Biomedical subjects

R Boucher

Publications and source records attributed to R Boucher.

At least 19 recordsLinked to original sources

PubMed1992

Effect of LY 171555 and CY 208-243 on tremor suppression in the MPTP monkey model of parkinsonism.

The antitremor effect of the D2 agonist LY 171555 and of the D1 agonist CY 208-243 alone and in combination was tested in a monkey previously rendered parkinsonian by MPTP and displaying exceptionally a rest tremor in the limbs. The D2 agonist suppressed rest tremor in a dose-dependent fashion. The D1 agonist by itself had no effect but it potentiated the effect of a small dose of LY 171555.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1992

Effect of ethosuximide on rest tremor in the MPTP monkey model.

Based on the hypothesis that low-threshold calcium conductance in the thalamus might be involved in the pathophysiology of parkinsonian tremor, ethosuximide was given chronically to a monkey previously treated with MPTP and displaying exceptionally a typical rest tremor. After 5 days of daily treatment, the tremor was reduced by 60%. Diltiazem and verapamil which act on different calcium channels had no such effect. Ethosuximide also potentiated the anti-tremor effect of the dopamine D2 agonist LY-171555.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1991

Effect of clonidine and atropine on rest tremor in the MPTP monkey model of parkinsonism.

The purported alpha 2-adrenergic agonist clonidine was found to inhibit rest tremor at doses of 0.023-0.1 mg/kg in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine monkey model of parkinsonism. The effect was dose dependent, but sedation and reduced mobility were observed. Atropine at doses of 0.1-1 mg/kg also reduced tremor in a dose-dependent fashion, but side-effects in the form of agitation, dilated pupils, and dry mouth were seen. When the two drugs were combined, however, we saw a significant potentiation of the antitremor effect. We could even abolish tremor with doses of atropine and clonidine that by themselves were without effect. The side-effects were almost eliminated by the combination.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1990

Expression of mucin synthesis and secretion in human tracheobronchial epithelial cells grown in culture.

The effects of culture conditions on growth and differentiation of human tracheobronchial epithelial (HTBE) cells have been defined. Epithelial cells were dissociated from tissues by protease treatment and were plated on tissue culture dishes in F12 medium supplemented with insulin, transferrin, epidermal growth factor, hydrocortisone, cholera toxin, bovine hypothalamus extract, and retinol. HTBE cells did not express any mucociliary function (ciliogenesis or mucin secretion) on tissue culture plastic, but they could be passaged 3 to 5 times with a total of 10 to 25 population doublings. Cells from early passages re-express both these functions when transplanted to tracheal grafts. When tissue culture plates were coated with collagen film or collagen gel substrata, cell attachment and proliferation were stimulated. However, the expression of mucous cell function in culture occurred only when cells were plated on collagen gel substrata and vitamin A (retinol) was present in the medium. Mucous cell differentiation under optimal conditions was defined by ultrastructural studies, by immunologic studies with mucin-specific monoclonal antibodies, and by carbohydrate and amino acid compositional analyses of mucin-like glycoproteins purified from culture medium. These results demonstrate for the first time that HTBE cells can express mucin synthesis and secretion under appropriate culture conditions.

Amino Acids↗

PubMed1989

Effect of D1 receptor stimulation in normal and MPTP monkeys.

The effect of a selective agonist of the dopamine D1 receptor (SKF 38393) and of the D2 receptor (LY-171555) was tested acutely in normal and in monkeys with a parkinsonian syndrome induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The D2 agonist induced a strong locomotor response and lingual dyskinesia in both normal and parkinsonian monkeys. The D1 agonist however had no locomotor effect by itself but induced tongue protrusions in normal monkeys only. It appeared to potentiate the dyskinetic effect of LY 171555 in MPTP monkeys but it antagonized the locomotor action of the D2 agonist in both normal and MPTP monkeys. The selective D1 and D2 antagonists SCH 23390 and sulpiride were also tested. Both compounds were able to suppress the dyskinetic action of the combined agonists in normal animals but only the D2 antagonist was effective in the same conditions in MPTP monkeys. These findings emphasize the importance of the D2 receptor in mediating the locomotor response as well as dyskinesia in monkeys.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1989

Phenytoin prodrug: preclinical and clinical studies.

The currently available phenytoin (PHT) solution has many disadvantages stemming from poor aqueous solubility of PHT. A novel approach to solve the problem has been the synthesis of a phosphate ester of PHT (PHT prodrug ACC-9653). This water-soluble compound is metabolized rapidly into PO4 and PHT. A four center open-label, baseline-controlled study of 43 patients with epilepsy maintained on oral twice-daily PHT monotherapy was performed to evaluate the safety and pharmacokinetic profile of the prodrug. Patients received an i.v. or i.m. dose of ACC-9653 at a dose equivalent to the patients' morning dose of PHT. Intravenous dosages were infused at a rate of 75 mg/min, and i.m. dosages were given as one or two injections. After a period of 6 days, during which patients were again maintained with oral PHT, they were given a dose of ACC-9653 via whichever route they had not yet received. The Tmax of the prodrug averaged 5.7 and 36 min (0.095 and 0.606 h) after i.v. and i.m. administrations, respectively. The elimination half-life of ACC-9653 (conversion from prodrug to PHT) after i.v. and i.m. administration was 8.4 and 32.7 min (0.140 and 0.545 h), respectively, and both were independent of the dose. The plasma clearance of ACC-9653 was not dependent on dose or route of administration and averaged 19.8 +/- 1.16 and 17.8 +/- 0.83 L/h after i.v. and i.m. administrations, respectively. The area under curve ratio of PHT after i.m. and i.v. ACC-9653 was 1.17 +/- 0.13 which was not significantly different from 1.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1988

Behavioral and biochemical effect of chronic treatment with D-1 and/or D-2 dopamine agonists in MPTP monkeys.

Monkeys developed a severe parkinsonian syndrome after intravenous administration of (MPTP). L-DOPA/carbidopa (D-1 and D-2) or bromocriptine (D-2) treatment relieved the parkinsonian symptoms, whereas SKF 38393 (D-1) was ineffective. No dyskinesia was seen in monkeys receiving bromocriptine or SKF 38393 as opposed to the L-DOPA-treated animals, in which the dyskinetic response appeared to increased with time. MPTP induced a significant increase (25%, P less than 0.01) in the number of [3H]spiperone binding sites (Bmax) in the caudate nucleus and in putamen. The Bmax of spiperone binding in the L-DOPA-treated monkeys was on average 18% lower (P less than 0.01) than that of the animals treated with MPTP alone. The Bmax for the bromocriptine-treated group was 29% (P less than 0.01) less than that in the MPTP-treated group or 11% (P less than 0.05) less than that in the L-DOPA-treated monkeys. The SKF 38393 treatment induced a 23% (P less than 0.01) decrease in the Bmax as compared to that of animals treated with MPTP alone, and no significant change compared to the L-DOPA- or bromocriptine-treated animals. These results suggest that stimulation of D-1 and D-2 dopamine receptors can differently influence the mechanisms controlling dopamine agonist-induced dyskinesia in MPTP-treated monkeys.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1988

Chloroprene and isoprene: cytogenetic studies in mice.

Groups of male B6C3F1 mice (n = 15) were exposed for 6 h per day to ambient air, to chloroprene (12, 32, 80, 200 p.p.m.) or to isoprene (438, 1750 and 7000 p.p.m.) on 12 days. These compounds are the 2-chloro and the 2-methyl analogues, respectively, of 1,3-butadiene, a genotoxic and carcinogenic chemical in B6C3F1 mice. Exposure to chloroprene resulted in a 100% incidence of mortality among the mice exposed to 200 p.p.m. At concentrations of 80 p.p.m. and below, chloroprene neither induced a significant increase in chromosomal aberrations (CA), sister chromatid exchanges (SCE) or micronucleated erythrocytes, nor significantly altered the rate of erythropoiesis or of bone marrow cellular proliferation kinetics. However, the mitotic index (MI) in the bone marrow of chloroprene-exposed mice was significantly increased. Under similar conditions, exposure to isoprene induced significant increases at all concentrations in the frequency of SCE in bone marrow cells and in the levels of micronucleated polychromatic erythrocytes (PCE) and of micronucleated normochromatic erythrocytes in peripheral blood. In addition, a significant lengthening of the bone marrow average generation time and a significant decrease in the percentage of circulating PCE was detected. However, exposure to isoprene did not induce in bone marrow a significant increase in the frequency of CA nor did the exposure significantly alter the MI. The dose-response curves for SCE and micronuclei induction were non-linear, appearing to saturate at 438 and 1750 p.p.m., respectively. These results suggest that, similarly to butadiene, inhaled isoprene can be expected to induce tumors at multiple sites in B6C3F1 mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1988

Assessment of maximal expiratory pressure in healthy adults.

Maximal static expiratory pressure developed at the mouth (PEmax) provides a useful clinical index of expiratory muscle function; however, the range of normal values among laboratories shows considerable variation. We examined the hypothesis that the wide variability could be attributable to the differences in technique among laboratories. We measured PEmax at functional residual capacity (PEmax FRC) in 28 healthy subjects using the following five techniques: 1) using a scuba-type mouthpiece with the cheeks supported by the hands ("hands on"), 2) without supporting the cheeks ("no hands"), 3) using a rigid, circular mouthpiece (2.8 cm ID, "tube"), 4) using the scuba-type mouthpiece but with the cheeks supported by an observer ("other hands"), and 5) using a large-bore circular mouthpiece (4.1 cm ID, "new tube"). Mean PEmax FRC obtained with hands on was significantly higher than no-hands and tube methods. PEmax FRC values obtained by the other-hands and new-tube maneuvers were similar to the hands-on maneuver. We conclude that the technique used to measure PEmax FRC can significantly affect the results and suggest that it should be measured using a large-bore circular mouthpiece or a scuba-diving mouthpiece with the cheeks supported.

Adult↗

PubMed1988

The introduction of biologically active foreign genes into human respiratory epithelial cells using electroporation.

A simple method for introducing genes into respiratory epithelial cells would assist molecular studies of a variety of pulmonary disorders. Several different techniques for introducing foreign DNA into cells have been described but have either not been useful for respiratory epithelial cells or are difficult and cumbersome to perform. Electroporation is a simple technique that consists of exposing a cell-DNA suspension to an electric shock. Although it has been used to introduce genes into a variety of cell types, it has not previously been applied to respiratory epithelial cells. Human nasal epithelial cells were transfected with the plasmid pRSVCAT, which is an expression vector containing the origin of replication of pBR322 coupled to the Rous sarcoma virus (RSV) long terminal repeat (LTR) region driving the coding sequence for the chloramphenicol acetyltransferase (CAT) gene. The CAT gene is useful for determining optimal conditions for electroporation since it is not normally present in eukaryotic cells, and CAT activity correlates with the level of CAT mRNA; this provides a measure of expression of introduced foreign genes. Successful expression of the CAT gene was demonstrated by electroporation, whereas calcium phosphate transfection resulted in very low CAT activity. Optimal conditions for electroporation of respiratory epithelial cells were determined. Electroporating nasal epithelial cells using 500 volts, a DNA concentration of 10 micrograms/ml, and a sucrose buffer yielded the highest CAT activity, which peaked at 48 h after electroporation.

Avian Sarcoma Viruses↗

PubMed1988

[Animal models of tardive dyskinesia].

It is possible to induce in monkeys abnormal movements of the mouth and tongue resembling strikingly tardive dyskinesia. Such movements can be induced by chronic treatment with neuroleptics or by lesions placed in the habenular interpeduncular tract or nucleus parafascicularis thalami. Dopaminergic D1 and D2 receptors are involved in the modulation of such movements.

Animals↗

PubMed1988

Uterine leiomyosarcoma with cardiac metastases.

Leiomyosarcoma metastatic to the heart is rare and is usually fatal. The authors present the case of a 58-year-old woman who had a history of uterine leiomyosarcoma. Echocardiography and cardiac catheterization revealed a large right ventricular mass. Computed tomography confirmed the presence of the mass which extended into the pulmonary artery. The inferior vena cava was free of disease. At operation, a large tumour originating in the right ventricle and protruding through the pulmonary valve was found. Histologically, it was a leiomyosarcoma. Because there were numerous septal and intramural foci of tumour, complete resection was impossible, but palliative resection was performed successfully and the patient was alive and active 1 year after operation.

Female↗

PubMed1987

Comparative cytogenetic analysis of bone marrow damage induced in male B6C3F1 mice by multiple exposures to gaseous 1,3-butadiene.

Groups of male B6C3F1 mice (N = 12) were exposed to ambient air or to gaseous 1,3-butadiene (BD) at 6.25, 62.5, and 625 ppm for 10 exposure days (6 hr + T90/day). Exposure to BD induced in bone marrow: 1) a significant increase in the frequency of chromosomal aberrations (CA); 2) a significant elevation in the frequency of sister chromatid exchanges (SCE); 3) a significant lengthening of the average generation time (AGT); 4) a significant depression in the mitotic index (MI); and, as measured in the peripheral blood, 5) a significant increase in the proportion of circulating polychromatic erythrocytes (%PCE), and 6) a significant increase in the level of micronucleated PCE (MN-PCE) and micronucleated normochromatic erythrocytes (MN-NCE). The most sensitive indicator of genotoxic damage was the frequency of SCE (significant at 6.25 ppm), followed by MN-PCE levels (significant at 62.5 ppm), and then by CA and MN-NCE frequencies (significant at 625 ppm). The most sensitive measure of cytotoxic damage was AGT (significant at 62.5 ppm), followed by %PCE (significant at 625 ppm), and then by MI (significant by trend test only). Because each cytogenetic endpoint was evaluated in every animal, a correlation analysis was conducted to evaluate the degree of concordance among the various indicators of genotoxic and cytotoxic damage. The extent of concordance ranged from a very good correlation between the induction of MN-PCE and the induction of SCE (correlation coefficient r = 0.9562) to the lack of a significant correlation between the depression in the MI and any other endpoint (r less than 0.37).

Animals↗

PubMed1987

An isovolume method for analysis of density dependence of maximal expiratory flows.

The usual method of measuring density dependence of maximum expiratory flows is superimposition at total lung capacity or residual volume of maximum expiratory flow volume (MEFV) curves obtained breathing air and a mixture of 80% He plus 20% O2 (HeO2). A major problem with this technique is the large variability in results, which has been thought to be due to errors in matching lung volumes on both gases. Accordingly, we obtained MEFV curves breathing air and HeO2 using a bag-in-the-box system so that the curves breathing the two gas mixtures could be directly superimposed without removing the mouthpiece (isovolume). Ten healthy, nonsmoking subjects performed MEFV curves on each gas mixture for six consecutive experiments. We compared the increase in flow at 50% of vital capacity (delta Vmax50) and volume of isoflow (Viso) by superimposing and matching the MEFV curves at total lung capacity, at residual volume, and using the isovolume method. The variability of each method was assessed by the mean intersubject and intrasubject coefficients of variation. In all subjects, the mean delta Vmax50 and Viso as well as their corresponding coefficients of variation were not significantly different among the three methods. We conclude that, in healthy nonsmoking young adults, the method chosen for superimposing and matching MEFV curves has no effect on the variability of delta Vmax50 and Viso.

Adult↗

PubMed1987

Effect of mouthpiece, noseclips, and head position on airway area measured by acoustic reflections.

To investigate whether it is possible to simplify the methodology of measuring airway area by acoustic reflections, we measured upper airway area in 10 healthy subjects during tidal breathing according to seven different protocols. Three protocols employed custom-made bulky mouthpiece with or without nose-clips, two protocols used a scuba-diving mouthpiece and cotton balls placed in the nostrils instead of noseclips, and two protocols employed neck flexion and extension. We found no significant difference in average pharyngeal, glottic, and tracheal areas for any of the protocols except for neck flexion, which was associated with a significantly lower mean pharyngeal area. Intraindividual variabilities were comparable for all protocols, except for protocol employing the customary bulky mouthpiece and no noseclips, which consistently resulted in the most variable measurements of area for all three airway segments: pharynx, glottis, and trachea. Furthermore, we found that the protocol employing the scuba-diving mouthpiece with or without cotton balls in the nostrils resulted in the lowest number of unacceptable measurements. We conclude that measurements of airway area by acoustic reflections may be further simplified by using a scuba-diving mouthpiece without noseclips; furthermore, control of head position during measurements is not critical provided there is no obvious neck flexion.

Acoustics↗

PubMed1987

Changes in pharyngeal cross-sectional area with posture and application of continuous positive airway pressure in patients with obstructive sleep apnea.

In an attempt to elucidate whether changes in posture (from sitting to supine) result in reduction in pharyngeal area, thus promoting pharyngeal occlusion during sleep in so predisposed persons, we studied 12 snoring apneic patients and 6 snoring nonapneic control subjects. in all subjects, we employed acoustic reflection technique to measure pharyngeal area at FRC sitting and supine. We also examined changes in pharyngeal area resulting from the application of positive intrapharyngeal pressure in sitting and supine posture. We found that (1) pharyngeal cross-sectional area at FRC was similar in both groups, (2) decrease in pharyngeal area with assumption of supine posture was also similar in both groups (21 +/- 11% in patients with OSA versus 15 +/- 13% in nonapneic control subjects), and (3) pharyngeal distensibility was significantly higher in apneic snorers than in nonapneic control subjects (0.090 +/- 0.039 cm H2O-1 in apneic snorers versus 0.032 +/- 0.027 cm H2O-1 in nonapneic control subjects; p less than 0.005). We conclude that changes in posture alone are not sufficient to convert a snorer into a patient with OSA; however, when physiologic abnormalities ("floppy" pharynx) are superimposed on postural reduction in pharyngeal area, airway occlusion results.

Humans↗

PubMed1986

Long-term effects of MPTP on central and peripheral catecholamine and indoleamine concentrations in monkeys.

5 Macaca fascicularis monkeys developed a severe parkinsonian syndrome in the days following intravenous administration of the toxin MPTP. One monkey remained untreated while two groups of two animals were treated daily for 5 months with supramaximal oral doses of either Sinemet or bromocriptine. Both drugs relieved the parkinsonian symptoms. Plasma prolactin concentrations were elevated in MPTP-treated monkeys compared to intact monkeys. MPTP caused a rapid decrease of homovanillic acid (HVA) concentrations in the CSF of these monkeys within days of the toxin injection and these values remained low until sacrifice of the animals 5 months later. By contrast, CSF 5-hydroxyindoleacetic acid (5-HIAA) concentrations were elevated a few days after the start of MPTP treatment and these values returned to control levels by 5 months. Five months after the start of MPTP treatment, epinephrine (E) and dopamine (DA) levels were decreased in the adrenal medulla while the norepinephrine (NE) concentration remained unchanged. Catecholamines were assayed in the caudate putamen, nucleus accumbens, amygdala and frontal cortex of these monkeys. NE concentrations were decreased in the frontal cortex of MPTP-treated monkeys while a decrease of E concentrations after MPTP was only observed in the n. accumbens. Dopamine and its metabolites dihydroxyphenylacetic acid (DOPAC) and HVA were reduced in the caudate, putamen, n. accumbens and frontal cortex. Our results show that MPTP treatment in the long-term (5 months) not only affects the dopaminergic system of the caudate-putamen but also has effects on dopaminergic systems in other regions as well as on noradrenergic and adrenergic systems in the brain and the periphery.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1986

Chronic treatment with L-DOPA, but not bromocriptine induces dyskinesia in MPTP-parkinsonian monkeys. Correlation with [3H]spiperone binding.

A group of 5 monkeys developed a severe parkinsonian syndrome after intravenous administration of the toxin MPTP. One remained untreated while two animals were treated daily for 5 months with supramaximal doses of Sinemet and two with bromocriptine orally. Both drugs relieved the parkinsonian symptoms but the animals on Sinemet developed after 2 weeks prominent lingual dyskinesia which remained visible after each dose until the end of the experiment. In the two animals on bromocriptine no dyskinesia was observed. After sacrifice, the levels of dopamine and [3H]spiperone binding were studied bilaterally in the anterior and posterior caudate nucleus, anterior and posterior putamen and in the nucleus accumbens. The loss of dopamine was equivalent in the Sinemet and the bromocriptine treated animals (more than 90%) and there was a complete disappearance of the substantia nigra pars compacta. In all structures studied, the Bmax for [3H]spiperone binding was on average 10% higher in the Sinemet than in the bromocriptine-treated animals. We therefore believe that L-DOPA and bromocriptine affect denervated postsynaptic dopamine receptors differently, that bromocriptine is less likely to induce agonist supersensitivity and that this probably explains the lesser tendency to induce dyskinesia after chronic treatment.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗