Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024312 (lymphopenia)
 4,859 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Codeine is used in a variety of pharmaceuticals including analgesics, sedatives, hypnotics, antiperistaltics, and antitussive agents. The National Cancer Institute and the Food and Drug Administration nominated codeine for study because it is a widely used drug and it is representative of the morphine class of compounds, for which chronic carcinogenicity studies had not been conducted. The oral route of administration was selected because it is the primary route of human exposure. Male and female F344/N rats and B6C3F1 mice were given codeine (99% pure) in feed for 14 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and cultured Chinese hamster ovary cells. 14-DAY STUDY IN RATS: Groups of five male and five female F344/N rats were given 0, 1,562, 3,125, 6,250, 12,500, or 25,000 ppm codeine in feed for 14 days, which resulted in daily doses of approximately 125, 250, 450, 650, or 750 mg codeine/kg body weight to males and 125, 250, 500, 700, or 300 mg/kg to females. One female exposed to 6,250 ppm, one male and three females exposed to 12,500 ppm, and all males and females exposed to 25,000 ppm died during the study. Final mean body weights and mean body weight gains of all exposed groups except 1,562 ppm females were significantly lower than those of the controls. No chemical-related gross lesions were observed in rats at necropsy. Thickening of the forestomach mucosa (hyperplasia and hyperkeratosis) and lymphoid depletion of the thymus in exposed males and females and testicular degeneration in exposed males, observed primarily in the 12,500 and 25,000 ppm groups, were associated with decreased survival and increased morbidity in these groups. 14-DAY STUDY IN MICE: Groups of five male and five female B6C3F1 mice were given 0, 781, 1,562, 3,125, 6,250, or 12,500 ppm codeine in feed for 14 days, which resulted in daily doses of approximately 150, 300, 600, 1,300, or 3,000 mg codeine/kg body weight to males and 200, 400, 750, 1,500, or 3,000 mg/kg to females. All mice survived to the end of the study. The final mean body weight of 3,125 ppm females was significantly greater than that of the controls; the final mean body weight of 12,500 ppm females and the mean body weight gains of 12,500 ppm males and females were significantly lower than those of the controls. Absolute and relative liver weights of 3,125, 6,250, and 12,500 ppm males and of 12,500 ppm females and the absolute and relative right kidney weights of 12,500 ppm males were significantly lower than those of the controls. No gross or histopathologic lesions were attributed to codeine exposure. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were given 0, 390, 781, 1,562, 3,125, or 6,250 ppm codeine in feed for 13 weeks, which resulted in daily doses of approximately 25, 50, 100, 200, or 450 mg codeine/kg body weight to males and 25, 50, 100, 250, or 500 mg/kg to females. There were no chemical-related deaths during the study. Final mean body weights and mean body weight gains of all groups of exposed males and of females exposed to 1,562, 3,125, and 6,250 ppm were significantly lower than those of the controls. Feed consumption decreased with increasing exposure concentration during the first week of the study; however, by the end of the study, feed consumption by most exposed groups was similar to that by the controls. There were alterations of various hematology and clinical chemistry parameters at the end of the study. There was a mild dose-dependent lymphopenia in females receiving 1,562 ppm and above and in 6,250 ppm males. There also was a minimal to mild macrocytosis that occurred in all exposed groups of males and in females exposed to 781, 3,125, or 6,250 ppm. No significant differences between control and exposed rats were observed in sperm morphology or vaginal cytology parameters. Absolute and relative adrenal gland weights of exposed males and of 3,125 and 6,250 ppm females were significantly greater than those of the controls. Absolute and relative liver weights of exposed males werees were significantly lower than those of the controls. Relative thymus weights of 3,125 and 6,250 ppm males were significantly lower than that of the controls. No chemical-related gross or histopathologic lesions were observed in male or female rats. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were given 0, 390, 781, 1,562, 3,125, or 6,250 ppm codeine in feed for 13 weeks, which resulted in daily doses of approximately 60, 120, 260, 460, or 1,000 mg codeine/kg body weight to males and 60, 130, 280, 530, or 1,200 mg/kg to females. Two male mice in the 3,125 ppm group died during week 7. All other mice survived to the end of the study. Final mean body weights of exposed males and females were similar to those of the controls. Feed consumption by exposed males and females was similar to that by the controls. Abnormal posture was observed in all exposed groups of males. There were no significant differences in hematology or urinalysis parameters in male or female mice. Minor, sporadic changes occurred in a few of the clinical chemistry parameters; they were not considered biologically significant. No significant differences in sperm morphology or vaginal cytology were attributed to codeine exposure. Absolute and relative kidney weights of 3,125 and 6,250 ppm males were lower than those of the controls. No chemical-related differences in organ weights were observed in females. No chemical-related gross or histopathologic lesions were observed in male or female mice. 2-YEAR STUDY IN RATS: Groups of 60 male and 60 female F344/N rats were fed diets containing 0, 400, 800, or 1,600 ppm codeine for up to 106 weeks, with 9 or 10 rats per group evaluated at 15 months. These exposure concentrations resulted in average daily doses of approximately 15, 30, and 70 mg codeine/kg body weight to males and 15, 40, and 80 mg/kg to females. Survival, Body Weights, Feed Consumption, and Clinical Findings Survival of 400 ppm females was significantly greater than that of the controls; survival of all groups of exposed males and of 800 and 1,600 ppm females was similar to that of the controls. There was an exposure-related decrease in mean body weights of males and females. The final mean body weight of 1,600 ppm males was 88% that of the controls, and the final mean body weight of 1,600 ppm females was 89% that of the controls. Feed consumption by exposed groups was similar to that by the controls. Chemical-related clinical findings were limited to ocular discharge in exposed males and females. Pathology Findings: Absolute and relative adrenal gland weights of 800 and 1,600 ppm males were significantly greater than those of the controls at 15 months. There were no increased incidences of neoplasms attributable to codeine exposure at any site. At 2 years, there were exposure-related decreases in the incidences of adrenal medulla hyperplasia in males and females. There was an exposure-related decrease in the incidence of benign pheochromocytomas in males, and the incidences in exposed males were significantly lower than that in the controls. In 1,600 ppm females the incidences of mammary gland fibroadenomas and of fibroadenomas or adenocarcinomas (combined) were significantly lower than those in the controls. The decreased incidences of benign pheochromocytomas in males and mammary gland neoplasms in females were considered to be related to codeine exposure. 2-YEAR STUDY IN MICE: Groups of 60 male and 60 female B6C3F1 mice were fed diets containing 0, 750, 1,500, or 3,000 ppm codeine for up to 106 weeks, with 9 or 10 mice per group evaluated at 15 months. These exposure concentrations resulted in average daily doses of approximately 100, 200, or 400 mg codeine/kg body weight to males and females. Survival, Body Weights, Feed Consumption, and Clinical Findings: Survival of exposed males and females was similar to that of the controls. Mean body weights of 750 and 1,500 ppm males and females were similar to those of the controls throughout most of the study. Mean body weights of 3,000 ppm males and females were less than those of the controls from about week 13, and the final mean body weights of these groups were 86% and 82% those of the respective controls. Feed consumption by exposed groups was similar to that by the controls. Pathology Findings: There were no increased incidences of neoplasms attributable to codeine exposure at any site. At 15 months, the incidence of thyroid gland follicular cell hyperplasia in 3,000 ppm males was significantly greater than that of the controls, and this lesion was observed in 1,500 and 3,000 ppm females. At 2 years, the incidences of follicular cell hyperplasia in all exposed groups of mice were significantly greater than those in the controls, but there were no increases in thyroid gland follicular cell neoplasms. The incidence of centrilobular fatty change in the liver of 3,000 ppm males was significantly lower than that in the controls at 15 months, and the decreased incidence appeared to be related to exposure level. At 2 years, the incidences of eosinophilic foci, foci of fatty change, centrilobular cytomegaly, and centrilobular fatty change in 3,000 ppm males were lower than those in the controls. The incidence of hepatocellular adenomas and the incidence of hepatocellular adenomas or carcinomas (combined) in 3,000 ppm males and females were significantly lower than those in the controls; this was considered to be related to lower body weights in these groups. GENETIC TOXICOLOGY: Codeine phosphate was not mutagenic in any of four strains of Salmonella typhimurium, with or without S9 metabolic activation enzymes. In cytogenetic tests with cultured Chinese hamster ovary cells, codeine phosphate induced dose-related increases in sister chromatid exchanges, with and without S9, only at concentration levels that caused cell cycle delay. No induction of chromosomal aberrations was noted in cultured Chinese hamster ovary cells treated with codeine phosphate, with or without S9. CONCLUSIONS: Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity of codeine in male or female F344/N rats exposed to 400, 800, or 1,600 ppm. There was no evidence of carcinogenic activity of codeine in male or female B6C3F1 mice exposed to 750, 1,500, or 3,000 ppm. Thyroid gland follicular cell hyperplasia was increased in exposed male and female mice. Decreased incidences of benign pheochromocytomas of the adrenal medulla in male rats and mammary gland fibroadenomas and fibroadenomas or adenocarcinomas (combined) in female rats were related to codeine exposure. Synonyms: 7,8-didehydro-4,5-epoxy-3-methoxy-17-methylmorphinan-6-ol; methylmorphine; 3-0-methylmorphine monohydrate; N-methylnorcodeine; morphine-3-methyl ether; morphine monomethyl ether Trade names: Codeinum, Codicept, Coducept, Metilmorfina
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PMID:NTP Toxicology and Carcinogenesis Studies of Codeine (CAS No. 76-57-3) in F344 Rats and B6C3F1 Mice (Feed Studies). 1258 21

FTY720 (2-amino-[2-(4-octylphenyl) ethyl]-1,3-propanediol hydrochloride) is an immunosuppressive agent that inhibits allograft rejection. We recently demonstrated that FTY-phosphate, the active metabolite of FTY720, acts as a full agonist for sphingosine-1-phosphate (S1P) receptors. Furthermore, activation of S1P receptors with their natural ligand, S1P, as well as pharmacological ligands leads to lymphopenia, probably due to sequestration of lymphocytes in secondary lymphoid organs. In the present study we used a local Ag-challenged mouse model to examine the effects of FTY720 on T cell activation in the draining lymph node (DLN) and on the release of activated T cells to the peripheral blood compartment. We showed that the number of Ag-activated CD4(+) T cells in the DLN after injection of Ag and CFA into a footpad was dramatically reduced after FTY720 treatment. However, T cell proliferation, both in vitro and in vivo, was not impaired by FTY720. Our results suggest that the reduced efficiency of T cell responses in the DLN in response to a local Ag is probably due to a defective recirculation of naive T cells caused by FTY720 treatment. Furthermore, we found that the numbers of naive and Ag-activated CD4(+) T cells in the peripheral blood of Ag-challenged mice were equally reduced with FTY720 treatment, suggesting that both T cell subsets are sequestered in the DLNs. Thus, FTY720 induces immunosuppression through inhibition of both the recirculation of naive T cells and the release of Ag-activated T cells from the DLN to lymph and to the blood compartment.
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PMID:Sphingosine-1-phosphate receptor agonism impairs the efficiency of the local immune response by altering trafficking of naive and antigen-activated CD4+ T cells. 1264 31

A 68-year old Japanese male with alcohol related rhabdomyolysis, hepatitis, and hematological disorders is presented. Biochemical data showed markedly elevated levels of serum hepatobiliary enzymes, lactate dehydrogenase and myoglobin, and decreased levels of serum sodium and phosphate. The serum creatine kinase level was approximately 40 times higher than the normal upper limit with 97% of MM fraction. Clinical manifestations of rhabdomyolysis, such as myalgia, muscle weakness and acute renal failure, were not recognized. Hematological examinations revealed mild neutropenia, lymphopenia, monocytopenia and thrombocytopenia but no anemia or macrocytosis. Initial treatment of an intravenous infusion of saline (30 mL/Kg body weight) and subsequent low sodium diet was successfully completed without severe complications. All the abnormal laboratory data were normalized within three weeks of his hospitalization. We suggest that hyponatremia and hypophosphatemia may be involved in the development of rhabdomyolysis, hepatitis and hematological disorders.
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PMID:Rhabdomyolysis, hepatitis and multiple hematological disorders associated with alcohol abuse: a case report. 1293 2

Blood lymphocyte numbers, which are maintained by recirculation through secondary lymphoid organs, are essential for the efficient development of immune responses. Recirculating populations of B and T lymphocytes are regulated by the sphingosine-1-phosphate (S1P) receptor-dependent control of lymphocyte egress. T-cell egress from thymus into blood, egress from lymph node and Peyer's patch into lymph, and B-cell egress into lymph are rapidly and completely inhibited by agonism of S1P receptors. Mesenteric lymph nodes show log-jamming of lymphocytes subjacent to sinus-lining endothelium. Agonism of S1P receptors produces rapid peripheral blood lymphopenia, which is maintained in the presence of receptor agonist. Effector CD4+ and CD8+ T cells, produced by clonal expansion in draining lymph node in response to antigen, are sequestered in lymph node and fail to reach the peripheral blood. The S1P receptor system may represent an early physiological link between the non-specific inflammatory response and the alteration of lymphocyte traffic through draining lymph nodes. Pharmacological subversion of the S1P receptor system, through systemic S1P agonist-induced inhibition of lymphocyte egress, suppresses antigenic responses to peripheral, but not to systemically, delivered antigen. This inhibition induces significant immunosuppression in models of transplantation and autoimmune tissue damage that may prove to be of clinical benefit.
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PMID:Egress: a receptor-regulated step in lymphocyte trafficking. 1296 17

The lysophospholipid (LPL) growth factors sphingosine 1-phosphate (S1P) and lysophosphatidic acid (LPA) are generated by macrophages, dendritic cells, mast cells, and platelets, which leads to lymph and plasma concentrations of 0.1-1 microM. Distinctive profiles of G protein-coupled receptors (GPCRs) for S1P and LPA are expressed by each type of immune cell and are regulated by cellular activation. At 1-100 nM, S1P signals T cells through their principal S1P(1) GPCRs with consequent protection from apoptosis, enhancement of chemotaxis, and facilitation of optimal regulatory activity of CD4(+)25(+) T cells. At 0.3-3 microM, S1P inhibits T cell chemotaxis and to a lesser extent other functions. These S1P-S1P(1) GPCR signals suppress homing of blood and spleen T cells to secondary lymphoid tissues. S1P(1) GPCR antagonists evoke lymphopenia by permitting blood T cells to enter lymph nodes and blocking S1P(1) GPCR-dependent T cell efflux from lymph nodes. Inversely, there is a decrease in lymphoid tissue traffic of T cells in transgenic mice, which overexpress lymphocyte S1P(1) GPCRs. The immunotherapeutic activity of S1P(1) GPCR antagonists, which limits T cell access to organ grafts and autoimmune antigens, does not reduce other functional capabilities of T cells. LPLs and their GPCRs thus constitute an immunoregulatory system of sufficient prominence for pharmacological targeting in transplantation, autoimmunity, and immunodeficiency.
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PMID:Sphingosine 1-phosphate and its type 1 G protein-coupled receptor: trophic support and functional regulation of T lymphocytes. 1498 46

The lysophospholipid growth factors sphingosine 1-phosphate (S1P) and lysophosphatidic acid (LPA) are generated by many cells involved in immunity, including macrophages, dendritic cells, mast cells, and platelets, with resultant lymph and plasma concentrations of 0.1-1 microM. All immune cells express distinctive profiles of G protein-coupled receptors (GPCRs) for S1P and LPA, which are regulated developmentally and by cellular activation. For T-cells, constitutive S1P signaling through their principal S1P(1) GPCR inhibits chemotactic responses to chemokines, with lesser suppression of proliferation and cytokine production. These S1P-S1P(1) GPCR signals tonically reduce T-cell chemotactic sensitivity to chemokines and thereby limit homing of blood and spleen T-cells to secondary lymphoid tissues. S1P(1) GPCR antagonists evoke lymphopenia by permitting blood T-cells to enter lymph nodes and blocking S1P(1) GPCR-dependent T-cell efflux from lymph nodes. Inversely, there is a longer than normal persistance in blood and a decrease in lymphoid transit time for T-cells overexpressing transgenic S1P(1) GPCRs. The immunotherapeutic potential of S1P(1) GPCR antagonists derives from their capacity to limit T-cell access to organ grafts and autoimmune antigens without reducing their other intrinsic functional capabilities. Lysophospholipids and their GPCRs thus constitute an immunoregulatory system of sufficient prominence for pharmacological targeting in transplantation, autoimmunity and immunodeficiency.
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PMID:Sphingosine 1-phosphate and its G protein-coupled receptors constitute a multifunctional immunoregulatory system. 1525 96

Sphingosine-1-phosphate (S1P), a lipid signaling molecule that regulates many cellular functions, is synthesized from sphingosine and ATP by the action of sphingosine kinase. Two such kinases have been identified, SPHK1 and SPHK2. To begin to investigate the physiological functions of sphingosine kinase and S1P signaling, we generated mice deficient in SPHK1. Sphk1 null mice were viable, fertile, and without any obvious abnormalities. Total SPHK activity in most Sphk1-/-tissues was substantially, but not completely, reduced indicating the presence of multiple sphingosine kinases. S1P levels in most tissues from the Sphk1-/- mice were not markedly decreased. In serum, however, there was a significant decrease in the S1P level. Although S1P signaling regulates lymphocyte trafficking, lymphocyte distribution was unaffected in lymphoid organs of Sphk1-/- mice. The immunosuppressant FTY720 was phosphorylated and elicited lymphopenia in the Sphk1 null mice showing that SPHK1 is not required for the functional activation of this sphingosine analogue prodrug. The results with these Sphk1 null mice reveal that some key physiologic processes that require S1P receptor signaling, such as vascular development and proper lymphocyte distribution, can occur in the absence of SPHK1.
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PMID:Mice deficient in sphingosine kinase 1 are rendered lymphopenic by FTY720. 1545 1

FTY720 (FTY), a novel immunosuppressive drug, can be distinguished from other immunosuppressive drugs by a completely different mechanism of action. FTY induces altered lymphocyte trafficking, leading to peripheral blood lymphopenia and to increased lymphocyte counts in lymph nodes. FTY mediates its immune-modulating effects by binding to sphingosine 1-phosphate receptors expressed on lymphocytes. In an attempt to identify mediators of the FTY-induced signal transduction, we used a proteomic approach. FTY-treated peripheral blood lymphocytes (PBLs) were investigated for the expression of 622 proteins. We identified 15 differentially expressed proteins in PBLs possibly related to FTY action. As indicated by protein function, several identified proteins could be linked to the cytoskeleton/cell motility, to cell adhesion, and vesicle trafficking. No changes were found concerning the expression of various apoptosis regulators as well as the immunophilins FKBP12 and calcineurin. Our data suggest that FTY affects cytoskeleton rearrangements, cell adhesion, and vesicle trafficking/sorting in human PBLs.
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PMID:Novel mediators of FTY720 in human lymphocytes. 1572 78

FTY720, a new class of immunomodulator, induces lymphopenia by sequestration of circulating lymphocytes into secondary lymphoid tissues. FTY720 at 0.1 to 1 mg/kg significantly prolonged the allograft survival in a dose-dependent manner and showed a marked synergistic effect in combination with cyclosporine (CsA) in rat skin and cardiac allograft models. In addition, the canine renal allograft survival was significantly prolonged by combination therapy with FTY720 at 0.03 to 1 mg/kg and CsA at 10 mg/kg as compared with monotherapy of FTY720 or CsA. By contrast, the combination therapy with CsA and azathioprine or CsA and mycophenolate mofetil resulted in only an additive effect in rat skin allograft. When FTY720 was administered to rats, FTY720 was metabolized by omega-oxidation of the octyl side chain, and beta-oxidation subsequently, or phosphorylated by sphingosine kinase. Omega- and beta-oxidized 4 metabolities of FTY720 at 10 mg/kg i.v. showed neither lymphopenia nor immunosuppressive activity in rat skin allograft. On the other hand, (S)-enantiomer of FTY720-phosphate at 0.1 and 1 mg/kg intravenously induced a marked lymphopenia and significantly prolonged the allograft survival in the rat allotransplantation. From these results, it is suggested the lymphopenia and the immunosuppression induced by FTY720 administration is due to the agonistic activity against SIP receptors of the active metabolite, (S)-FTY720-phosphate.
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PMID:Immunosuppressive activity of FTY720, sphingosine 1-phosphate receptor agonist: I. Prevention of allograft rejection in rats and dogs by FTY720 and FTY720-phosphate. 1580 61

FTY720 is an immunosuppressive agent that modulates lymphocyte trafficking. It is phosphorylated in vivo to FTY720-phosphate (FTY-P) and binds to a family of G protein-coupled receptors recognizing sphingosine 1-phosphate (S1P) as the natural ligand. It has previously been reported that FTY-P blocks egress of lymphocytes from the thymus and lymph nodes, resulting in peripheral blood lymphopenia. We now report that FTY-P also causes displacement of marginal zone (MZ) B cells to the splenic follicles, an effect that is similar to that observed after in vivo administration of lipopolysaccharide. This effect is specific to B cells in the MZ, as treatment with FTY-P does not cause redistribution of the resident macrophage population. A small but statistically significant decrease in the expression of beta1 integrin on MZ B cells was observed with FTY-P treatment. The redistribution of MZ B cells from the MZ sinuses does not abolish the ability of these cells to respond to the T-independent antigen, trinitrophenol-Ficoll. It has been proposed that the displacement of MZ B cells to the follicles is an indication of cell activation. Consistent with this, FTY-P caused an increase in percentage of MZ B cells expressing activation markers CD9, CD1d, and CD24. These results suggest that S1P receptors on MZ B cells are responsible for their mobilization to follicles.
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PMID:Sphingosine 1-phosphate receptor agonist FTY720-phosphate causes marginal zone B cell displacement. 1589 89


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