Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1 The effects of the immunosuppressant drugs cyclosporin A and tacrolimus (FK506) on nitric oxide synthesis were examined in a murine macrophage cell line (J774) and rat vascular smooth muscle cells (VSMC) in culture for 24 and 48 h, respectively. 2 Cyclosporin A (0.01-10 microM) inhibited by up to 90% accumulation of nitrite induced by lipopolysaccharide (LPS) in both cell lines, but FK506 (0.01-10 microM) had a weaker effect on nitrite accumulation in these cells. Cyclosporin A and FK506 (at 1 microM) also significantly inhibited nitrite production induced by recombinant murine interferon-gamma (rIFNgamma) and recombinant murine interleukin-1beta (rIL-1beta) in J774 and VSMC, respectively. 3 In J774 cells, cyclosporin A (but not FK506) at 1 microM was inhibitory when co-incubated with the inducing agents but not when the cells were treated with the immunosuppressant before or after the inducer. In VSMC, nitrite production was inhibited by co-incubation of cyclosporin A or FK506 with the inducer, or when the immunosuppressants were pre-incubated with cells. In contrast, N-monomethyl L-arginine (NMMA) abolished nitrite production when incubated with either cell type during or after addition of inducing agent, but not if cells were preincubated with NMMA. 4 RNA extracted from treated J774 and VSMC was subjected to reverse transcription-polymerase chain reaction (RT-PCR). Cyclosporin A, but not FK506, suppressed expression of mRNA for NOS2 in a concentration-dependent manner when co-incubated with LPS. 5 The fact that the potency difference between cyclosporin A and FK506 for NO suppression is the opposite to that for inhibition of interleukin-2 generation suggests that the immunosuppressants act in J774 macrophages and VSMC through intracellular mechanisms that differ from those elucidated in T-cells. Cyclosporin A suppresses NOS2 gene transcription, but FK506 acts post-transcriptionally to suppress NO generation in VSMC. 6 Taken together the present data suggest that therapeutic concentrations of cyclosporin A, but not FK506, might well suppress NO production, but FK506 would not have this effect. Suppression of NO might contribute to the side effects of hypertension and nephrotoxicity associated with long-term use of cyclosporin A to prevent transplant rejection.
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PMID:Cyclosporin A and tacrolimus (FK506) suppress expression of inducible nitric oxide synthase in vitro by different mechanisms. 1051 Apr 43

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage and administration of sirolimus are reviewed. Sirolimus can be used as an adjunct to cyclosporine and corticosteroids for preventing organ rejection in renal allograft recipients. It appears to block cell-cycle progression in the mid-to-late G1 phase; it also inhibits interleukin-2-dependent and independent proliferation of B-lymphocytes and production of immunoglobulins A, M, and G. Sirolimus is extensively metabolized by the liver and undergoes O-demethylation and hydroxylation. The mean oral clearance is 208 +/- 95 mL/hr/kg with an elimination half-life of 57 to 63 hours in kidney transplant recipients. Sirolimus is poorly absorbed from the gastrointestinal tract; its apparent oral bioavailability is about 15%. Two pivotal Phase III, multicenter, randomized, double-blind trials evaluating the efficacy of sirolimus in the prophylaxis of acute renal allograft rejection after transplantation have been conducted. A significant reduction in the occurrence of acute rejection was noted in both trials compared with azathioprine- or placebo-treated patients. Also, both sirolimus groups required significantly less antibody therapy for treatment of rejection. The primary adverse effects associated with sirolimus therapy include hypercholesterolemia and hypertriglyceridemia. Hypertension, diarrhea, increased creatinine, hypokalemia, arthralgia, rash, acne, leukopenia, and thrombocytopenia have also been observed. The labeled recommendations are a 6-mg loading dose as soon as possible after transplantation and a maintenance dose of 2 mg per day. Sirolimus is a potent novel immunosuppressive agent with proven efficacy in the prevention of acute rejection after renal transplantation. Use of sirolimus may lead to effective therapeutic strategies for sparing the use of cyclosporine and corticosteroids.
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PMID:Sirolimus: a new agent for prevention of renal allograft rejection. 1071 24

Noncardiogenic pulmonary edema (NCPE) is a rare and less well-recognizable pulmonotoxic syndrome of anticancer therapy than pneumonitis/fibrosis. NCPE is a clinical syndrome characterized by simultaneous presence of severe hypoxemia, bilateral alveolar infiltrates on chest radiograph, and no evidence of left atrial hypertension/congestive heart failure. The diagnosis of drug-related NCPE relies upon documented exclusion of any infectious, metabolic, or cancer-related causes. The time proximity to therapy with drugs that are known to precipitate NCPE, any preceding episodes of flu-like symptoms during previous chemotherapy courses and possible response to corticosteroids may further support such a diagnosis. Cancer therapeutic agents clearly associated with NCPE are cytarabine, gemcitabine, and interleukin-2, as well as all-trans retinoic acid in acute promyelocytic leukemia patients, while a few other compounds have rarely or occasionally been implicated. The pathophysiology of lung injury in drug-induced NCPE remains unclear. There are indications suggesting that both a direct cytotoxic insult to the lung epithelial cells and induction of a cytokine-triggered inflammatory response may be involved in its pathogenesis. By distinction to drug-induced pulmonary pneumonitis that may lead to permanent pulmonary fibrosis, NCPE if not fatal, can be reversed upon prompt recognition, following immediate discontinuation of the offensive drug and start of intensive supportive treatment and intravenous corticosteroids.
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PMID:Noncardiogenic pulmonary edema: an unusual and serious complication of anticancer therapy. 1130 27

Cyclosporin A (CyA) is a cyclic peptide used as an immunosuppressive agent because it can block the synthesis of interleukin-2 and other cytokines produced by CD4+ lymphocytes. It is widely used for the prevention of allograft rejection and treatment of autoimmune diseases. Several side-effects of CyA treatment have been reported, among which are chronic nephrotoxicity, hepatotoxicity and neurotoxicity, lymphoproliferative neoplasms, hypertension, thromboembolic complications and gingival overgrowth. Here, using a rat molar model, it is demonstrated that CyA immunosuppression inhibits the activity of matrix metalloproteinases 2 and 9 in the early phase of granulation tissue in the healing dental socket. These observations suggest that CyA may interfere with the wound healing following dental extractions.
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PMID:The effect of cyclosporin A on the activity of matrix metalloproteinases during the healing of rat molar extraction wounds. 1142 61

After 10 wk of feeding an experimental diet enriched with (n-3) polyunsaturated fatty acids (PUFA), i.e., eicosapentaenoic acid [EPA, 20:5(n-3)] and [DHA, 22:6(n-3)] (EPAX), blood pressure in spontaneously hypertensive rats (SHR), but not in normotensive Wistar-Kyoto (WKY) rats was reduced relative to rats fed an unsupplemented control diet. Concanavalin A-stimulated T-cell proliferation was diminished in both strains of rats fed the PUFA/EPAX diet. The experimental diet lowered secretion of interleukin-2 in SHR, but not in WKY rats compared with rats fed the control diet. To determine whether there was a defect in calcium homeostasis in T cells during hypertension, we employed the following agents: caffeine, which recruits calcium from the cytosolic Ca(2+)-induced Ca(2+)-release pool; ionomycin, which at low concentrations opens calcium channels; and thapsigargin (TG), which mobilizes [Ca(2+)]i from the endoplasmic reticulum (ER) pool. Caffeine-induced increases in [Ca(2+)]i were not modified by the PUFA/EPAX diet. The ionomycin-induced increases in [Ca(2+)]i in T cells from SHR were greater than in those from WKY rats; consumption of the PUFA/EPAX diet did not modify Ca(2+) influx in cells of either strain. The TG-induced increases in [Ca(2+)]i in T cells from SHR were greater than those in cells from WKY rats. Interestingly, consumption of the experimental diet reduced TG-evoked increases in [Ca(2+)]i in T cells from SHR and increased those in T cells from WKY rats, indicating that the PUFA/EPAX diet could reverse the calcium mobilization from the ER pool in T cells. These results suggest that (n-3) PUFA exert antihypertensive effects and modulate T-cell calcium signaling during hypertension in rats.
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PMID:Dietary (n-3) polyunsaturated fatty acids exert antihypertensive effects by modulating calcium signaling in T cells of rats. 1153 80

Several studies have shown a significant reduction of acute cellular graft rejection in adult liver and kidney graft recipients treated with monoclonal anti-interleukin-2 (IL-2)-receptor antibodies. The mechanism was inhibition of activated T-helper cells by blocking the alpha-chain (CD25) of the IL-2 receptor. The pilot study described here evaluated the use of basiliximab in pediatric liver transplantation (LTx), which is the first report on its use in children. Fifty-two liver-transplanted children were analyzed in this study. A matched-pair historical control group (n = 26) received cyclosporin A (CsA) and prednisolone, and patients in the basiliximab group (n = 26) were treated with low-dose CsA and basiliximab (after reperfusion and on day 4 post-transplant). The incidences were compared of acute graft rejections, infectious complications, and the adverse effects of immunosuppressive medication within the first 6 months post-transplant. The incidence of acute rejection was significantly higher in the control group (61.5% vs. 11.5%, p = 0.0004). The frequency of infectious complications was similar (46.1% vs. 53.8%). Patients in the basiliximab group showed less arterial hypertension; however, the differences were not statistically significant (30.7% vs. 7.7%, p = 0.07). Nephrotoxicity, hepatotoxicity or neurotoxicity were only seen in the control group (7.7%; 3.8%; 3.8%, respectively). Hence, the use of basiliximab in combination with CsA and steroids in pediatric liver transplant recipients is safe and reduces the incidence of acute graft rejection. Further studies are needed to confirm our preliminary results and to analyze long-term effects on post-transplant lymphoproliferative disease, chronic rejection, and patient survival.
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PMID:First experience with basiliximab in pediatric liver graft recipients. 1173 61

An attempt was made to generate an unrestricted cellular immune response against peptide antigens of the circumsporozoite protein (CSP) of Plasmodium vivax. The peptides used represent the repeat-region sequences of the type-I variant (AA and DA) or type-II variant (ANG) and the conserved region (region II) containing the hepatocyte-binding region extended to include a T-cell epitope (HBP). The study was conducted in outbred mice and two genetically unrelated inbred strains of mice. Spleen cells, recovered from mice that had been primed either with one peptide or a conjugate formed of HBP linked to one of the repeat-region peptides, were pulsed in vitro with varying amounts of individual peptides/conjugates, both in soluble and particulate form (with and without a human beta-casein bio-active fragment analogue as adjuvant). In the tests using the cells from the mice primed with an individual peptide(s), HBP showed a high proliferation index, and the repeat-region peptides, especially AA, showed T-cell activity in at least one of the mouse strains studied. In vitro, higher concentrations of the free peptides than of liposomal preparations of the peptides had to be used to elicit the optimal proliferation of the cells from each strain of mice. Interestingly, the cells from the conjugate-primed mice showed enhanced proliferation (compared with that observed in the cells from mice primed with individual peptides) when stimulated with each component, and especially the repeat-region sequence, of the relevant conjugate. In such cases there was no evidence of restriction of the immune response by the major histocompatibility complex. The major secreted cytokines were found to be from CD4(+) Th1 (interferon-gamma and interleukin-2), with relatively low levels of the Th-2 cytokines interleukin-4 and interleukin-6. The delivery of cohered 'B-T' peptide(s) sequences from the same protein, ideally with an immunostimulatory adjuvant or as a liposomal preparation, should greatly enhance the cell-mediated immune response and should improve clearance of mosquito-inoculated P. vivax sporozoites.
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PMID:Inducing a cell-mediated immune response against peptides of the Plasmodium vivax circumsporozoite protein. 1167 63

Ciclosporin, produced by the fungus Tolypocladium inflatum GAMS is endowed with potent immunosuppressive properties. Ciclosporin interferes with nuclear factors of activated T-cells, specifically by preventing cytokine gene transcription, particularly interleukin-2, which induces maturation and proliferation of helper T-cells. Initially, a traditional formulation of Sandimmun(R) was used, but its oral bioavailability varies. Absorption of a new formulation, Neoral(R), is significantly better and more reproductible. Ciclosporin has become a major agent in the prevention and treatment of organ transplant rejection. It is also efficient in treating various immune-related diseases. In dermatology, its efficacy has been proven in numerous double-blind, placebo-controlled studies for severe psoriasis and atopic dermatitis. Treatment with ciclosporin is also beneficial for many dermatologic diseases. However, the effect of this drug has principally been studied in open trials and in small cohorts. Ciclosporin provokes serious adverse reactions especially nephrotoxicity and arterial hypertension. Treatment is occasionally stopped because of these complications. The other common side-effects include muco-cutaneous, neurological and gastro-intestinal symptoms. Increased risk for malignancy is reported with ciclosporin. However, in patients with cutaneous diseases, the incidence is low.
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PMID:[Ciclosporin]. 1205 38

Rejection is the leading cause of corneal graft failure, induced by loss of the so-called eye immune privilege. Prevention of graft rejection with immunosuppressive therapy is then necessary. Topical corticosteroids are currently the gold standard, and steroids are the only treatment for acute rejection episodes. Steroids are nonspecific immunosuppressive agents, and they can induce glaucoma, cataract, infections, and epithelial defects. Cyclosporin has a specific effect, because it inhibits interleukin-2 transcription and, consequently, the specific activation of T lymphocytes. When cyclosporin is given orally, it effectively prevents graft rejection in high-risk recipients, but it may induce severe side effects (i.e., systemic hypertension, kidney deficiency, and malignant tumor induction). When cyclosporin is given topically, it can effectively replace steroids in case of dexamethasone-induced glaucoma and graft infection, but it can also induce serious corneal epithelial defects. Cyclosporin is not a treatment for acute rejection episodes. Mycophenolate mofetil and FK 506 are promising drugs, but currently they cannot be used routinely to prevent corneal graft rejection.
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PMID:[Immunosuppression in corneal transplantation]. 1291 Feb 7

Barbiturates are frequently used for the treatment of intracranial hypertension after brain injury but their application is associated with a profound increase in the infection rate. The mechanism of barbiturate-induced failure of protective immunity is still unknown. We provide evidence that nuclear factor of activated T cells (NFAT), an essential transcription factor in T cell activation, is a target of barbiturate-mediated immunosuppression in human T lymphocytes. Treatment of primary CD3+ lymphocytes with barbiturates inhibited the PMA and ionomycin induced increase in DNA binding of NFAT, whereas the activity of other transcription factors, such as Oct-1, SP-1, or the cAMP response element-binding protein, remained unaffected. Moreover, barbiturates suppressed the expression of a luciferase reporter gene under control of NFAT (stably transfected Jurkat T cells), and of the cytokine genes interleukin-2 and interferon-gamma that contain functional binding motifs for NFAT within their regulatory promotor domains (human peripheral blood CD3+ lymphocytes). Neither GABA receptor-initiated signaling nor direct interactions of barbiturates with nuclear proteins affected the activity of NFAT. In contrast, barbiturates suppressed the calcineurin-dependent dephosphorylation of NFAT in intact T cells and also inhibited the enzymatic activity of calcineurin in a cell-free system, excluding upstream regulation. Thus, our results demonstrate a novel mechanism of direct inhibition of the calcineurin/calmodulin complex that may explain some of the known immunosuppressive effects associated with barbiturate treatment.
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PMID:Barbiturates directly inhibit the calmodulin/calcineurin complex: a novel mechanism of inhibition of nuclear factor of activated T cells. 1474 77


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