMP, HIPDM, IP, amphetamine derivatives to determine the relation between structure and accumulation in the lung. The incubation of phenylalkylamines in competition with 3H-Imipramine, for human lung membrane and microsomes was performed and led to the extraction of a competitive constant (KI). The results showed that the compounds can be classified in order of their decreasing affinity: Iodoamphetamine, iodoisopropylamphetamine, dimethyliodophentermine, hydroxyiodobenzyl propane diamine (HIPDM), isopropylamphetamine and amphetamine. Iodine set in the para position of the ring seemed to increase the affinity of phenylalkylamines for the lung. Adjunction of isopropyl or methyl groups to the lateral chain decreased this affinity.

Amines↗