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)

Administration of the novel thiazole C-nucleoside, 2-beta-D-ribofuranosylthiazole-4-carboxamide (NSC 286193), to BDF1 mice bearing subcutaneous implants of P388 leukemia provoked a sharp depression in the concentration of intratumoral guanine nucleotides and a correspondingly large expansion of the IMP pools. Measurements of IMP dehydrogenase in the tumors of treated mice revealed that this enzyme was inhibited in a dose-responsive way, with approximately 50% inhibition engendered by the administration of the drug at a dose of 25 mg/kg and greater than 90% inhibition by all doses greater than 100 mg/kg. The inhibition of enzyme activity, seen after a dose of 250 mg/kg, reached a maximum 120 min after treatment and had subsided substantially 8 hr after dosing; by 24 hr. enzyme activity was fully restored. These results, coupled with the observation that the antitumor activity of the drug could be prevented in large part by the simultaneous administration of guanosine, support the conclusion that 2-beta-D-ribofuranosylthiazole-4-carboxamide, after anabolism, exerts its antineoplastic effects via a state of guanine nucleotide depletion. In extracts of the tumors of mice given parenteral injections of the thiazole nucleoside, a potent dialyzable inhibitor of IMP dehydrogenase was demonstrable: its concentration fluctuated in parallel with enzyme inhibition. Although the chemical identity of the proximate inhibitory species has yet to be established, it is concluded on kinetic grounds that it is neither the native nucleoside nor its 5'-monophosphate.
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PMID:Studies on the mechanism of action of 2-beta-D-ribofuranosylthiazole-4-carboxamide (NSC 286193)--II. Relationship between dose level and biochemical effects in P388 leukemia in vivo. 613 Jul 68

The pharmacological effects and metabolism of tiazofurin have been compared in the six transplantable tumors comprising the NCI rodent tumor panel, viz. the P388 leukemia (S); the L1210 leukemia (S); the Lewis lung carcinoma (S); the B16 melanoma (R); the colon 38 carcinoma (R); and the M5076 sarcoma (R), where (S) denotes sensitivity and (R) resistance to tiazofurin. In addition, a variant of the P388 leukemia rendered resistant to the drug in vitro, and maintaining stable resistance in vivo, P388/TR, was also studied. Intraperitoneal administration of tiazofurin (100 mg/kg) resulted in a 3- to 30-fold greater accumulation of thiazole-4-carboxamide adenine dinucleotide (TAD), the proposed active metabolite of the drug in S versus R lines. In general, levels of TAD, percent inhibition of IMP dehydrogenase (mean 40% in S versus 10% in R), depression in the concentration of guanosine nucleotides, (50% in S versus 20% in R) and percent elevation of levels of IMP (500% in S versus 60% in R) correlated well with sensitivity or resistance. However, the B16 melanoma, although resistant to tiazofurin treatment, showed certain biochemical features characteristic of an S line. The sensitive and resistant tumors displayed comparable abilities to phosphorylate tiazofurin, but there was significant depression only in the R lines of the pyrophosphorylase which converts tiazofurin-5'-monophosphate to TAD (mean 78 nmoles/mg protein/hr in S versus 22 nmoles/mg protein/hr in R). The naturally resistant tumors were also found to exhibit a greater ability to degrade synthetic TAD than the sensitive lines (mean 102 nmoles/mg protein/hr in R versus 29 nmoles/mg protein/hr in S lines). The state of sensitivity or resistance could not be attributed to the basal levels of IMP dehydrogenase, to the specific activities of the enzymes of purine salvage, or to the basal concentration of purine and pyrimidine nucleotides. Moreover, treatment with tiazofurin did not influence the enzymes of TAD synthesis or of purine salvage.
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PMID:Studies on the mechanism of action of 2-beta-D-ribofuranosylthiazole-4-carboxamide--V. Factors governing the response of murine tumors to tiazofurin. 614 62

ATP, ADP, AMP, IMP, adenosine, inosine and cyclic AMP were measured in slices of the rat hippocampus maintained in vitro. Immediately following cutting ATP was low (3.5 +/- 0.6 nmol/mg protein) and AMP high (8.6 +/- 0.9 nmol/mg), giving an energy charge of only 0.34 +/- 0.02. Over the next 90 min the energy charge gradually normalized (to 0.92 +/- 0.01), partly due to conversion of AMP to ATP, but mainly to breakdown to adenosine and other purines which were recovered in the incubation medium. Total purine content decreased from approximately 18 to 10 nmol/mg protein in the first hour following cutting. In slices from old rats the energy charge was lower 60 min following preparation than in younger rats, while cyclic AMP and adenosine levels were higher. The adenosine antagonist 8-phenyl-theophylline tended to enhance the recovery of responsiveness after preparation of the slices. Stimulation of excitatory afferent fibers at a frequency of 10 Hz for 5 min did not significantly alter the purine levels in brain slices, while hypoxia decreased the energy charge significantly and tended to increase adenosine levels. These changes occurred somewhat later than the fall in electrophysiological responsiveness. 8-Phenyl-theophylline was able to delay somewhat the decline in the amplitude of synaptic responses under hypoxic conditions. It is concluded that the viable part of the hippocampal slice, which accounts for about half of the tissue, has levels of adenine nucleotides and adenosine which are similar to those found in the intact rat brain. The return of electrophysiological function following slice preparation is paralleled by a normalization of the energy charge, the adenosine level and the concentration of cyclic AMP. The absence of electrophysiological activity following cutting, and the decreases in such responses following either prolonged afferent stimulation or hypoxia may be related to changes in purine concentration in the slice. Although adenosine accumulating in the slice may contribute to the depression of electrophysiological responses it is probably not the major factor responsible for the reduction in synaptic responsiveness.
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PMID:Levels of adenosine and adenine nucleotides in slices of rat hippocampus. 632 48

Tiazofurin and ribavirin are clinically used inhibitors of IMP dehydrogenase (DH), binding to the NAD and IMP sites, respectively, of the target enzyme. In patients with chronic granulocytic leukemia in blast crisis, daily tiazofurin infusions decreased the high IMP DH activity in blast cells and resulted in 77% response (G. Weber. In: R. A. Harkness et al., Purine and Pyrimidine Metabolism in Man, Vol. VII, Part B, pp. 287-292, 1991). However, patients relapsed in a few weeks with emergence of high IMP DH activity (G. Tricot et al., Int. J. Cell Cloning, 8: 161-170, 1990). The present study showed that the tiazofurin-induced depression of IMP DH activity in rat bone marrow can be maintained by ribavirin injection. Tiazofurin (150 mg/kg, i.p., once a day for 2 days) decreased IMP DH activity to 10% and ribavirin (250 mg/kg, i.p., once a day for the subsequent 3 days) maintained the enzymic activity at 20 to 30% of control values. In control rats where no ribavirin was given, IMP DH activity of the tiazofurin-treated rats rapidly returned to the range of untreated animals. The decrease of IMP DH activity (t1/2 = 2.6 h) sharply preceded that of the bone marrow cellularity (t1/2 = 17.4 h). In addition to the target enzyme, IMP DH, tiazofurin also decreased activities of the guanylate metabolic enzymes, guanine phosphoribosyltransferase and GMP reductase, and the pyrimidine salvage enzymes, deoxycytidine and thymidine kinases with t1/2 of 2.6, 4.7, 6.0, 3.4, and 6.5 h, respectively. In cycloheximide-treated rats, where much of protein biosynthesis was blocked, the t1/2(8) of these five enzymes in bone marrow were shorter, 1.6, 4.3, 3.0, 0.6, and 0.8 h, respectively. Thus, the impact of tiazofurin in the bone marrow entails a decrease in the activity of the target enzyme, IMP DH, and also of other enzymes in purine and pyrimidine biosynthesis as a result of the enzyme half-lives shortened by this drug. These novel observations should assist in achieving better protection and recovery of bone marrow during and after chemotherapy.
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PMID:Sequential impact of tiazofurin and ribavirin on the enzymic program of the bone marrow. 790 99

A patient with progressive supranuclear palsy (PSP) showing severe akinesia, postural instability and gait disturbance like frozen gait was treated with amitriptyline (30 mg/day). Four weeks after drug administration, we recognized tendencies for improvement on akinesia, postural instability, frozen gait and vertical gaze palsy. Thereafter, gait disturbance almost disappeared and slow motor response and depression also improved with the amitriptyline for 8 weeks. The changes of cerebral blood flow (CBF) with amitriptyline treatment were evaluated in this case by 123I-IMP single photon emission computed tomography. Before the treatment, clear reduction of CBF was shown in the frontal lobes, especially in the frontal cortices, while this frontal hypoperfusion markedly improved 6 weeks after the treatment. These results, showing marked improvements of frontal hypoperfusion, as well as parkinsonism with amitriptyline treatment, may imply possibilities that these symptoms of PSP result from the frontal hypoperfusion and the improvement of the hypoperfusion with amitriptyline is involved in the improvement of these symptoms.
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PMID:[A case of progressive supranuclear palsy showing marked improvements of frontal hypoperfusion, as well as parkinsonism with amitriptyline]. 833 95

The regional distribution of I-123 iofetamine (IMP) in the brain of 12 patients with rapid cycling bipolar disorder was studied by single-photon computed emission tomography imaging. Patients who were either medication free (n = 4) or on lithium monotherapy (n = 8) were assessed serially in depressed/dysphoric, manic/hypomanic, or euthymic states. In 23 imaging studies, IMP images of the brain were taken on a GE Starcam system 20 min after injection of 3-4 mCi of I-123 labeled IMP. The I-123 IMP distribution in the anterior part of the temporal lobes was asymmetric in both depression/dysphoria and mania/hypomania but not in euthymia. Images taken sequentially on the same patient showed temporal lobe asymmetry in the pathological mood states that diminished or disappeared in the euthymic state. The observed changes most likely reflect an altered cerebral blood flow and changes in high-affinity IMP binding to amine receptors in the temporal lobes. This pilot study suggests the presence of a state-dependent temporal dysfunction in bipolar disorder.
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PMID:I-123 iofetamine single-photon computed emission tomography in rapid cycling bipolar disorder: a clinical study. 901 85

The purpose of this paper was to clarify critical aspects of the behavior of signal transduction activity in normal and cancer cells. 1. Signal transduction activity in the conversion of phosphatidylinositol through PI and PIP kinases and PLC to IP3 is regulated at multiple sites. In liver, hepatomas and human carcinomas PIP kinase is the rate limiting enzyme and PLC activity is present in great excess. 2. The steady-state signal transduction activity as measured by the three enzyme activities and IP3 concentration was markedly up-regulated in rat hepatomas of different growth rates. The steady-state specific activities of the three signal transduction enzymes were elevated in ovarian carcinomas as compared to normal ovary. Increased enzyme activities were also observed in human breast carcinoma cells as compared to normal human breast parenchymal cells. In breast, ovarian and rat hepatoma cells as they go through lag, log and plateau phases, IP3 concentration in the early lag phase increased 4.5- to 20-fold and PI and PIP kinase activities peaked in mid-log phase. These events returned to baseline levels in the plateau phase. PLC activity did not change. 3. The bone marrow PI and PIP kinase activities in 3-day starvation were decreased to 13% and IP3 concentration was reduced to 24%; at 1-day refeeding they returned to normal. PLC activity changed little. These alterations are in line with the rapid t1/2 degradation rates (12 min) of PI and PIP kinases observed in studies with cycloheximide. By contrast, PLC has a long half-life. 4. The molecular action of tiazofurin entails inhibition of IMP DH activity, decrease in GTP and IP3 concentrations, reduction of ras and myc oncogene expression, and signal transduction enzyme activities. These events are followed by induced differentiation and apoptosis. There are also decreases in enzyme activities which have rapid turnover, including TdR kinase, dTMP synthase, and GPRT. In vitro studies indicated that these events are abrogated by addition of guanine which restores GTP concentrations. Therefore, most or all these events were brought about by the reduced GTP concentration in the tiazofurin target cells. 5. Quercetin and genistein are able to inhibit PI and PIP kinase activities and reduce IP3 concentration in vivo and in tissue culture systems. These flavonoids are also inhibitors of cell proliferation and clonogenic ability in rat hepatoma 3924A and in human OVCAR-5 and MDA-MB-435 cells. Quercetin down-regulated the expression of c-myc and Ki-ras oncogenes and led to induced differentiation and apoptosis in K562 cells. Genistein reduced IP3 concentration in vivo and in the tissue culture system. Genistein is antiproliferative and has cytototoxicity in human carcinoma cells. All three drugs, tiazofurin, quercetin and genistein, act, in part at least, through depression of cellular IP3 concentration although the mechanisms may not be identical. 6. Quercetin and genistein, which attack different targets and different phases of the cell cycle, proved to be synergistic in OVCAR-5 cells. The impact of tiazofurin, genistein and quercetin is of interest because the drugs crucially inhibit the display of the neoplastic program of cells and lead to induced differentiation and apoptosis.
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PMID:Regulation of the signal transduction program by drugs. 938 80

Alpha, omega-adenine dinucleotides (Ap(n)A) consist of two adenosine molecules linked at the 5' position by phosphate groups, the number of which is denoted by n and can range from 2 to 6. The aim of this study was to investigate the effect of Ap4A and Ap5A on the rate of epileptiform activity. Hippocampal slices (450 microm), when perfused with a medium containing no added magnesium and 4-aminopyridine (50 microM), generate epileptiform activity of an interictal nature. Ap4A and Ap5A at 1 microM depressed the discharge rate to a significant extent. At this concentration adenosine (1 microM) did not produce any effect. However at 10 microM adenosine, Ap4A and Ap5A all decreased the burst frequency. Adenosine deaminase (0.2 U/ml) totally annulled the inhibition of epileptiform activity produced by 10 microM adenosine or 1 microM Ap4A and Ap5A. Adenosine deaminase did not significantly change the maximum depression of activity produced by 10 microM Ap4A and Ap5A. 8-cyclopentyl-1,3-dimethylxanthine, an A1, receptor antagonist, increased the basal rate of epileptiform activity and prevented the depression of burst discharges by Ap4A. 5'-adenylic acid deaminase converts AMP into IMP which is inactive. 5'-adenylic acid deaminase did not prevent the inhibitory effects of Ap4A. The results suggests that in the CA3 region of the hippocampus, Ap4A and Ap5A act partly by stimulating xanthine-sensitive receptors directly and partly through the formation of the metabolite, adenosine.
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PMID:The effects of adenine dinucleotides on epileptiform activity in the CA3 region of rat hippocampal slices. 960 13

A 13-year-old mentally retarded boy suffered from repeated vomiting attacks since infancy. Each episode lasted 2 to 10 days, and was precipitated by respiratory infection, exercise or stress. During an attack he became irritated, agitated and amnesic, but did not have headaches or seizures. Associated findings were transient elevation of serum creatine kinase (CK) (331-3381 IU/l), and of plasma ACTH and cortisol. The raised CK level was the result of muscle hypertonicity. Ictal EEGs showed delta activity in the front-temporal areas, and inter-ictal IMP-SPECT revealed hypoperfusion in both temporal regions. Unlike the periodic ACTH-ADH discharge syndrome, neither hypertension nor depression developed. These attacks were diagnosed as a migraine equivalent and were suppressed with phenytoin. From the EEG and SPECT findings, we concluded that the vomiting and behavioural changes were related to the paroxysmal vascular abnormality in the temporal regions, but it was not easy to make the distinction between migraine and focal epilepsy. Before a diagnosis of the periodic ACTH-ADH discharge syndrome is made, the possibility of migraine equivalent should be considered.
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PMID:Cyclic vomiting and elevation of creatine kinase associated with bitemporal hypoperfusion and EEG abnormalities: a migraine equivalent? 962 97

Alcoholism, especially the urge to drink and relapse from abstinence, is deeply associated with obsession. And also alcoholics on abstinent 10 years or more are still higher on the obsessive-compulsive symptom dimension more than the depression and interpersonal sensitivity. Obsession was introduced by Kraepelin in 1915 and has been studied extensively since. When a person with obsession becomes exhausted with chronic rumination accompanied suspicion, he or she is driven to impulsive acts like alcoholics, and develops a personality disorder that displays persistent abnormal activities. Impulsive-compulsive spectrum characterizes by dimensions of risk-aversive/risk-seeking and harm-avoidant/harm- minimizing behaviors. Disorders on the compulsive end of the spectrum include obsessive-compulsive disorder, hypochondriasis, body dysmorphic disorder, anorexia nervosa an depersonalization. Mixed compulsive and impulsive disorders include Tourette's disorder, trichotillomania, pathologic gambling, sexual compulsions and alcoholism. Disorders on the impulsive end of the spectrum include borderline personality disorder and antisocial personality disorder. Using 123I-IMP SPECT, regional cerebral blood flow significantly decreased in alcoholics without Korsakoff sign (WAIS FIQ 90 or over) than alcoholics with Korsakoff signs (WAIS FIQ 89 or under) and control on the frontal lobe and thalamus. Recent model of obsessive-compulsive pathophysiology demonstrating that cortical regions have different effects on the direct and indirect pathways, indicates that the the different effects of serotonergic agents in the cortex alone could result in a change in balance between the direct versus indirect basal ganglia pathway. This article reviews alcoholism and obsession, ego dystonic and ego syntonic, approach-avoidance conflict, a recent biological approach to alcoholics and a spectrum for obsession.
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PMID:[Dependence and obsession]. 1020 21


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