Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

EMD 49980 is a dopamine agonist with selective affinity to dopamine autoreceptors. Following pharmacological findings in animal studies, it was postulated that a hyperactivity of dopaminergic neurons, which is possibly present in acute schizophrenia, may be reduced by autoreceptor stimulation. To investigate the antipsychotic efficacy of EMD 49980, 20 acutely ill schizophrenics (ICD No. 295.3) were treated over four weeks with dosage increasing up to 3 mg or 9 mg. According to previously defined criteria four patients were clear responders, but clinically none of them revealed a full remission. Ten patients were nonresponders, and three of these patients were drop-outs because of marked deterioration of schizophrenic symptoms. The explorative analysis of BPRS subscales shows a statistically significant reduction of anxiety/depression and anergia, but no clear influence on the subscales THOT, HOST, and ACTV, which are the more specific scales for acute schizophrenia. EMD 49980 was subjectively well tolerated and there was no case of drug-induced extrapyramidal side-effects. In view of the only moderate antipsychotic efficacy in acute schizophrenia and the fact that antidepressant and anxiolytic effects were also observed, a clinical investigation of EMD 49980 in affective disorders and in schizophrenia with depression or anergia should be performed.
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PMID:Antipsychotic efficacy of the dopaminergic autoreceptor agonist EMD 49980 (Roxindol). Results of an open clinical study. 168 39

Electromechanical dissociation (EMD) is inconsistently defined in the literature. Our definition is the presence of discernible electrical complexes (excluding ventricular tachycardia and ventricular fibrillation) and the absence of palpable pulses. It has been noted that EMD may present with a variety of morphological complexes. It was the purpose of this study to categorize the electrical morphologic characteristics of patients presenting in EMD and to correlate morphology with patient outcome and response to therapy. From the 6-year period, January 1st, 1980 to December 31st, 1985, 503 evaluable adult patients presented to an urban paramedic system in non-traumatic, non-poisoned, cardiorespiratory arrest and were determined to be in EMD. The rhythm strips obtained from paramedics on all patients were retrospectively reviewed and were arbitrarily categorized in the following manner: Group 1, normal QRS width, isoelectric ST and normal appearing T-waves; Group 2A, atrial activity, widened QRS width (greater than or equal to 0.12 ms) or abnormal ST and/or T-waves (ST depression, elevation, slurring or T-wave inversion); Group 2B, same as Group 2A but without atrial activity; Group 3, essentially monophasic, slurred RST complexes. The respective initial distribution was Group 1, 147 (29%); Group 2A, 248 (49%); Group 2B, 60 (12%); Group 3, 48 (10%). The relative frequency of morphologies preceding the attainment of a pulse was as follows: Group 1, 30 (24%); Group 2A, 82 (65%); Group 2B, 8 (6%); Group 3, 6 (5%) (P less than or equal to 0.01 with no significant difference between Group 2B and 3).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Defining electromechanical dissociation: morphologic presentation. 254 35

The effects of a novel purine derivative, N6-[2-(4-chlorophenyl)-bicyclo-2.2.2.octyl-(3)]-adenosine (EMD 28422), that has been found to influence central benzodiazepine receptors, has been compared to those of other adenosine analogues such as L-phenylisopropyladenosine (L-PIA), cyclohexyladenosine (CHA) and adenosine-5'-N-ethyl-carboxamide (NECA). EMD 28422 was about 30 times less potent than CHA and 4 times less potent than NECA in displacing bound [3H]-L-PIA from specific binding sites in the rat brain, presumably reflecting adenosine A1-receptors. A similar relative potency was found using depression of field e.p.s.p. in the hippocampal slice in vitro. In isolated fat cells EMD 28422 was antilipolytic, but some 1000 times less potent than L-PIA. In rat isolated hippocampal slices, which have adenosine A2-receptors, EMD 28422 was more than 300 times less potent than NECA and in guinea-pig thymocytes, which similarly have A2-receptors, EMD 28422 was about 60 times less potent. The results are compatible with the opinion that EMD 28422 is a rather weak agonist at adenosine receptors, with limited selectivity for A1- or A2-receptors. The compound is highly lipophilic, which plays a role in determining its potency in a given biological system. The results are discussed in relation to reported adenosine modulation of benzodiazepine receptors.
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PMID:The adenosine receptor activity of EMD 28422, a purine derivative with reported actions on benzodiazepine receptors. 298 59

Phenylethylamine is an endogenous neuroamine conceptualized as the body's natural amphetamine. PEA has been suggested to play a role in the etiology of several neuropsychiatric disorders. Increased PEA turnover in phenylketonuria contributes to the pathophysiology of this condition. Depressed and chronic paranoid schizophrenic patients show decreased and increased PEA urinary excretion, respectively. Parkinsonian patients show decreased urinary PEA excretion. In animals, drugs that relieve or produce depression and parkinson result in increased or decreased brain PEA levels, respectively. PEA has been postulated to play a role in the etiology of migraine headache and aggression.
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PMID:Phenylethylamine in neuropsychiatric disorders. 635 95

The effects of the thiadiazinone derivative, 5-[1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydrochinolin-6-yl]-6-met hyl-3,6- dihydro-2H-1,3,4-thiadiazin-2-on (EMD 53998), and of its (+)EMD 57033 and (-)EMD 57439 enantiomers, were tested on the contractile properties and cytosolic [Ca2+] ([Ca2+]i) transients of single intact guinea pig cardiac myocytes. Cells were loaded with the ester form of the fluorescent probe, indo-1, and bathed in a N-2-hydroxyethyl-piperazine-N'-2-ethanesulfonic acid-buffered solution at 25 degrees C (1 mM of CaCl2, 1 Hz stimulation rate). All three substances exerted a pronounced increase in twitch amplitude: the maximal effect of the racemate (380% of control value) was approximately the sum of the effects of its two enantiomers (186 and 236% of control value for the (+)- and (-)-enantiomer, respectively). The [Ca2+]i transient, measured as the 410-to-490 nm indo-1 fluorescence ratio transient after excitation, was increased by the racemate and its (-)-enantiomer (172 and 152% of control value, respectively), but was not increased by the (+)-enantiomer. The racemate and the (-)-enantiomer, but not the (+)-enantiomer, markedly reduced the contraction duration and [Ca2+]i transient duration. In unstimulated cells resting length was significantly reduced by the (+)-enantiomer, and this was accompanied by a decrease in indo-1 fluorescence; the (-)-enantiomer had no effect on either parameter. In the presence of 2,3 butanedione monoxime (BDM), which markedly reduces twitch amplitude by inhibiting cross-bridge mechanics, addition of the (+)-enantiomer restored the twitch contraction to above the pre-BDM level without augmenting the [Ca2+]i transient. In contrast, the (-)-enantiomer failed to reverse the BDM-induced contractile depression, even though it caused a significant increase of the [Ca2+]i transient. Thus, in intact cells the positive inotropic effect of EMD 53998 is due to specific properties of its enantiomers: the (-)-enantiomer has adenosine 3',5'-cyclic monophosphate-like effects (increase in amplitude and reduction of [Ca2+]i transient and contraction durations), whereas the (+)-enantiomer enhances the myofilament-Ca2+ interaction.
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PMID:Enantiomeric dissection of the effects of the inotropic agent, EMD 53998, in single cardiac myocytes. 838 21

The thiadiazinone enantiomers [+]-EMD 60263 and [-]-EMD 60264 ((+)-5-(1-(alpha-ethylimino-3,4-dimethoxybenzyl)-1,2,3,4-tetrah ydroquinoline-6-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazine-2 -on) exhibit distinct stereoselectivity for Ca2+-sensitizing action ([+]-enantiomer) and phosphodiesterase inhibition ([-]-enantiomer). However, in isolated guinea pig papillary muscle, both compounds cause an action-potential prolongation that has been related to a nonselective depression of the delayed rectifier potassium current. Because [-]-EMD 60264 did not increase force of contraction despite phosphodiesterase inhibition, we postulated that one or several additional actions may oppose the anticipated positive inotropic effect. Therefore we investigated whether other membrane currents were also affected in voltage-clamped ventricular cardiomyocytes. Both [+]-EMD 60263 and [-]-EMD 60264 reduced sodium current as well as L-type calcium current in guinea pig ventricular myocytes, but steady-state inactivation or conductance curves of I(Na) and I(Ca) were not shifted along the voltage axis. Inward rectifier and transient outward current were studied in rat myocytes, but neither current was affected. We conclude that the positive inotropic action of [+]-EMD 60263 can be explained by prevalence of the Ca2+-sensitizing effect over its inhibitory actions on Na+ and Ca2+ current, whereas the negative inotropic effect of [-]-EMD 60264 may be caused by inhibition of I(Ca) predominating over PDE inhibition.
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PMID:Effects of the calcium sensitizer [+]-EMD 60263 and its enantiomer [-]-EMD 60264 on cardiac ionic currents of guinea pig and rat ventricular myocytes. 1002 41

Serotonin(1A) (5-HT(1A)) receptors have been implicated in the pathophysiology and treatment of anxiety and depression and are a target for novel drug development. In this qualitative study, positron emission tomography (PET) and [carbonyl-(11)C]WAY-100635 were used to assess 5-HT(1A) autoreceptor and postsynaptic receptor occupancy in man in vivo by five different compounds with nanomolar affinity for this site. Occupancy by pindolol, penbutolol, buspirone, EMD 68843, and S 15535 was compared to test-retest data from 10 healthy volunteers. All drugs, apart from buspirone, displayed occupancy at the 5-HT(1A) receptor site. Pindolol demonstrated a preferential occupancy at the autoreceptor compared to the postsynaptic receptor over a plasma range of about 10-20 ng/mL. Differential occupancy may be an important component of novel drug action. The level of autoreceptor or postsynaptic occupancy needed to achieve significant physiological effects is not known, although it is of note that none of the drugs in this study achieved occupancies beyond 60%. Overall this study demonstrates the utility of PET in aiding novel drug development.
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PMID:Drug action at the 5-HT(1A) receptor in vivo: autoreceptor and postsynaptic receptor occupancy examined with PET and [carbonyl-(11)C]WAY-100635. 1096 59

Myocardial stunning is a form of acute reversible cardiac dysfunction that occurs after brief periods of ischemia and reperfusion. In several animal models, stunning is associated with proteolytic truncation of troponin I (TnI). Mice expressing the same proteolytic TnI fragment [TnI-(1-193)] demonstrate cardiac depression with a decreased maximal calcium-activated tension. We therefore hypothesized preferential improvement in mice expressing TnI-(1-193) treated with the calcium-sensitizing drug EMD-57033. TnI-(1-193) and nontransgenic myofibrils exhibited significant sensitization to calcium in Mg-ATPase assays after EMD-57033 exposure. However, only transgenic myofibrils exhibited an increase in maximal activity (P = 0.023). EMD-57033 also increased maximal calcium-activated force in TnI-(1-193) muscle, such that it was comparable to nontransgenic cardiac muscle. EMD-57033 enhanced in vivo systolic function modestly in controls but had a marked effect in transgenic mice, with an almost threefold greater leftward shift of the end-systolic pressure-volume relation (P = 0.0005). These data indicate a targeted efficacy of EMD-57033 in offsetting the contractile defect in TnI-(1-193) mice, and this may have therapeutic implications in models displaying this myofilament defect.
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PMID:Augmented systolic response to the calcium sensitizer EMD-57033 in a transgenic model with troponin I truncation. 1469 78

Alteration in myofilament response to Ca2+ is a major mechanism for depressed cardiac function after ischemia-reperfusion (I/R) dysfunction. We tested the hypothesis that hearts with increased myofilament response to Ca2+ are less susceptible to I/R. In one approach, we studied transgenic (TG) mice with a constitutive increase in myofilament Ca2+ sensitivity in which the adult form of cardiac troponin I (cTnI) is stoichiometrically replaced with the embryonic/neonatal isoform, slow skeletal TnI (ssTnI). We also studied mouse hearts with EMD-57033, which acts specifically to enhance myofilament response to Ca2+. We subjected isolated, perfused hearts to an I/R protocol consisting of 25 min of no-flow ischemia followed by 30 min of reperfusion. After I/R, developed pressure and rates of pressure change were significantly depressed and end-diastolic pressure was significantly elevated in nontransgenic (NTG) control hearts. These changes were significantly blunted in TG hearts and in NTG hearts perfused with EMD-57033 during reperfusion, with function returning to nearly baseline levels. Ca2+- and cross bridge-dependent activation, protein breakdown, and phosphorylation in detergent-extracted fiber bundles were also investigated. After I/R NTG fiber bundles exhibited a significant depression of cross bridge-dependent activation and Ca2+-activated tension and length dependence of activation that were not evident in TG preparations. Only NTG hearts demonstrated a significant increase in cTnI phosphorylation. Our results support the hypothesis that specific increases in myofilament Ca2+ sensitivity are able to diminish the effect of I/R on cardiac function.
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PMID:Specific enhancement of sarcomeric response to Ca2+ protects murine myocardium against ischemia-reperfusion dysfunction. 1602 65

The phenomenology of pediatric bipolar disorder is a controversial topic in the field of child psychiatry. The first National Institute of Mental Health-funded study in the field, Phenomenology and Course of Pediatric Bipolar Disorders, selected a conservative phenotype for credibility in a contentious field. To address the problems of differentiation of mania from attention-deficit/hyperactivity disorder (ADHD) and of the ubiquitous manifestation of irritability across child psychiatry diagnoses, a prepubertal and early adolescent bipolar I disorder phenotype (PEA-BP) was defined by DSM-IV bipolar I disorder (manic or mixed phase) with elation and/or grandiosity as one criterion. This criterion avoided diagnosing mania by symptoms that overlapped with those of ADHD (e.g., hyperactivity, distractibility) and ensured that subjects had at least 1 of the cardinal symptoms of mania (i.e., elation or grandiosity). This definition was analogous to the requirement that DSM-IV major depressive disorder include at least 1 of the cardinal symptoms of depression (i.e., sad mood or anhedonia). Subjects were 93 children with a mean +/- SD age of 10.9 +/- 2.6 years. Validation of the phenotype was shown according to Robins and Guze criteria: unique symptoms that did not overlap with those of ADHD, stability of the diagnosis (did not become ADHD or other disorders on follow-up) as shown by a 4-year prospective longitudinal study, significantly higher familial aggregation of bipolar disorder in relatives of PEA-BP versus ADHD and healthy control probands, and family-based linkage disequilibrium of the brain-derived neurotrophic factor Val66 allele in PEA-BP probands. Furthermore, PEA-BP resembled the most severe adult bipolar disorder, manifested by a chronic, ultradian-cycling, mixed manic, psychotic course. A conservatively defined child mania phenotype met the Robins and Guze criteria for establishing diagnostic validity in psychiatric illness. Continuities between PEA-BP and adult bipolar disorder and relationships of PEA-BP to other descriptions of child mania are discussed.
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PMID:Prepubertal and early adolescent bipolar I disorder: review of diagnostic validation by Robins and Guze criteria. 1612 38


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