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)

There have been six different phase I trials of Fludara I.V. (fludarabine phosphate) in patients with solid tumors and three different phase I trials of Fludara I.V. in patients with acute leukemia. In addition, one trial of the agent given intraperitoneally has also been published. In patients with solid tumors, the two most often used schedules are a daily bolus schedule of 18 to 25 mg/m2/d for 5 days repeated every 28 days, and a 20 mg/m2 loading dose followed by a 48-hour continuous infusion of the agent at a dose of 25 to 30 mg/m2/d. The dose-limiting toxicity in these studies has been myelosuppression. No dosage or schedule could be recommended for patients with acute leukemia because of the severe neurotoxicity (progressive dementia with blindness leading to coma) noted with doses greater than or equal to 96 mg/m2/d for 5 to 7 days. Other toxicities noted in phase I trials have included somnolence, mild to moderate nausea and vomiting, and a rare and reversible interstitial pneumonitis. Of greatest interest is that a profound lymphopenia has been noted as a side effect of Fludara I.V. That toxicity has proven to be of benefit for patients with chronic lymphocytic leukemia, low-grade lymphoma, and mycosis fungoides, all of which are responsive to Fludara I.V. therapy.
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PMID:Phase I clinical trials with fludarabine phosphate. 169 81

Rats were vaccinated with a toxoid (D-toxoid) prepared from purified heat-labile toxin (D-toxin) produced by Pasteurella multocida serogroup D. Vaccination of rats with D-toxoid prevented death and other effects of D-toxin (hepatic necrosis, development of elevated leukocyte counts, lymphopenia, neutrophilia, and elevated complement titers) that occurred in phosphate buffered saline (PBS)-vaccinated control rats.
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PMID:Immunity induced in rats vaccinated with toxoid prepared from heat-labile toxin produced by Pasteurella multocida serogroup D. 206 48

The protective effects of altered arachidonic acid metabolism, using either methylprednisolone or a dual cyclooxygenase and 5-lipoxygenase inhibitor (SK&F 86002), were compared in a rat model of adult respiratory distress syndrome (ARDS). Rats were either unexposed (n = 9) or pretreated with vehicle (n = 25), 100 mg/kg SK&F 86002 (n = 8) or 30 mg/kg methylprednisolone (MP, n = 7) 1 h prior to the intratracheal administration of 7 mg/kg aerosolized endotoxin (LPS) or phosphate buffered saline (PBS). Twenty-four hours later, blood samples were collected and the rats were anesthetized and exsanguinated. The lungs were surgically removed, weighed and bronchoalveolar lavage (BAL) was performed. LPS caused 30-35% mortality and induced significant differences in body weight, BAL erythrocyte and neutrophil counts, lung wet/dry weight ratio (W/D), total BAL protein (TP), hemoglobin (Hb), hematocrit (HCT), and circulating leukocyte and platelet counts as compared with controls. Pretreatment with MP reduced mortality to zero and also attenuated the LPS-induced alterations in body weight, W/D, TP, BAL erythrocyte count, and circulating platelet count. However, MP exacerbated LPS-induced increases in Hb, HCT and circulating neutrophil counts while enhancing lymphopenia. Pretreatment with SK&F 86002 also reduced mortality to zero and attenuated LPS-induced alterations in W/D, TP, HCT and circulating platelet count. Like MP, SK&F 86002 exacerbated the LPS-induced lymphopenia, and increased circulating neutrophils above baseline values. We conclude that both MP and SK&F 86002 provided protection against LPS-induced responses in this model of ARDS. Mechanistically, this indicates the critical role of eicosanoid mediators in this model. Therapeutically, SK&F 86002, or a similar compound, may be beneficial in preventing the acute phase responses so harmful to ARDS patients.
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PMID:Therapeutic intervention in a rat model of ARDS: I. Dual inhibition of arachidonic acid metabolism. 212 22

For phase II studies in patients with solid tumors, the National Cancer Institute recommended that the starting dose of fludarabine phosphate be 20 mg/m2/day as a short intravenous infusion for 5 days every 21 days. Twenty-one patients with untreated, advanced, measurable colorectal carcinoma received fludarabine phosphate as a 30-minute infusion at a median dose of 25 mg/m2/day (range 15-35 mg/m2/day) for 5 consecutive days repeated every three weeks. Antitumor response was evaluated following two courses of therapy. No patient achieved complete or partial response. Minor regression of lung metastases occurred for less than 12 weeks in one patient. Therapy was generally well tolerated. Frequent toxicities included lymphopenia, mild nausea and vomiting, mucositis, and anorexia. One patient died of sepsis, bleeding, and progressive disease while she was severely myelosuppressed. Neurotoxicity was not observed in any patient. Fludarabine phosphate at this schedule and dose range is inactive against colorectal carcinoma.
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PMID:Phase II study of fludarabine phosphate in patients with advanced colorectal carcinoma. 245 66

Hypercalcemia associated with malignancy was diagnosed in a 2-year-old Thoroughbred filly admitted because of weight loss and reduced exercise tolerance of approximately 2 months' duration. Laboratory findings included hypercalcemia, hypophosphatemia, anemia, marked neutrophilia with lymphopenia and eosinopenia, and normal immunoreactive parathyroid hormone concentration. At necropsy, a 53.6-kg tumor was located in the cranioventral aspect of the abdominal cavity. Gross renal lesions were not noticed. Bone tissue appeared to be normal on gross and histologic examinations. The parathyroid glands were not grossly identified at necropsy. A specific test does not exist for detection of hypercalcemia associated with malignancy. The diagnosis of hypercalcemia associated with malignancy was made on the basis of clinical history, physical examination, radiographic interpretation, laboratory findings, histologic examination, and ruling out other causes of hypercalcemia. Hypercalcemia, increased renal phosphate excretion in the presence of hypophosphatemia, absence of bone metastases, and identifying an abdominal mesenchymal tumor that may have originated from the left ovary satisfied the basic criteria for hypercalcemia associated with malignancy from a solid tumor.
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PMID:Hypercalcemia associated with malignancy in a horse. 373 8

Leucocytosis with neutrophilia, lymphopenia and eosinopenia, and decreases in plasma endogenous glucocorticoid levels were used to study the pharmacological kinetics of dexamethasone in pigs. The return to baseline of endogenous plasma glucocorticoid levels was the most sensitive index of dexamethasone action. Intravenous administration of 38 microgram/kg of the soluble phosphate ester produced a maximal response. Higher dosages (76 and 152 microgram/kg) did not increase the intensity of the response, but did increase its duration, which was less than 24 hours. The same response was obtained when dexamethasone phosphate (75 microgram/kg) was given by the intramuscular route. Insoluble esters had a weaker but longer action which lasted for 28 hours with terethoxy-acetate, and approximatively 48 hours with acetate and isonicotinate, on the basis of the pituitary-adrenal axis inhibition. After intramuscular administration, dexamethasone esters induced a weak hyperglycemia but no changes in plasma sodium, chloride or calcium levels were observed.
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PMID:[Comparative pharmacological effectiveness of dexamethasone esters in pigs (author's transl)]. 745 40

X-linked severe combined immunodeficiency (XSCID) is a hereditary disorder characterized by severe T cell lymphopenia and abnormal B cell function. The disease is caused by mutations in IL2RG, the gene encoding the interleukin-2 receptor common gamma chain (gamma c) shared by several interleukin receptors. A Harvey retroviral bicistronic vector containing an IL2RG cDNA and cDNA encoding the multidrug transporter (MDR1) was constructed to investigate the correction of XSCID. Translation of the MDR1 cDNA is achieved from an internal ribosome entry site (IRES). Mouse fibroblasts transfected or transduced with the vector expressed both membrane proteins as detected with specific monoclonal antibodies by fluorescence activated cell sorting. Two human XSCID B cell lines were transduced using a filter concentration method in combination with phosphate depletion. Significant expression of both proteins was detected by Western blot analysis. This construct might be particularly useful if high expression of gamma c is required, as might be achievable through in vivo selection for drug resistance of recipient lymphocytes.
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PMID:Characterization of an MDR1 retroviral bicistronic vector for correction of X-linked severe combined immunodeficiency. 979 72

Immunosuppression as a consequence of acute and chronic stress can increase the susceptibility of cattle to a range of infectious diseases. In order to develop a panel of immune function assays for investigating the effects of potential stressors on immune competence in cattle, the effect of treatment with short- and long-acting preparations of the synthetic glucocorticoid dexamethasone was examined. Short-acting dexamethasone (dexamethasone sodium phosphate 0.08 mg/kg) followed 37 h later by long-acting dexamethasone (dexamethasone-21 isonicotinate 0.25 mg/kg) was injected intramuscularly and blood was collected to assess immune functions at intervals over the subsequent 11 days from 6 treated and 6 control Hereford steers. Dexamethasone induced leukocytosis (neutrophilia, eosinopenia, lymphopenia, monocytosis), an increased neutrophil:lymphocyte ratio, an elevated percentage of CD4+ lymphocytes, a decreased total CD8+ lymphocyte count, decreased total and percentage WC1+ lymphocytes, an elevated percentage of IL-2 receptor alpha (IL-2Ralpha)+ lymphocytes, and an elevated percentage of B lymphocytes. In vitro chemotaxis of peripheral blood neutrophils to human C5a and ovine IL-8 was increased by dexamethasone treatment. Lymphocyte proliferation in the presence of phytohaemagglutinin, and serum concentrations of IgM, but not IgA or IgG1, were suppressed by dexamethasone treatment, whereas mitogen-induced production of interferon-gamma (IFN-gamma), neutrophil expression of CD18, neutrophil myeloperoxidase activity and natural killer (NK) cell activity were not influenced by dexamethasone treatment. The results indicate the potential for haematology and immune function assays to reflect elevated activity of the hypothalamic-pituitary-adrenocortical axis in cattle. Immunological parameters may thus provide a useful adjunct to cortisol and behavioural observations for assessing the impact of stress on the welfare of cattle.
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PMID:The effect of dexamethasone on some immunological parameters in cattle. 1059 72

Blood lymphocyte numbers, essential for the development of efficient immune responses, are maintained by recirculation through secondary lymphoid organs. We show that lymphocyte trafficking is altered by the lysophospholipid sphingosine-1-phosphate (S1P) and by a phosphoryl metabolite of the immunosuppressive agent FTY720. Both species were high-affinity agonists of at least four of the five S1P receptors. These agonists produce lymphopenia in blood and thoracic duct lymph by sequestration of lymphocytes in lymph nodes, but not spleen. S1P receptor agonists induced emptying of lymphoid sinuses by retention of lymphocytes on the abluminal side of sinus-lining endothelium and inhibition of egress into lymph. Inhibition of lymphocyte recirculation by activation of S1P receptors may result in therapeutically useful immunosuppression.
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PMID:Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. 1192 95

Immunosuppressant drugs such as cyclosporin have allowed widespread organ transplantation, but their utility remains limited by toxicities, and they are ineffective in chronic management of autoimmune diseases such as multiple sclerosis. In contrast, the immune modulating drug FTY720 is efficacious in a variety of transplant and autoimmune models without inducing a generalized immunosuppressed state and is effective in human kidney transplantation. FTY720 elicits a lymphopenia resulting from a reversible redistribution of lymphocytes from circulation to secondary lymphoid tissues by unknown mechanisms. Using FTY720 and several analogs, we show now that FTY720 is phosphorylated by sphingosine kinase; the phosphorylated compound is a potent agonist at four sphingosine 1-phosphate receptors and represents the therapeutic principle in a rodent model of multiple sclerosis. Our results suggest that FTY720, after phosphorylation, acts through sphingosine 1-phosphate signaling pathways to modulate chemotactic responses and lymphocyte trafficking.
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PMID:The immune modulator FTY720 targets sphingosine 1-phosphate receptors. 1196 57


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