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)

The optimal dose of cyclosporine to achieve minimal toxicity and adequate control of rejection remains undetermined. We initiated our program with an immunosuppressive protocol designed to reduce drug toxicity, to reduce early severe rejection, and to provide adequate long-term immunosuppression. Because of increasing reports of nephrotoxicity associated with cyclosporine, we adopted a protocol of low-dose cyclosporine combined with steroids and equine antithymocyte globulin. The mean preoperative creatinine was 0.12 +/- 0.08 mmol/L and by 1 year after transplant was 0.13 +/- 0.04 mmol/L. Cyclosporine dose at 1 year was 5 +/- 2 mg/kg/day, and the serum cyclosporine level was 120 +/- 40 ng/ml. However, at 1 year 85% of the patients were hypertensive. The incidence of rejection in the first year after transplantation was 1.46 episodes per patient. Incidence of infection was 0.85 episodes per patient. The 3-month survival was 91%, and the actuarial 1-year survival was 76%. Seventy percent of our mortality was due to rejection, and four patients suffered significant graft damage in the period 3 months to 1 year, two requiring retransplantation. Although these low doses of cyclosporine have reduced nephrotoxicity and infectious complications, hypertension remains a significant problem. Moreover, although survival is acceptable, the incidence of graft rejection causing death or loss of function is of concern. This may indicate that cyclosporine at this dosage needs supplementation by a third immunosuppressive agent such as azathioprine.
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PMID:Effectiveness of minimal dosage cyclosporine in limiting toxicity and rejection. 330 58

1. Cyclosporin A (CyA; 12 mg/kg/day) was infused into six conscious sheep over 5 days to examine the haemodynamic effects of the drug in normal animals. 2. Mean arterial pressure was increased from 73(1) mmHg to 90(4) mmHg (P less than 0.001). There was no change in cardiac output but calculated total peripheral resistance was elevated from 16(1) to 21(2) mmHg min/1 (P less than 0.001) on day 4. 3. There was no change in plasma [Na], but a fall in plasma [K]. Urinary Na excretion decreased. Glomerular filtration rate, filtration fraction, renal blood flow, renal vascular resistance, body weight, plasma renin and blood aldosterone concentration were unchanged. 4. CyA produces an increase in blood pressure in sheep associated with an increase in total peripheral resistance on days 1, 3, and 4, in the absence of changes in renal function. This suggests that CyA hypertension is not simply a consequence of nephrotoxicity.
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PMID:The haemodynamic effects of cyclosporin A in sheep. 343 3

Cyclosporine is known to cause hypertension, and we have recently reported that it causes hypomagnesemia and renal magnesium wasting in marrow transplant recipients. We performed a case-control study to ask whether hypomagnesemia might be related to this form of drug-induced hypertension. The charts of 188 patients treated with cyclosporine were evaluated for the development of hypertension. The 32 patients who became hypertensive were age, sex, and disease-matched with 32 cyclosporine-treated controls. Baseline serum Mg levels were normal in both groups. However at the time of development of hypertension, the hypertensive patients had a mean (+/- SD) Mg of 1.22 +/- 0.20 mEq/L versus controls 1.40 +/- 0.33 mEq/L (P less than 0.01). Serum calcium, albumin, creatinine, potassium, and cyclosporine concentrations were not different between the two groups. This study may indicate that hypertension and hypomagnesemia are coincident toxicities in cyclosporine-treated patients. Alternatively, our data support the hypothesis that acquired derangements in magnesium metabolism may contribute to the development of hypertension. Magnesium replacement may prove beneficial in the treatment and/or prevention of cyclosporine-associated hypertension.
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PMID:Correlation of hypomagnesemia with the onset of cyclosporine-associated hypertension in marrow transplant patients. 351 Apr 94

A multivariate analysis dissected the impact of donor procurement variables, immunologic risk factors, and alternate cyclosporine and prednisone induction immunosuppressive regimens on the early and eventual function of 303 consecutive cadaveric renal allografts. Primarily warm, but to a slight extent cold, ischemia time had an adverse impact on allograft function, as did the requirement for vasopressor or diuretic therapy. The occurrence of initial graft non-function adversely affected the probability of three-month graft survival, but did not alter either the longevity of organs, which subsequently recovered function, or patient mortality rate. The major immunologic risk factor was a second or multiple transplant, which was associated with an increased incidence of early graft failure, and impaired renal function in successful transplants. Correlations with HLA-B and DR matching were reflected in the quality of renal function, but not in graft survival rates. Cyclosporine (CsA) administration by continuous intravenous infusion, in order to avert initial elevated mean three-day, serum radioimmunoassay drug levels reduced the incidence of initial graft non-function. High levels were also associated with impaired early and eventual renal function. Rapid posttransplant taper of corticosteroids to 30 mg prednisone by day six was associated with a greater incidence of rejection episodes and early graft failure than a taper that achieved 30 mg prednisone at 60 days. Both the serum creatinine value and the degree of hypertension observed at one month afforded good prognostic indices of eventual graft survival. Therefore, renal allografts in CsA-treated patients were sensitive not only to adverse donor and immunologic risk factors, but also to excessive CsA drug levels in the early postoperative period. These findings suggest an induction immunosuppressive strategy utilizing slightly higher initial doses of steroids for CsA-sparing during the first three days, followed by increased, but judicious, administration of CsA to achieve steroid-sparing by virtue of effective rejection prophylaxis.
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PMID:Multivariate analysis of risk factors impacting on immediate and eventual cadaver allograft survival in cyclosporine-treated recipients. 354 26

Twelve patients with refractory rheumatoid arthritis were included in a 1-year open trial of cyclosporin A (CsA), 5 mg/kg/day. Clinical efficacy was observed 1 month after beginning treatment, was well established after 4 months of therapy, and remained stable for the remainder of the 1-year treatment period. Among the numerous side effects observed, renal toxicity and hypertension occurred suddenly during the trial and required constant monitoring, adequate therapy, and modulation of CsA dosage. Cyclosporin A seems to be an effective treatment for active rheumatoid arthritis, but it requires close monitoring for toxicity.
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PMID:Cyclosporin A in rheumatoid arthritis: preliminary clinical results of an open trial. 354 23

Cyclosporine (CsA) is a new immunosuppressive agent that has adverse effects of nephrotoxicity and de novo appearance of hypertension. It has been hypothesized that the mechanism of the contrary effects is through an action of CsA on vascular smooth muscle. To test this hypothesis, thoracic aortas were isolated from Wistar Kyoto rats and ring segments prepared for measurement of tension. CsA (5 X 10(-6) M) induced a slow increase in tone of the isolated rings with a response at 3 hr of 0.70 +/- 0.17 N/m2 X 10(4). This contraction was significantly inhibited by the Ca2+ channel blocker verapamil (0.30 +/- 0.08 N/m2 X 10(4) after 3 hr, P less than 0.05) and by the noncompetitive alpha-antagonist phenoxybenzamine (0.06 +/- 0.07 N/m2 X 10(4) after 3 hr, P less than 0.05). The competitive alpha-antagonist phentolamine had mixed effects. CsA does not irreversibly alter vascular smooth muscle contractile ability since a 3 hr exposure to the agent had no effect on either the maximal contractile response or sensitivity to KCl. We conclude that CsA can directly induce contraction in vascular smooth muscle, perhaps by inducing a release of norepinephrine from adrenergic nerve terminals. The data are consistent with the hypothesis that CsA induces nephrotoxicity and de novo hypertension through a contractile effect on vascular smooth muscle.
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PMID:Induction of contraction in isolated rat aorta by cyclosporine. 357 78

In 5 cases with minimal change nephritis Cyclosporine A has been added to the conventional steroid therapy, when relapse of nephrotic syndrome occurred while reducing the daily prednisolone dose. The intended cyclosporine trough level ranged from 250 ng/ml to 450 ng/ml whole blood, estimated by the RIA method. Proteinuria disappeared in 4 out of the 5 cases, in the other one urinary protein excretion was strikingly reduced. In the 4 cases with complete remission of proteinuria prednisolone was tapered. These patients have cyclosporine A as the sole immunosuppressive drug since 56 weeks and do not show proteinuria. Side effects of cyclosporine therapy have been slight deterioration of kidney function in 2 out of the 5 cases and the occurrence of hypertension in 4 patients.
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PMID:[Cyclosporin therapy in minimal change nephritis]. 359 Aug 4

Cyclosporin A administration is associated with an increased incidence of hypertension. To evaluate the direct effects of the drug on the contractile responses of vascular tissue to adrenergic stimuli, rat caudal artery ring segments were studied before and after the addition of cyclosporin A or its ethanol vehicle in vitro. In a dose-related manner, cyclosporin A augmented the contractile response to transmural nerve stimulation, with a highly significant (p less than 0.001 relative to that produced by the vehicle) lowering of the stimulation rate, a 50% of maximum contractile response (ED50) that elicited. The difference between pretreatment and treatment maximal responses to transmural nerve stimulation was also significantly greater (p less than 0.01) in the cyclosporin A-treated preparations than in those receiving the vehicle. In similar experiments, the responses to exogenous norepinephrine were not significantly affected. The effect of cyclosporin A on transmural nerve stimulation was demonstrated at several extracellular calcium concentrations. The results suggest that cyclosporin A enhances nerve stimulation responses by a presynaptic mechanism.
Hypertension 1987 Jun
PMID:Direct augmentation by cyclosporin A of the vascular contractile response to nerve stimulation. 359 90

Ten patients with rheumatoid arthritis were entered into a 24-week pilot study of oral cyclosporin A at a starting dosage of 6 mg/kg/day, followed by a 12-week washout period. Significant improvement in clinical parameters was observed at 12 weeks and 24 weeks (P less than 0.02 versus baseline for joint pain and joint swelling indexes and patient and physician assessments; P less than 0.04 versus baseline in the numbers of painful/tender joints and swollen joints). Adverse reactions were varied: renal impairment occurred in all patients and hypertension occurred in 7. All patients demonstrated an increase in defined disease activity at cessation of treatment and through the washout period. Cyclosporin A is clinically effective in the treatment of patients with refractory rheumatoid arthritis, but its value as an intervention therapy is limited by its toxicity.
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PMID:Cyclosporin A treatment of refractory rheumatoid arthritis. 381 92

Cyclosporine has gained acceptance as the immunosuppressive agent of choice in cardiac transplantation, but the validity of this assumption has yet to be established. Since January 1983, 25 patients have been randomly assigned to receive either conventional immunosuppression (azathioprine/antithymocyte globulin/prednisone) and pretransplant transfusion (PAAP, n = 11) or cyclosporine immunosuppression (cyclosporine and prednisone [CyA], n = 14). There was no difference in the age distribution (41 +/- 9 vs 38 +/- 11 years), indications for transplantation, preoperative serum creatinine level (1.2 +/- 0.2 vs 1.4 +/- 0.3 mg/dl), or postoperative follow-up time (13.5 +/- 5.4 vs 13.5 +/- 5.2 months). Mortality was not different (PAAP = 2, CyA = 3) and there was no difference in rejection episodes per patient (PAAP = 1.8, CyA = 1.9). Patients in the PAAP group had more serious infections (PAAP = 8, CyA = 3; P less than .02), but those in the CyA group developed a greater incidence of systemic hypertension (PAAP = 1, CyA = 10; p less than .02), pericardial effusion (PAAP = 0, CyA = 6; p = .05), and impaired renal function (creatinine 1.5 mg/dl, PAAP = 2, CyA = 11; p less than .02). Thus it appears that in this small series, cyclosporine is not associated with a significant increase in early survival. It does appear that patients on PAAP immunosuppression develop a greater number of serious infections, but the incidence of rejection episodes appears to be the same. Renal dysfunction and hypertension in patients receiving cyclosporine continue to be long-term concerns and may add to the morbidity and mortality of patients treated with this immunosuppressive regimen.
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PMID:A prospective randomized trial of pretransfusion/azathioprine/prednisone versus cyclosporine/prednisone immunosuppression in cardiac transplant recipients: preliminary results. 389 55


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