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)

Various nitrogen analogs of delta6a,10a-tetrahydrocannabinol were synthesized by a general procedure described in an earlier communication. Minimum effective doses (MED50's) and lethal doses (LD50's) were determined by a modified Irwin mouse screen after iv administration of compounds in PEG 200. The most potent compounds were the propargyl (5t), allyl (5m), and chloroallyl (5o-q) derivatives. Overt behavioral effects (CNS depression, static ataxia, and hypersensitivity) of 5t and Roger Adams' carbocyclic analog (III) were found to be similar in the mouse, cat, dog, and monkey. Dichloroisoproterenol prevented and reversed many of the depressant effects of both III and 5t but had no effect on the ataxia produced by these compounds. In antinociceptive tests, 5t was active in the phenylquinone and Eddy hot-plate tests but was inactive in the tail-flick test.
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PMID:Drugs derived from cannabinoids. 1. Nitrogen analogs, benzopyranopyridines and benzopyranopyrroles. 81 19

We have used 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) as a selective and irreversible inhibitor of oxidized glutathione reductase (GSSG-R) to determine how human erythrocytes with various degrees of GSSG-R deficiency recover their reduced glutathione (GSH) after exposure to acetylphenylhydrazine or diamide. Pentose phosphate dehydrogenases and glutathione synthesis were not inhibited, de novo glutathione synthesis was negligible within the experimental time frame, and the reappearance of GSH was strictly under the control of GSSG-R. Results obtained with acetylphenylhydrazine or diamide were concordant. In red cells stressed by these reagents, GSSG-R deficiency began to impair the regeneration of GSH only after greater than 80% of the normal enzyme activity had been abolished. Thereafter GSH recovery deteriorated as drug-induced GSSG-R depression increased. Only erythrocytes that had been rendered almost totally GSSG-R deficient, that is, had lost greater than 90% of baseline activity, became functionally equivalent to GdA- glucose-6-phosphate dehydrogenase-deficient cells. The reserve capacity of GSSG-R in human erythrocytes is extremely large. Of all types of isolated GSSG-R "deficiencies" reported so far, only two can be considered pathogenically significant: the homozygous genetic defect found in a single family, and much more commonly, the acute pharmacologic phenocopy induced by BCNU.
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PMID:Consequences of erythrocytic glutathione reductase deficiency. 357 7

1. Rat kidney cortical slices, with metabolism suppressed by iodoacetate, were incubated anaerobically at 26 degrees C in hyperosmotic saline media. Changes in tissue composition with time, up to 12 hr, were studied. Despite initial shrinkage, gross swelling occurred, even in saline media of more than twice the concentration of normal extracellular fluid.2. The composition of non-metabolizing kidney slices incubated at 26 degrees C in a balanced saline medium containing 7 g polyethylene glycol 6000 (PEG 6000)/100 ml. was determined at intervals up to 12 hr. The tissue water, sodium and chloride contents had reached constant levels by 6 hr. Potassium continued to leak slowly from the tissue, but there was no significant further loss between 10 and 12 hr.3. Non-metabolizing kidney slices were incubated in PEG medium containing additional quantities of either a non-electrolyte (400 m-osmole glucose/kg H(2)O) or an electrolyte (400 m-osmole NaCl/kg H(2)O), both of which penetrated the tissue to attain approximately uniform concentrations in cells and media. Whereas the slices in the glucose medium attained the same equilibrium water content as those incubated in PEG medium alone, the final water content of slices in the medium containing additional NaCl was significantly lower. This difference might have resulted from depression of intracellular colloid osmotic pressure by the high salt concentration.
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PMID:The effects of high concentrations of an electrolyte on the swelling of non-metabolizing tissue slices. 555 65

Production of oxygen-free radicals has been proposed as one pathophysiologic mechanism for postburn cardiac contractile dysfunction in adults. To examine this hypothesis in young subjects, we studied the cardiac effects of polyethylene glycol-superoxide dismutase (PEG-SOD) and PEG-catalase (PEG-CAT), each given as 20 U/g of body weight with fluid resuscitation (Parkland formula), after a third-degree burn constituting 33% of the total body surface area in young (6- to 7-day old) guinea pigs (group 3, n = 12). Fluid-treated burns without scavenger therapy (group 2, n = 15) and sham burn controls (group 1, n = 15) were included. Animals were killed 24 hours postburn, and hearts were studied in vitro (Langendorff). Compared with sham burn controls, fluid-treated burns (group 2) had significant cardiac dysfunction as indicated by a lower peak systolic left ventricular (LV) pressure (LVP: 67 +/- 2 vs. 57 +/- 4 mm Hg, p = 0.01, mean +/- SEM), maximal rate of LV pressure development (+dP/dt max: 1169 +/- 45 vs. 988 +/- 45 mm Hg/second, p = 0.01), and fall (-dP/dt max: 1109 +/- 45 vs. 919 +/- 49 mm Hg/second, p = 0.01). In addition, LV function curves calculated for group 2 were shifted downward and to the right of those calculated for sham burn controls in the direction of contractile depression, p = 0.01. PEG-SOD/PEG-CAT treatment in burns did not significantly improve LVP (60 +/- 5 mm Hg), but scavenger therapy improved +/-dP/dt max values (1112 +/- 74 and 988 +/- 98 mm Hg/second, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The role of toxic oxygen metabolites in a young model of thermal injury. 747 25

The effect of adding cottonseed hulls to casein- and cottonseed-kernel-based diets on the apparent and true ileal digestibility of N and amino acids, and the proportion of this effect accounted for by condensed tannin (CT), were determined using the growing rat. Sixty rats were allocated randomly to ten semipurified diets, containing either casein (four diets) or purified unheated solvent-extracted cottonseed kernel (six diets) as the sole protein source, with Cr2O3 added as an indigestible marker. Two of the casein diets contained no hulls whilst the remaining two diets contained 70 g cottonseed hulls/kg. Two of the cottonseed-kernel-based diets contained no hulls, with two containing 23 g hulls/kg and the remaining two containing 46 g hulls/kg. For each pair of diets, PEG was either included or excluded. The effect of CT was quantified by comparing control rats (-PEG; CT acting) with PEG-supplemented rats (+PEG; CT inactivated) at each level of dietary hulls. The rats were given their respective experimental diets for 14 d. Each rat was given the food ad libitum for 10 min hourly from 08.00 to 18.00 hours. On day 14, samples of digesta were collected at death from the terminal 150 mm of ileum at 7 h from the first meal. Apparent and true ileal digestibilities were calculated for DM, N and the individual amino acids. The principal finding was that the inclusion of hulls depressed the apparent and true ileal digestibilities of N and amino acids, but with the response differing between diets. With the casein-based diet the mean apparent and true ileal amino acid digestibilities were significantly depressed from 0.89 and 0.96 to 0.85 and 0.92 respectively, by the inclusion of 70 g hulls/kg in the diet, and addition of PEG then restored these to 0.89 and 0.95. All of the depression could be explained by the CT content of the hulls. However, with the cottonseed-kernel-based diet the responses fell into three categories. The apparent and true ileal digestibilities of the essential amino acids cystine and methionine were not affected by hull addition, ileal digestibilities of leucine, isoleucine, lysine, threonine and valine were markedly depressed by hull addition with approximately 50% of the depression being explained by CT, whilst the ileal digestibilities of histidine, arginine and phenylalanine were depressed by hull addition but little or none of this effect could be explained by CT. Thus the effect of hulls on protein digestion clearly differed with source of protein. With the cottonseed-kernel-based diet it seems that components of the hulls other than CT also depressed the apparent and true ileal digestibilities of N and amino acids. The identity of these components is unknown.
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PMID:The effect of cottonseed condensed tannins on the ileal digestibility of amino acids in casein and cottonseed kernel. 869 96

We investigated the effect of hemorrhagic shock and reinfusion on the cardiac function and contractility, plasma CK and CK-MB activity and lactate concentration, oxyradical-producing activity of polymorphonuclear leukocytes (PMNL-CL), cardiac chemiluminescence (LV-CL), antioxidant enzyme activity [superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-PX)] and malondialdehyde (MDA) concentration in anesthetized dogs to determine the role of oxyradicals in cardiac depression and cellular injury in hemorrhagic shock and reinfusion. The dogs were assigned into three groups: I (sham), 4 h duration; II (S + R), 2 h of shock followed by reinfusion for 2 h; III (SOD + S + R), as II but pretreated with PEG-SOD. Hemorrhagic shock was produced by withdrawal of blood to maintain the mean arterial pressure at 50 +/- 5 mm Hg. Cardiac function and contractility were depressed during hemorrhagic shock. Plasma CK, CK-MB and lactate increased during shock. Following reinfusion after 2 h of shock hemodynamic parameters and plasma lactate tended to return towards control values. Plasma CK and CK-MB, PMNL-CL and cardiac MDA, total-, Mn- and CuZn-SOD activity increased while LV-CL decreased. In spite of the increase in the antioxidant reserve, there was oxidative damage. Pretreatment with SOD attenuated the deleterious effects of shock and reinfusion on the cardiovascular function, plasma CK, and CK-MB, PMNL-CL, cardiac MDA, SOD, and LV-CL. Protection was incomplete for cardiovascular function and plasma CK and CK-MB. These results suggest that oxyradicals may partly be involved in the deterioration of cardiovascular function and cellular injury during hemorrhagic shock and reinfusion.
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PMID:Cardiac depression and cellular injury in hemorrhagic shock and reinfusion: role of free radicals. 940 75

The bioavailability of buprenorphine, HCl (BPP) in sheep after nasal administration of two formulations has been studied. 0.9 mg BPP in 150 microl was administered nasally and compared to 0.6 mg i.v. The test solutions were formulated with 30% polyethylene glycol 300 (PEG 300) and 5% dextrose, respectively. The bioavailability for PEG 300 was 70% (S.D.+/-27%, n=6), whereas the bioavailability for 5% dextrose was 89% (S.D.+/-23%, n=6). A two-compartment model with initial and terminal serum half-lives of 10 and 23 min, respectively, may describe the pharmacokinetics. The rate of absorption for both nasal formulations was very fast (t(max)=10 min). The C(max) was 37 ng/ml (S.D.+/-17) and 48 (S.D.+/-10) for PEG 300 and dextrose, respectively. No significant difference was found between the two formulations, but PEG 300 has advantages in relation to freezing point depression and solubility, which may be considered if further studies are going to be initiated. The high nasal bioavailability and short time to maximal plasma concentration suggests that it is possible to make a clinically relevant nasal formulation of BPP for the treatment of pain.
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PMID:Intranasal absorption of buprenorphine--in vivo bioavailability study in sheep. 1100 May 52

Thermoanalytical, chromatographic, and microscopic methods of analysis were used for identification of hard dispersions (HD) and their differences from physical mixtures (PM) by benzene PEG-4000 model systems. A complex of physiocochemical methods showed that benzonal and PEG-4000 are not thermally destroyed during simultaneous melting at 140 degrees C. Differences in thermoanalytical characteristics of PM and HD, expressed in suppression of phase transition temperatures, changes in the type of melting peaks and heats, and in the absence of drug melting peak and heats in HD vs. PM confirm the formation of new physiochemical systems differing from PM. The resultant quantitative relationships between temperature depression and melting heats for HD and PM of different composition correlate with chromatographic findings.
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PMID:[Prospects of using hard dispersions in development of dosage forms for therapeutic and prophylactic use]. 1125 53

A single dose of Mpl ligand (Mpl-L) given immediately after lethal DNA-damaging regimens prevents the death of mice. However, the mechanism of this myeloprotection is unknown. The induction of p53-dependent apoptosis in response to DNA damage signals suggests that immediate administration of Mpl-L may inhibit p53-dependent apoptosis. This hypothesis was tested by administering a single injection of pegylated murine Megakaryocyte Growth and Development Factor (PEG-rmMGDF, a truncated recombinant Mpl-L) to p53(-/-) and wild-type mice immediately after carboplatin (80 mg/kg) and 7.5 Gy total body gamma-irradiation. PEG-rmMGDF was required to prevent the death of wild-type mice, whereas p53(-/-) mice survived with or without the exogenous cytokine. The degree of platelet depression and subsequent recovery was comparable in p53(-/-) mice to wild-type animals given PEG-rmMGDF. Hence, either Mpl-L administration or p53-deficiency protected multipotent hematopoietic progenitors and committed megakaryocyte precursors. The myelosuppressive regimen induced expression of p53 and the p53 target, p21(Cipl) in wild-type bone marrow, indicating that Mpl-L acts downstream of p53 to prevent apoptosis. Constitutive expression of the proapoptotic protein Bax, was not further increased. Bax(-/-) mice survived the lethal regimen only when given PEG-rmMGDF; however, these Bax(-/-) mice showed more rapid hematopoietic recovery than did identically-treated wild-type mice. Therefore, administration of Mpl-L immediately after myelosuppressive chemotherapy or preparatory regimens for autologous bone marrow transplantation should prevent p53-dependent apoptosis, decrease myelosuppression, and reduce the need for platelet transfusions.
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PMID:Mpl ligand prevents lethal myelosuppression by inhibiting p53-dependent apoptosis. 1156 94

Chronic hepatitis C (HCV) infection affects more than 170 million people throughout the world and 2 to 3 million Americans. End-stage liver disease secondary to chronic HCV infection is the most frequent indication for liver transplantation in this country. Currently, the gold standard for treatment for immunocompetent patients is a combination of peginterferon (PEG-IFN) and ribavirin for 6 to 12 months depending on the genotype. This treatment achieves a sustained virological response (SVR) in 54% to 61% of patients overall. Almost 50% of patients do not respond or have recurrences posttreatment and progress in over 10 to 20 years into chronic liver disease and its complications. Liver transplantation is the only therapeutic modality that impacts on quality of life and survival of these patients. However, recurrence of HCV in the new allograft is universal with accelerated progression to cirrhosis in 5 to 10 years. Response to treatment is usually low (20% to 30%), and associated with significant side effects and depression. A significant percentage of patients with recurrent HCV after transplantation require retransplantation to control the complications of end-stage liver disease. Other solid organ transplants recipients already HCV-positive, or infected at the time of transplantation from blood transfusions or an infected graft, develop accelerated, progressive liver disease facilitated by the adverse effects of immunosuppression in addition to HCV replication. To prevent morbidity, mortality, and high costs related to the consequences of HCV infection, all solid organ transplant candidates should be tested for HCV infection and treated appropriately with PEG-IFN and ribavirin prior to transplantation.
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PMID:Should patients with chronic hepatitis C infection be transplanted? 1525 56


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