UMLS:C0020538 - FACTA Search

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Query: UMLS:C0020538 (hypertension)
170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The introduction of new techniques for the determination of renal parenchymal oxygenation and intrarenal microcirculation has elucidated some important aspects in the pathophysiology of acute renal failure (ARF). Data accumulated over the last decade with these techniques, together with improved morphologic evaluation of the kidney, indicate that medullary damage may play a pivotal role in various forms of acute and chronic renal hypoxic and toxic insults. The outer medulla functions normally under hypoxic conditions, as a result of limited regional oxygen supply and high oxygen consumption for urinary concentration. Outer medullary oxygenation is critically balanced by mechanisms designed to adjust oxygen demand and supply, and their insufficiency may lead to ARF with hypoxic medullary damage. In this article, we outline our current concept of the physiologic control of medullary oxygenation and review the clinical conditions that predispose to hypoxic medullary damage, including rhabdomyolysis, hypercalcemia, or the exposure to endotoxin, nonsteroidal anti-inflammatory drugs, radiologic contrast agents, cyclosporine, FK506, and amphothericin. We shall indicate a possible role for medullary oxygen insufficiency in clinical conditions known to predispose to ARF, such as preexisting renal disease, diabetes mellitus, hypertension, atherosclerosis, effective volume depletion, urinary obstruction, or aging, and suggest potential strategies to preserve medullary oxygenation and integrity.
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PMID:The role of medullary ischemia in acute renal failure. 857 90

Tacrolimus (FK 506) is a new, more powerful immunosuppressant and is more effective in the prevention and treatment of allograft rejection in humans than cyclosporine (CysA). The present study was conducted to determine whether FK 506 increases ET(A) receptor mRNA in blood vessels in rats. FK 506 5 mg/kg/day for 4 weeks increased blood pressure and expression of ET(A) receptor mRNA in mesenteric arteries of Wistar-Kyoto rats. However, 0.5 mg/kg/day of FK 506 did not increase blood pressure or ET(A) mRNA levels in the vasculature. The dose of 0.1 microM CysA used in clinical practice induced expression of ET(A) receptor mRNA in cultured rat vascular smooth-muscle cells (VSMCs). A clinical dose (0.01 microM) of FK 506 did not increase expression of ET(A) receptor mRNA in VSMCs. However, 0.1 microM FK 506 increased the levels of ET(A) receptor mRNA in VSMCs. These results indicate that the upregulating effect of FK 506 on the ET(A) receptor in the vasculature may contribute to the genesis of FK 506-induced hypertension. The lower incidence of complications seen with FK 506 may be due in part to its use at a lower clinical dose compared to that of CysA.
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PMID:Effect of FK 506 on the expression of endothelin receptor mRNA in the vasculature. 858 92

FK506 (Prograf) is a new immunosuppressive agent, recently approved for use in solid organ transplants. The first use of FK506 was for the indication of refractory liver allograft rejection. This revealed a marked ability to reverse ongoing rejection, even in cases where chronic changes were observed. Between 50 and 70% of patients converted to FK506 had shown improvement. In long-term follow-up of patients with chronic rejection, 75% of patients were still alive at 3 years following FK506 conversion, and 65% of liver allografts were still functioning. FK506 has been compared to cyclosporine in primary liver transplantation. In the three randomized trials, freedom from rejection was statistically greater in the FK506-treated group, as compared to the cyclosporine-treated group. By intent-to-treat analysis, the patient and graft survival in the FK506 group was the same or better than the cyclosporine group. The good results in the cyclosporine limb was due, in part, to the ability of FK506 to treat rejection in the cyclosporine group. Freedom from steroid use, and the lower incidence of hypertension, were prominent features of FK506 patients. FK506 has been used for rescue of rejecting kidney allografts, with results similar to the liver transplant trials. When used as primary immunosuppression, FK506 was shown to be effective, as measured by graft survival. FK506-based immunosuppression has also been used in primary heart transplantation, as well as for primary adult pulmonary transplantation. Results from these small series of patients are equally encouraging. The results of these studies suggest that FK506 is effective for solid organ transplantation. Both FK506 and cyclosporine administration have been associated with side effects, many of which are similar, and some of which are peculiar to a given organ transplant.
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PMID:FK506 in solid organ transplantation. 858 26

Between January 1, 1989, and December 31, 1994, we have treated 122 primary heart recipients with FK 506 (group I) and 121 with cyclosporine (group II). Fifty patients in the cyclosporine (CyA) group received no lympholytic induction (CyA alone) and 71 others received lympholytic induction with either rabbit antithymocyte globulin or OKT3 (CyA+LI). The mean follow-up was longer in the FK 506 group than in the CyA groups (3.2 +/- 1.3 vs 2.3 +/- 1.8 years; p< 0.01). Patient survival did not differ on the basis of the type of immunosuppression used. At 3 months after transplantation, the freedom from rejection in the FK 506 group was higher than that of the CyA-alone group (47% vs 22%, p < 0.01) but similar to that of the CyA+LI group (47% vs 53%). The linearized rejection rate (episodes/100 patient-days) of the FK 506 group (0.09 episodes) was lower (p < 0.05) than that of the CyA-alone group (0.26) and the CyA+LI group (0.13). The requirement for pulsed steroids to treat rejection was less in common in the FK 506 group than in either CyA group. Eighteen patients in the CyA group had refractory rejections; all resolved with FK 506 rescue. Two patients in the FK 506 group had refractory rejection that resolved with total lymphoid irradiation (n=1) and methotrexate therapy (n=1). Patients receiving FK 506 had a lower risk of hypertension and required a lower dose of steroids. Although the mean serum creatinine concentration at 1 year was higher in the FK 506 group, this difference disappeared after 2 years. No patients required discontinuation of FK 506 because of its side effects. Our intermediate-term results indicate that FK 506 compares favorably with CyA as a primary immunosuppressant in heart transplantation.
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PMID:A prospective trial of tacrolimus (FK 506) in clinical heart transplantation: intermediate-term results. 861 36

FK506 (Tacrolimus) recently has been shown to be an effective immunosuppressant after renal transplantation. It is associated with less hypertension, hypercholesterolemia and steroid use compared with cyclosporine. We report 10 patients on FK506 who showed fibrin thrombi within the glomerular capillaries and/or arterioles at renal allograft biopsy. These biopsies were generally performed to assess increasing serum creatinine levels; laboratory evidence of hemolytic uremic syndrome was present in one instance. Plasma or whole blood FK506 levels were elevated in eight of 10 cases. Reduction of immunosuppression led to clinical improvement or biopsy-proven resolution of thrombi in all cases. These observations suggest that FK506 may occasionally produce microvascular changes in the renal allograft. The estimated incidence of this occurrence (1%) is comparable with that reported with cyclosporine (3%).
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PMID:Microvascular changes in renal allografts associated with FK506 (Tacrolimus) therapy. 877 84

Many patients receiving primary cadaver renal transplants have complications in their early post-transplant courses which can affect and possibly confound long-term outcome analyses. Forty-four percent of primary cadaver recipients in the present study were excluded because of early events: delayed graft function (DGF) and early rejection episodes (ERE). Even with these exclusions, similar conclusions to the previous study (1) were noted: that is, the patients with systemic diseases (NS, HTN and IDDM) had the lowest 5-year graft survivals (57-62%) compared to those with diseases that were primarily renal (ALP, IGA and PC) which had better 5-year graft survival results (76-81%). Long-term half-life calculations also demonstrated improved graft survival prognoses in patients with primarily renal diseases (15-18 years in ALP, IGA and PC vs 6-8 years in IDDM, HTN and NS). Again, with the exclusions of patients with early events, Black recipients with HTN did not fare as well as non-Blacks (5-year graft survival of only 52% vs 69%). Many long-term graft losses were due to deaths, oftentimes from cardiovascular diseases. This was especially prominent in disease states with the greatest potential for arteriosclerosis (IDDM, HTN and NS). When patients with early events were excluded, the percent of graft losses attributable to patient death ranged from 21-58%, but were the highest with HTN, PC (age related) and IDDM: 41%, 45% and 58%. A similar analysis in IDDM patients receiving either a LD, SPK or KAT-type transplant revealed that although there was a 10% reduction in 5-year graft survival for KAT patients, most of these graft losses were owing to patient death. Outcomes in SPK and LD in IDDM patients were similar, suggesting selection bias and center effects with the latter two types of transplants going to healthier IDDM patients. It is too soon to conclude whether FK506 has a particularly beneficial role in one primary disease or another as compared to CsA. Combined kidney transplantation with a liver or heart transplant appears to be a reasonable risk. When graft losses due to patient deaths are accounted for, kidney graft survival was approximately that of kidney alone transplantation, suggesting again that graft loss due to patient death must be accounted for when analyzing transplant graft survival.
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PMID:Primary disease effects and associations in patients without early posttransplant events. 879 82

1. The full therapeutic potential of the main immunosuppressive drug, cyclosporin A (CsA), is limited because of its side effects, namely nephrotoxicity and hypertension. Several lines of evidence suggest that the origin of both side effects could be CsA-induced vasoconstriction. However, the underlying molecular mechanisms are not well understood. 2. Diameter measurements of rat isolated mesenteric arteries showed an increase in noradrenaline- and [Arg]8vasopressin-induced vasoconstriction when arteries were pretreated with CsA. 3. Measurements in cultured vascular smooth muscle cells (VSMC) of either cytosolic calcium concentration or of 45Ca2+ efflux showed that CsA potentiated the calcium influx to several vasoconstrictor hormones: [Arg]8vasopressin, angiotensin II, endothelin-1 and 5-hydroxytryptamine. On the other hand, 45Ca2+ efflux in response to thapsigargin, which depletes calcium from intracellular pools, was not potentiated by CsA. 45Ca2+ uptake was not altered by CsA or by any of the analogues tested. 4. Time-course studies in cultured VSMC showed that maximal CsA-induced Ca2+ potentiation occurred after ca. 20 h and this effect was reversed over approximately the next 20 h. 5. To investigate the possible role played by the known intracellular targets of CsA, namely cyclophilin and calcineurin, CsA derivatives with variable potencies with respect to their immunosuppressive activity, were tested on the calcium influx to [Arg]8vasopressin. Derivatives devoid of immunosuppressive activity (cyclosporin H, PSC-833) potentiated calcium signalling, while the potent immunosuppressant, FK520, a close derivative of FK506, and MeVal4CsA, an antagonist of the immunosuppressive effect of CsA did not. The latter compound was unable to reverse the calcium potentiating effect of CsA. 6. Our results show that CsA increases the calcium influx to vasoconstrictor hormones in smooth muscle cells, which presumably increases vasoconstriction. Loading of the intracellular calcium pools appears not to be involved. Experiments with derivatives of CsA and FK520 suggest that interactions with cyclophilins and calcineurin are not the mechanism involved. This indicates, for the first time, that the immunosuppressive activity can be dissociated from the calcium potentiating effect of CsA in vascular smooth muscle.
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PMID:Effect of cyclosporin A and analogues on cytosolic calcium and vasoconstriction: possible lack of relationship to immunosuppressive activity. 879 58

The aim of this study was to investigate the mechanism of hypertension and thromboembolic events induced by cyclosporin (CyA) and tacrolimus (FK506) in respect to their action on the serotonergic blood system. The study was carried out on healthy rats and those with experimental chronic renal failure. CyA injected into healthy and uremic rats caused an increase in serotonin (5-HT) concentration levels in whole blood and platelets. Concomitantly a rise in systolic blood pressure was observed. Platelet aggregation values were significantly higher in uremic rats given CyA. FK506 had no influence on 5-HT blood content, blood pressure or platelet aggregation values. It is concluded that 5-HT may play a role in the development of hypertension and thrombotic events caused by CyA. Furthermore, lower incidence of these complications during FK506 treatment could be the result of this drug's limited effect on the serotonergic blood system.
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PMID:The effect of tacrolimus (FK506) and cyclosporin A (CyA) on peripheral serotonergic mechanisms in uremic rats. 883 16

The safety and potential efficacy of FK506 in combination with a short course of methotrexate (MTX) for the prevention of acute graft-versus-host disease (GVHD) after marrow transplantation from HLA-matched unrelated donors was evaluated in a single-arm Phase II study conducted at two centers. Forty-three patients, 15 to 54 (median 41) years of age, were transplanted for hematologic malignancies. Thirty-seven of 43 evaluable patients had evidence of sustained marrow engraftment. Five patients died before day 17 after transplantation. The median time to an absolute neutrophil count of > 0.5 x 10(5)/L was 21 (range, 14 to 30) days. Nephrotoxicity (serum creatinine concentration > 2 mg/dL or doubling of baseline) occurred in 32 patients (74% cumulative incidence during the first 100 days after transplant). Other adverse effects included hypertension (n = 27), hyperglycemia (n = 27), neurotoxicity (n = 9) and thrombotic thrombocytopenic purpura (n = 2). Severe veno-occlusive disease of the liver occurred in 9 (21%) of the 43 patients. Eighteen patients (42%) developed grades II to IV acute GVHD and five (12%) developed grades III to IV acute GVHD. Twelve of 25 evaluable patients developed extensive chronic GVHD within 1 year of marrow transplantation resulting in an estimate of the probability of developing this complication of 48%. The cumulative incidence of transplant-related mortality during the first 100 days was 37%. Kaplan-Meier estimates of disease-free survival at 2 years for good-risk, poor-risk, and all patients were 65%, 4%, and 32%, respectively. FK506 in combination with a short course of MTX appears active in preventing acute GVHD after marrow transplantation from unrelated donors. Further studies comparing the combination of FK506 and MTX with cyclosporine and MTX for the prevention of acute GVHD are warranted.
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PMID:FK506 in combination with methotrexate for the prevention of graft-versus-host disease after marrow transplantation from matched unrelated donors. 889 34

To provide a more definitive assessment of the efficacy and safety of tacrolimus therapy in comparison with cyclosporin, the extended follow-up of the European multicentre study is reported. Two-year Kaplan-Meier estimates indicated significant reductions in acute (tacrolimus 45.4%, cyclosporin 55.8%; P = 0.006), refractory (1.2% versus 6.4%; P = 0.003) and chronic rejection (2.0% versus 6.9%; P = 0.015) despite significantly lower steroid usage in patients receiving tacrolimus therapy. Patient and graft survival rates (80.6% versus 74.8% and 74.5% versus 70.0%, respectively) were also superior, although these failed to reach statistical significance. Safety profiles were comparable for most major categories (including renal, neurological and glucose metabolic disorders) and in certain aspects were more favourable for tacrolimus. Hypertension (28.0% versus 39.6%, P < 0.01) and cytomegalovirus infection (14.8% versus 22.3%, P < 0.01), two events with important long-term clinical consequences, were reported significantly less frequently. Hirsutism (0.0% versus 8.7%, P < 0.01) and gum hyperplasia (0.0% versus 2.3%, P < 0.05) were absent in patients receiving tacrolimus. Tacrolimus appears to provide effective and safe long-term immunosuppression.
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PMID:Two-year data from the European multicentre tacrolimus (FK506) liver study. 895 12

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