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)

Part I: The side-effects of Sandimmune that have been of most significance clinically are renal dysfunction, renal vascular damage and arterial hypertension. To examine the nature and the origin of such effects, the actions of Sandimmune on the renal tubule, the renal vessels and systemic vessels have been analyzed. To evaluate whether common vasoconstrictory systems may be involved, changes in the renin-angiotensin-aldosterone system and prostaglandin-thromboxane system have been assessed. Comparison between animal and human data obtained in vivo and in vitro shows the actions of Sandimmune on the renal tubule to be modest and involve only a few specific effects. The major action of Sandimmune is on the vessels, vasoconstriction being the major cause of renal dysfunction and also the cause of arterial hypertension. Neither the circulating renin-angiotension-aldosterone system nor the prostaglandin-thromboxane system is clearly responsible for vasoconstriction. Although not itself a vasoconstrictor, Sandimmune seems to modulate the constrictory and dilatory response to other agents in several vascular beds.
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PMID:The pathophysiology of Sandimmune (cyclosporine) in man and animals. 224 27

The microemulsion-based formulation of cyclosporin (Neoral; referred to as the microemulsion formulation in this review) is a microemulsion preconcentrate which has been developed to overcome problems associated with the poor and unpredictable absorption of the standard oral formulation of this drug. These include marked intra- and interpatient variability in the extent of absorption, a poor correlation between trough blood concentrations of cyclosporin and total systemic exposure, and the need for regular monitoring of blood cyclosporin concentrations. In healthy volunteers and renal or liver transplant recipients, administration of the microemulsion formulation resulted in cyclosporin absorption which was significantly faster, more extensive and more predictable than that seen with the standard oral formulation. Furthermore, measurement of whole-blood trough cyclosporin concentrations provided a better estimate of systemic drug exposure in renal transplant recipients who received the microemulsion formulation than in those who received the standard formulation. Systemic exposure of cyclosporin delivered by the new formulation appears to be relatively unaffected by food intake. Initial data suggest that drug absorption from the microemulsion formulation is enhanced in comparison with that achieved from the standard formulation in liver transplant recipients undergoing biliary diversion or with cholestasis, although absorption from the new formulation does not appear to be completely independent of bile. Preliminary results from other groups that experience cyclosporin malabsorption from the standard formulation (patients with cystic fibrosis or diabetes, and children) are also encouraging. Clinical trials specifically designed to investigate the relative immunosuppressive efficacy of the microemulsion formulation have not been reported; further data are required to fully establish the relationship between the more rapid and extensive absorption of cyclosporin from the microemulsion formulation and the probability of graft rejection or adverse events (including nephrotoxicity and hypertension). However, no statistically significant differences have been noted between the 2 formulations in the incidence of these events in studies to date. The incidence of rejection in new renal or liver transplant recipients treated for a minimum of 3 months was approximately 31 to 50% in those receiving the microemulsion formulation and approximately 24 to 56% in those receiving the standard formulation. Thus, although confirmation of existing efficacy and tolerability data is required, the characteristic pharmacokinetic properties of the microemulsion formulation make it an attractive option for the oral delivery of cyclosporin in transplant recipients, offering more predictable and more extensive drug absorption than the standard formulation. The microemulsion formulation may be of particular benefit in patients who show poor absorption of cyclosporin from the standard oral formulation, such as liver transplant recipients with biliary diversion or cholestasis.
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PMID:Cyclosporin. A review of the pharmacokinetic properties, clinical efficacy and tolerability of a microemulsion-based formulation (Neoral). 858 33

Cyclosporin, as the microemulsion formulation Neoral, was given to two groups of patients with severe psoriasis (Psoriasis Area and Severity Index: PASI > 12.0). Group A (10 patients) were receiving the traditional formulation of cyclosporin, Sandimmun, at the start of the study, with a partial clinical response, and were switched to Neoral at the same dose (3.3 mg/kg per day). Group B patients, who had previously been treated with Sandimmun but were treatment failures, were given Neoral, 3.5 mg/kg per day. This led to rapid improvement in psoriasis in both groups. In Group A mean PASI fell from 22.3 to 11.6 on Sandimmun, after 82 +/- 30 weeks, and to 4.0 (P < 0.05) after 32 weeks of Neoral. In Group B mean PASI decreased from 20.3 to 3.7 (P < 0.05) at a dose of 3.1 mg/kg per day. Pharmacokinetic data demonstrated significant decrease in tmax from 2.3 to 1.4 hours. After 2 weeks Cmax and the area under the curve (AUC) (0-4 h) were significantly increased by 41% and 61%, respectively. Further pharmacokinetic data at 3 months showed similar results. No significant changes in renal function from pre-treatment status were seen in either group. None of the patients developed hypertension. No serious adverse events were reported. The microemulsion formulation of cyclosporin showed greater efficacy and bioavailability. Improved outcome was seen at doses which were on average 15% lower than with the traditional formulation, leading to a reduction in cost of treatment.
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PMID:Increased bioavailability and improved efficacy, in severe psoriasis, of a new microemulsion formulation of cyclosporin. 888 3

Cyclosporin A (CyA) is the primary immunosuppressive agent for the prophylaxis of rejection episodes in renal, cardiac, liver, and other transplants. Recently, its use in autoimmune diseases has been investigated as well. Although several studies have produced promising results, nephrotoxicity and hypertension can result from CyA treatment, and their development must be understood in order to facilitate patient management. This article describes the diastolic blood pressure (DBP) responses in two populations of patients during three months of CyA therapy. Study A involved psoriasis patients and Study B involved postoperative renal transplant patients. The relationship between blood pressure and systemic CyA exposure and other covariates was evaluated using linear mixed effects modeling. Temporal patterns of blood pressure changes with varying duration of CyA exposure were investigated. In Study A, the psoriasis patients showed transient exposure-related increases in DBP on CyA. These elevations, while statistically significant, were clinically insignificant. In Study B, the renal transplant patients showed no CyA-related rises in DBP. In neither study was there evidence for a difference in effect on DBP between Sandimmune and Neoral, the two formulations of CyA presently approved for marketing by the Food and Drug Administration, after differences in CyA exposure were taken into account.
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PMID:Description of blood pressure changes in patients beginning cyclosporin A therapy. 902 41

Immunosuppressive efficacy of Neoral and Prograf following primary hepatic transplantation was comparable. Incidence of rejection episodes, infectious complications, hypertension, and postoperative diabetes mellitus was comparable. Although clinical use of both immunosuppressants was associated with early compromise in renal function, no progressive renal dysfunction was observed.
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PMID:Renal function in primary liver transplant recipients receiving neoral (cyclosporine) versus prograf (tacrolimus). 963 66

Following primary liver transplantation, immunosuppressive efficacy of Neoral and Prograf was similar and superior to that of Sandimmune. Rejection incidence was statistically increased with Sandimmune therapy. Incidence of hypertension, posttransplant diabetes mellitus, and infectious complications was not statistically different. Although early compromise in renal function was associated with Sandimmune, Neoral, and Prograf immunosuppression, no progressive renal dysfunction was identified.
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PMID:Impact of Sandimmune, Neoral, and Prograf on rejection incidence and renal function in primary liver transplant recipients. 972 99

Cyclosporine (Sandimmune) is an effective immunosuppressive drug but may be poorly absorbed in the early postoperative period after liver transplantation, exposing the recipient to an increased risk for rejection. Neoral is a new oral formulation of cyclosporine that uses a mixture of surfactant, lipophilic, and hydrophilic solvents to permit microemulsification that leads to potentially better absorption. This oral drug has not been evaluated in children immediately posttransplantation. The aim of this study was to evaluate the pharmacokinetics, bioavailability, and safety of Neoral during the first week post-liver transplantation in children. Twelve children, 8 boys and 4 girls, with a median age of 2.6 years (range, 1 to 8 years) were administered Neoral within 12 hours posttransplantation. Pharmacokinetic profiles were performed over a 12-hour period on each child on days 1, 3, and 5 and twice-daily trough levels were obtained on days 2, 4, 6, and 7. The maximum concentration (Cmax), time to reach Cmax (Tmax), 12-hour trough levels, and area under the curve were calculated, and rejection episodes and adverse events were documented over a 12-week period. Neoral was well absorbed, even on the first postoperative day. After the introduction of enteral feeding, the peak levels increased (Cmax, 655 ng/mL) and were achieved significantly sooner (Tmax, 2 hours). There was no significant difference in drug exposure between days 1, 3, and 5 (P > .05). The incidence of acute rejection was 25% and hypertension was reported in 4 of 12 patients during the first week. Neoral was well absorbed in the early post-liver transplantation period, provided effective immunosuppression, and was not associated with a high incidence of adverse events or toxicity. The introduction of enteral feeding improved absorption.
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PMID:Efficacy of Neoral in the immediate postoperative period in children post-liver transplantation. 979 Nov 60

Female solid organ recipients with good graft function generally tolerate pregnancy well. However, the combination of mother, fetus, transplanted organ, and immunosuppressive and other medications increases the complexity of management and raises the specter of adverse outcomes. For the mother, considerations include the nature of the original disease (i.e. genetic risk of transmission), co-morbid conditions which increase pregnancy risk (i.e. hypertension, diabetes, renal insufficiency), and long-term maternal prognosis. For the fetus, questions include the adequacy of maternal physiology (cardiac, renal, glycernic control, etc.), exposure to medications, and exposure to infectious agents. The transplanted organ must accommodate the increased workload of pregnancy and the needs of the fetus. The delicate balance between immunosuppression and rejection may be altered by the pregnancy. The impact of pregnancy on recurrent disease can also be an issue. Medication issues include changes in drug pharmacokinetics and the potential for adverse effects on the fetus. These effects could include chromosomal aberrations, structural malformations, organ-specific toxicity, intrauterine growth retardation, and immune system development. For female kidney recipients there are sufficient data to demonstrate a direct relationship between creatinine levels before and during pregnancy and risk of graft loss in the postpartum period. Pregnancy itself does not appear to adversely affect stable graft function. Among liver recipients, those with recurrent viral hepatitis may have deterioration of graft function with subsequent pregnancies. These recipients should be apprised accordingly, as maternal deaths have occurred in this setting. Postpartum depression and potential for medication noncompliance require vigilance. The safety of pregnancy from the NTPR analysis to date has been largely derived from the experience with CsA-based regimens. For recipients on CsA there have been good maternal outcomes without any specific or predominant malformation patterns in the offspring. For the general population, malformations occur in approximately 3% of live births. To date, there is no indication that this incidence has increased despite the complex medical regimens of transplant recipients. Data are accruing with tacrolimus and Neoral. Continuing data entry and continued follow-up of off-spring will allow for further recommendations, especially in light of the new medications and combinations. Recipients should be advised to wait one to 2 years after transplant before considering pregnancy. Those with stable graft function, and with no rejection, graft dysfunction, or deterioration should still be apprised of the high risk of prematurity and low birthweight, although maternal risks appear low. These are high-risk pregnancies, requiring close communication and cooperation between the high-risk obstetrician and the transplant team. The use of the FDA pregnancy categories should not be the sole reason for choosing a particular immunosuppressive drug. Agents such as Neoral and tacrolimus would appear to offer some advantage as blood levels can be measured. At present, no safety guidelines can be given for mycophenolate mofetil, OKT3, or ATG. Identification of prepregnancy factors predictive of higher risks and appropriate counseling and management guidelines are major NTPR goals, and depend on the continued assistance and cooperation of the transplant community.
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PMID:Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation. 991 94

The greater and more consistent absorption of cyclosporine from the microemulsion formulation (Neoral; Novartis Pharmaceuticals Ltd., Frimley, UK) when compared with that from the original form (Sandimmune; Novartis Pharmaceuticals Ltd., Frimley, UK) results in greater systemic exposure. Lung transplant recipients could particularly benefit from this enhanced exposure, but not at the expense of excessive cyclosporine toxicity. We compared the pharmacodynamics of Neoral and Sandimmune over the first postoperative year in 50 lung transplant recipients. Twenty-eight patients were randomly selected to receive Neoral and 22 to receive Sandimmune. Nine patients with cystic fibrosis (CF) were randomly selected independently (5, Neoral; 4, Sandimmune). Patients were maintained on similar trough blood cyclosporine concentrations (C0) throughout the 12-month follow-up. A limited blood sampling strategy was adopted to compare the pharmacokinetics of the two formulations at the end of weeks 1 to 4, and of weeks 13, 26, 39, 52. The influence of any difference between the pharmacokinetics of Neoral and Sandimmune on either efficacy or toxicity of the drug was investigated during the follow-up period. Patients in the Neoral and the Sandimmune groups were matched demographically. There were no differences in dose-normalized blood cyclosporine concentrations measured predose (C0) or 6 hours postdose between the two groups. However, the measurement at 2 hours postdose (C2) and the total AUC0-6 were significantly greater in the Neoral group in both CF and non-CF patients at all visits (p < 0.001). Non-CF patients required 9% lower doses of Neoral to achieve comparable C0 measurements to those patients receiving Sandimmune. However, patients with CF required 2 to 3 times the dose of both Neoral and Sandimmune to achieve the same C0 as non-CF patients. The linear rejection rate in the Sandimmune group was 1.87 episodes per patient year, which was similar to the rejection rate of 1.97 episodes per patient year in the Neoral group. Serial lung function, blood biochemistry and hematology, mortality and the incidence of severe renal dysfunction, hypertension, infection, seizures, and new-onset diabetes were all similar in the two groups. Despite equivalent C0, those in the Neoral group were consistently exposed to greater blood cyclosporine concentrations during the dosing interval than those in the Sandimmune group. This did not increase the incidence of serious cyclosporine-associated side effects or influence the rate of acute rejection either. When data from the Neoral and Sandimmune groups were combined, measurements of C0 but not C2 or C6 were associated with the risk of acute lung allograft rejection.
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PMID:Randomized, trough blood cyclosporine concentration-controlled trial to compare the pharmacodynamics of Sandimmune and Neoral in de novo lung transplant recipients. 1005 Oct 50

One of the most serious side effects of the immunosuppressive agent, cyclosporin A (CsA), is drug-related hypertension. As it is generally accepted, the sympathetic nervous system may play an important role in the development or maintenance of this abnormal pathophysiological situation. This study is aimed at assessing plasma and platelet catecholamines, and a possible connection to cyclosporin A-induced increased arterial blood pressure. It was thus based on an investigation in which Wistar rats were divided into three groups: one taking only orange juice (control) and the other two receiving 5 and 30 mg kg(-1)('trough' and 'peak') of cyclosporin A (Sandimmun Neoral), daily, for 7 weeks. Plasma and platelet noradrenaline, adrenaline and dopamine levels and arterial blood pressures were evaluated before the start of the study (week 0) and after 2, 4 and 7 weeks. Plasma and platelet catecholamines increased drastically in the 'peak' CsA concentration-treated group, which contrasts with the slight decrease observed in the group treated with the 'trough' concentration. However, both groups revealed an increase in blood pressures, when compared with the control group. These findings suggest that at least 'peak' cyclosporin A concentration alters significantly the plasma and platelets catecholamines levels, which may contribute to the cyclosporin A-induced hypertension. Other contributions, regardless of catecholamine content disturbances, might occur, at least at 'trough' CsA concentrations.
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PMID:The distribution of catecholamines between plasma and platelets in cyclosporin A-induced hypertensive rats. 1062 80


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