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Biomedical subjects

D Luttinger

Publications and source records attributed to D Luttinger.

At least 19 recordsLinked to original sources
PubMed2001

The public health surveillance of asthma.

Asthma is a highly prevalent disease that affects the quality of life of many people in the United States. Yet there is limited descriptive epidemiological understanding of the disease, particularly at the state and local levels. Minimal surveillance of asthma is occurring across the country. Surveillance of a disease requires that public health workers have the ability to accurately identify cases, have access to needed data, and have adequate resources so that they can collect, assess, report, and use the data-all considerable challenges in the case of asthma. We consider four groups of questions that asthma surveillance should address: (1) How much asthma is there and what are the trends in asthma occurrence over time? (2) How severe is the asthma and what are the trends in asthma severity over time? (3) How well is asthma controlled and what are the trends in asthma management over time? (4) What is the cost of asthma? Because wise decision making in public health depends on the availability of appropriate data for program planning, implementation, and evaluation, we encourage increased surveillance of asthma in jurisdictions across the country.

Asthma↗
PubMed1995

WIN 63480, a hydrophilic TCP-site ligand, has reduced agonist-independent NMDA ion channel access compared to MK-801 and phencyclidine.

NMDA channel blockers are potentially advantageous therapeutic agents for the treatment of ischemia and head trauma, which greatly elevate extracellular glutamate, because they should most effectively inhibit high levels of receptor activation. A novel high affinity TCP site ligand, WIN 63480, does not produce MK-801- or PCP-like behavioral activation at anti-ischemic doses. While WIN 63480, MK-801 and PCP were all observed to be effective blockers of open NMDA channels, WIN 63480 had much less access to closed NMDA channels. This difference may be due to the fact that WIN 63480 is hydrophilic (logD = -4.1) while MK-801 and PCP are lipophilic (logD = +1.8). In vivo, closed channel access may result in a non-competitive profile of antagonism for MK-801 and PCP compared to a more uncompetitive profile for WIN 63480. Release of glutamate, and depolarization, are likely to produce a high level of NMDA receptor activation in ischemic areas compared to normal tissue. Consequently, at anti-ischemic doses, WIN 63480 may produce less inhibition of physiological NMDA-mediated processes in neural systems involved in behavioral regulation than MK-801 or PCP, leading to an improved side effect profile.

Animals↗
PubMed1994

Pharmacologic reversal of acute changes in diffusion-weighted magnetic resonance imaging in focal cerebral ischemia.

Recently, diffusion-weighted magnetic resonance imaging (DWI) has been shown to visualize acute ischemic lesions in the brain before changes are observable with conventional magnetic resonance imaging. However, the underlying mechanisms of these acute DWI changes are unclear and may include both reversible and irreversible damage. In this study, we demonstrate that acute DWI lesions may be reversed with MK801 therapy postischemia. Sprague-Dawley rats (n = 12) were subjected to middle cerebral artery occlusion and DWI scans were obtained beginning 60 min postocclusion. Distinct regions of hyperintensity were observed in the basal ganglia and cortex, corresponding with the expected distribution of ischemia in this model. After the first scan, animals were treated with MK801 (0.5 mg/kg i.v.) or normal saline and subsequently scanned again 30 and 60 min after treatment. In the control group, the area of hyperintense lesions continued to increase, by 55% in the cortex and 57% in the basal ganglia. MK801 therapy significantly (p < 0.01) reduced the area of damage by the third DWI scan at 60 min posttreatment (-50% cortex, -22% basal ganglia, -41% total hemisphere) compared to pretreatment scans. Tetrazolium (TTC) stains at 24 h confirmed that MK801 significantly reduced the volumes of infarction (p < 0.05). These results demonstrate that significant portions of the acute ischemic lesion on DWI are reversible with pharmacologic intervention.

Animals↗
PubMed1993

Sigma receptor binding affinity and inhibition of apomorphine-induced climbing.

Several relatively selective compounds with affinity for the sigma binding site were assessed for their ability to inhibit apomorphine-induced climbing in the mouse. Although, the majority of compounds inhibited apomorphine-induced climbing, there was no correlation between the ability to inhibit climbing and potency in sigma binding assays using [3H]1,3-di-o-tolylguanidine (DTG) or [3H](+)-pentazocine as ligands. The potency of the compounds to inhibit binding to muscarinic M1 or M2 receptors correlated with the potency to inhibit apomorphine-induced climbing. However, several of the compounds that inhibit climbing had microM affinity at muscarinic receptors. Whether these concentrations were achieved in vivo is unclear. Our data suggest that sigma activity per se is not responsible for inhibition of apomorphine-induced climbing.

Animals↗
PubMed1990

In vivo assessment of napamezole, an alpha-2 adrenoceptor antagonist and monoamine re-uptake inhibitor.

Napamezole is an alpha-2 adrenergic receptor antagonist and a selective inhibitor of 5-hydroxytryptamine re-uptake in vitro. In the present study, napamezole was evaluated in vivo for its ability to antagonize alpha-2 adrenergic receptors and to inhibit 5-hydroxytryptamine re-uptake. The alpha-2 blocking activity of napamezole was demonstrated by its ability to: 1) antagonize clonidine-induced antinociception in mice (ED50 value, 36 mg/kg p.o.; 3 mg/kg s.c.); 2) enhance norepinephrine turnover in rat brain (minimum effective dose, 30 mg/kg p.o.); and 3) enhance locus coeruleus neuronal firing (active at doses greater than or equal to 1 mg kg i.v.) and to reverse clonidine-induced suppression of locus coeruleus firing in rats. The rank order of potencies of napamezole and reference alpha-2 antagonists to inhibit clonidine-induced antinociception (based upon s.c. ED50 values) were: idazoxan greater than yohimbine greater than rauwolscine greater than or equal to napamezole greater than tolazoline greater than or equal to piperoxan greater than RS21361. The relative potencies of compounds to enhance alpha-methyltyrosine-induced depletion of forebrain norepinephrine following p.o. administration were: idazoxan = yohimbine greater than mianserin greater than napamezole greater than RS21361. The ability of each of these compounds to enhance alpha-methyltyrosine-induced depletion of rat-forebrain norepinephrine was reversed by the administration of clonidine. These results indicate that napamezole blocks alpha-2 adrenergic receptors in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗
PubMed1989

Behavioral effects of neurotensin: operant responding and assessment of 'anhedonia'.

Neurotensin and antipsychotic drugs share certain properties. This study investigates whether neurotensin and neuroleptics share the ability to produce 'anhedonia'. A dose-response curve for the effect of neurotensin on continuously reinforced behavior was obtained in Experiment 1. Centrally administered neurotensin reduced food-reinforced responding. Based on the results of Experiment 1, a dose of neurotensin (0.95 micrograms) was chosen which had minimal effects on food-reinforced operant responding. To test for anhedonia, repeated presentations of this dose were given. Because response rates did not decrease over repeated testing, no evidence for anhedonia was found.

Animals↗
PubMed1989

Evaluation of adenosine agonists as potential analgesics.

Adenosine agonists, N6-cyclohexyladenosine (CHA), N6-cyclopentyladenosine (CPA), N6-phenylisopropyladenosine (PIA), 5'-N-ethylcarboxamidoadenosine (NECA), 5'-N-methylcarboxamidoadenosine (MECA) and 2-chloroadenosine (CADO), produced a dose-related inhibition of acetylcholine (ACh)-induced writhing in mice. The antinociceptive potency of adenosine agonists was comparable to that of morphine. Adenosine agonists were 10-1000 times more potent when given i.c.v. than p.o., suggesting a central site of action. Theophylline antagonized the antinociceptive activity of R-PIA in the writhing assay, suggestive of an adenosine receptor-mediated event. The sedative/ataxic properties of adenosine agonists were evaluated using a rotorod assay. Adenosine agonists impaired performance on the rotorod in doses comparable to and in some cases lower than those active in the ACh writhing assay. The results of the present study suggest that adenosine agonists attenuate nociceptive responding to a chemical stimulus through a central purinergic mechanism. The ability of adenosine agonists to inhibit ACh-induced writhing may be secondary to their sedative/ataxic properties.

Adenosine↗
PubMed1987

Two tests in rats for antianxiety effect of clinically anxiety attenuating antidepressants.

The effects of mianserin, trazodone, amoxapine, maprotiline, and doxepin were assessed in punishment and pentylenetetrazol drug discrimination paradigms. These two procedures are used to identify antianxiety activity in rats. In the punishment procedure, misanserin produced an inverse dose-related increase in punished responding. The magnitude of the increase in punished responding with mianserin was comparable to that observed with the anxiolytic, buspirone. This effect was not observed with any of the other antidepressants tested. None of the antidepressants were found to be active in antagonizing the discriminative stimulus effects of pentylenetetrazol. In fact, at high doses there was a suggestion that the antidepressants may generalize to the pentylenetetrazol discriminative stimulus. Therefore, several antidepressants with purported clinical antianxiety activity, were not active in two procedures that detect antianxiety activity in rats.

Animals↗
PubMed1987

Alpha 2-adrenergic agonists/antagonists: the synthesis and structure-activity relationships of a series of indolin-2-yl and tetrahydroquinolin-2-yl imidazolines.

The synthesis and alpha 2-adrenergic activity of a series of indolin-2-yl and tetrahydroquinolin-2-yl imidazolines are described. The indolin-2-yl imidazoline 4b was found to possess potent alpha 2-adrenergic agonist and antagonist activity. The modification of the substituents on the indoline ring of 4b has led to the separation of these activities. Substitution on the aromatic ring of 4b with halogen or increasing the size of the N-alkyl substituent of 4b gave alpha 2-adrenergic antagonists without agonist activity. The N-allylindoline 4d is more potent than idazoxan in vitro and is equipotent in vivo, but is less receptor selective (alpha 2 vs. alpha 1) than idazoxan. The cis-1,3-dimethylindolin-2-yl imidazoline 6a is an alpha 2-adrenergic agonist equal in potency to clonidine in vitro, while the trans-1,3-dimethylindolin-2-yl imidazoline 6b is a moderately potent alpha 2-adrenergic antagonist.

Adrenergic alpha-Agonists↗
PubMed1987

Pharmacologic profile of fezolamine fumarate: a nontricyclic antidepressant in animal models.

Fezolamine [N,N-dimethyl-3,4-diphenyl-1H-pyrazole-1-propanamine-(E)-2- butenedioate] is a new, nontricyclic agent under investigation as a potential antidepressant. In vitro, it was 3 to 4 times more selective in blocking synaptosomal uptake of [3H]norepinephrine than uptake of [3H]serotonin or [3H]dopamine. In classical behavioral tests using monoamine-depleted animals, it prevented the depressant effects of reserpine and tetrabenzine. In addition, it was active in the "behavioral despair" procedure. Its potency in three of these models was similar to that of standard tricyclics (e.g., imipramine, amitriptyline) or newer nontricyclic antidepressants (e.g., bupropion). In the mouse mydriasis and oxotremorine antagonism models, anticholinergic properties of fezolamine were weak or absent compared with imipramine and amitriptyline. Locomotor activity in mice was not increased by fezolamine at doses 2 to 16 times greater than effective antidepressant doses, suggesting the absence of central nervous system stimulant properties. Fezolamine did not inhibit monoamine oxidase activity in ex vivo studies and, unlike pargyline, did not produce locomotor hyperactivity in mice pretreated with L-tryptophan. In vitro studies using canine Purkinje tissue suggest that fezolamine has significantly less ability to depress myocardial conduction parameters than similar concentrations of imipramine. In a myocardially infarcted cat model, plasma levels of fezolamine 19 to 28 times greater than those achieved with imipramine were required before inducing significant depression of cardiac function and mean arterial pressure. Fezolamine, unlike imipramine, did not increase sinus rate. Fezolamine may thus show antidepressant efficacy in man with minimal anticholinergic or cardiovascular side effects common to tricyclic antidepressants.

Animals↗
PubMed1986

Adaptation to cold antagonizes neurotensin-induced hypothermia in mice.

Intracerebrally-administered neurotensin produces a marked hypothermia in a variety of mammals. In this study, prior adaptation to a cold environment was found to significantly antagonize the hypothermia produced by intracisternally-administered neurotensin in mice. This antagonism required both previous exposure to cold ambient temperatures and cold exposure immediately prior to, or simultaneously with, neurotensin administration. The antagonism of neurotensin-induced hypothermia by prior cold-adaptation was blocked by indomethacin, but not by acetylsalicylic acid, suggesting that brain prostaglandin synthesis may be essential for this newly-discovered phenomenon.

Adaptation, Physiological↗
PubMed1986

Alpha 2-adrenergic antagonists effect on amphetamine-induced behaviors.

The effects of alpha 2-adrenergic antagonists on amphetamine-induced locomotion and stereotypy were studied in mice. Six alpha 2-antagonists (i.e., yohimbine, rauwolscine, piperoxan, tolazoline, RX781094, and RS21361) selectively attenuated amphetamine-induced increases in locomotion at doses which did not effect amphetamine-induced stereotypies. Higher doses of the antagonists which attenuated baseline stereotypies also attenuated amphetamine-induced increases in stereotypies. The effect of the alpha 2-antagonists was qualitatively similar to that observed with the atypical antipsychotic clozapine. Furthermore, the in vivo relative potency of the alpha 2-antagonists in the present study was comparable to that reported in other studies. These results suggest that alpha 2-adrenergic receptors may modulate the effects of amphetamine on locomotion in mice.

Adrenergic alpha-Antagonists↗
PubMed1985

Determination of antinociceptive efficacy of drugs in mice using different water temperatures in a tail-immersion test.

A variety of analgesic drugs were tested for their ability to alter the response to noxious stimuli of differing severity in an attempt to develop a procedure to evaluate differences in efficacy of different analgesics. The severity of a noxious stimuli delivered to mice was varied by immersing the mouse tails in water maintained at 45, 50, 55 degrees C. As has been previously observed, the opiate analgesics morphine and nalorphine were active at all temperatures. Pentazocine was active at 45 and 50 degrees C, but not at 55 degrees C. The cyclooxygenase inhibitors tested showed a wide variety of activity. Naproxen was active at all temperatures. Zomepirac was active at 45 and 50 degrees C, but not 55 degrees C. Acetaminophen, ibuprofen, and fenoprofen were active at 45 degrees C, but not at higher temperatures. Aspirin and indomethacin were inactive at all temperatures tested. These results roughly paralleled the differences in the severity of pain for which these analgesics are effective.

Analgesics↗
PubMed1985

Pharmacological analysis of alpha-2 adrenergic mechanisms in nociception and ataxia.

In order to assess the involvement of alpha-2 adrenergic receptors in nociception, the in vitro potencies of seven alpha-2 adrenergic agonists (clonidine, guanabenz, guanfacine, BHT-920, ICI 106270, xylazine and lofexidine) were compared with their ability to prevent the writhing response elicited by i.p. administration of phenyl-p-guinone. Administration of each compound elicited antinociception, and this effect was attenuated by pretreatment with the alpha-2 adrenergic antagonists, yohimbine. The potency of these compounds to cause antinociception was correlated with their potency to displace [3H]clonidine from its binding site on brain membranes and with their ability to inhibit the twitch of the electrically stimulated vas deferens, suggesting an alpha-2 involvement in the antinociceptive action. In addition to causing antinociception, administration of these agonists also impaired rotorod performance in mice. These agonists were 2.5 to 72 times more potent in inhibiting writhing than in impairing rotorod performance, and, except for ICI 106270, there was a correlation between antinociceptive and ataxic potency. ICI 106270 was a notable exception to this correlation, however, producing only minimal ataxia, which unlike the other agonists was not reversed by yohimbine. These results indicate that alpha-2 adrenergic agonists can produce antinociception and further suggest that this may be dissociable from the ataxia.

Adrenergic alpha-Agonists↗
PubMed1984

The effects of serotonin antagonists in a behavioral despair procedure in mice.

Six serotonin antagonists (pizotifen, mianserin, cyproheptadine, ketanserin, trazodone and methysergide) were tested in mice in a behavioral despair procedure. The behavioral despair procedure detects most antidepressant compounds. Pizotifen, mianserin and cyproheptadine were found to be active and the others were inactive. The serotonin binding potency at serotonin1 or serotonin2 receptors, or the ratio of potency at these receptors did not correlate with activity in the behavioral despair procedure. However, the serotonin antagonists that were active in the behavioral despair procedure were all found to be potent antagonists at histamine1 receptors. It is suggested that the activity of some serotonin antagonists in the behavioral despair procedure is best explained by their antihistaminergic potency.

Animals↗
PubMed1983

The effects of neurotensin, beta-endorphin, and bombesin on ethanol-induced behaviors in mice.

The effects of the three peptides neurotensin, beta-endorphin, and bombesin on ethanol-induced behaviors were studied in mice. Intracisternal administration of these peptides to mice prolonged the duration of sleep induced by ethanol (5.2 g/kg). Neurotensin and beta-endorphin also enhanced ethanol-induced hypothermia. None of the peptides, when administered alone, produced sleep. However, all three compounds impaired the aerial righting reflex and induced sleep when followed by an IP dose of ethanol (3.5 g/kg), which alone did not induce sleep. These results, taken together with previous findings, suggest that neuropeptides may be involved in the complex mechanisms of action of ethanol on the CNS.

Animals↗