Cyclosporine Whole Blood Levels Research Articles

Efficacy of Cyclosporine for Chronic, Refractory Stomatitis in Cats: A Randomized, Placebo-Controlled, Double-Blinded Clinical Study

Sixteen cats with chronic stomatitis, that had previously undergone premolar-molar or full-mouth extractions, were randomly assigned a group to receive 2.5 mg/kg cyclosporine or placebo orally twice daily Neither the clinician nor the clients were aware of the group assignments. Cats were evaluated prior to treatment and every 2 weeks for 6 weeks using a 30 point Stomatitis Disease Activity Index (SDAI) score. Mean improvement in SDAI scores among cats in the treatment group after 6 weeks was 52.7 %. This was significantty diffrent fom the mean improvement (12.2 %) of cats in the placebo group. During the 6 week study period, 7 of the 9 cats in the treatment group (77.8 %) showed a > 40 % improvement in SDAI score, while 1 of 7 cats in placebo group (14.3 %) showed a > 40 % improvement in SDAI score. This difference was statistically significant. Individual variability in the absorption of orally-administered cyclosporine was high. Trough whole-blood cyclosporine levels ranged firm 32.1 ng/ml to 1,576.2 ng/ml. At the end of the 6 week observation period, there was a statistically significant diference among cats with trough whole-blood cyclosporine levels >300 ng/ml (72.3 % improvement) compared with cats with cyclosporine levels < 300 ng/ml (28.2 % improvement). Whole-blood cyclosporine levels > 300 ng/ml were associated with significant improvement in oral inflammation in cats with chronic stomatitis that had previously undergone premolar-molar or fuill-mouth extraction.

Greater impact of oral fluconazole on drug interaction with intravenous calcineurin inhibitors as compared with intravenous fluconazole

Although the drug interaction between fluconazole and calcineurin inhibitors has been established, the influence of the route of fluconazole administration on its drug interaction with calcineurin inhibitors has yet to be fully examined. The aim of the present study is to examine whether different routes of fluconazole administration alter its drug interactions with intravenous calcineurin inhibitors. In 53 recipients of allogeneic hematopoietic cell transplantation receiving calcineurin inhibitors intravenously, steady-state whole-blood levels of cyclosporine A (CsA) or tacrolimus were measured after the route of fluconazole (200 mg/day) administration was switched from intravenous to oral. The mean steady-state whole-blood level of CsA or tacrolimus significantly increased after the route of fluconazole administration was switched from intravenous to oral (CsA: to 394 +/- 28.4 from 362 +/- 17.8 ng/mL; tacrolimus: to 18.8 +/- 0.64 from 17.4 +/- 0.39 ng/mL, P < 0.05). This finding strongly suggests that oral fluconazole has a greater impact on its drug interactions with intravenous calcineurin inhibitors than intravenous fluconazole. Monitoring of blood levels of intravenous calcineurin inhibitors is recommended when the route of fluconazole administration is switched from intravenous to oral.

Prediction of Cyclosporine Blood Levels in Heart Transplantation Patients Using a Pharmacokinetic Model Identified by Evolutionary Algorithms

Artificial intelligence (AI)-based computation methods have been recently shown to be applicable in several clinical diagnostic fields. The purpose of this study was to introduce a novel AI method called evolutionary algorithms (EAs) to clinical predictions. The technique was used to create a pharmacokinetic model for the prediction of whole blood levels of cyclosporine (CyA). One hundred one adult cardiac transplant recipients were randomly selected and included in this study. All patients had been receiving oral cyclosporine twice daily, and the trough levels in whole blood were measured by monoclonal-specific radioimmunoassay. An evolutionary algorithm (EA)-based software tool was trained with pre- and post-operative variables from 64 patients. The results of this process were then tested on data sets from 37 patients. The mean value of the predicted CyA level throughout the measurement period for the test data was 175 +/- 27 ng/ml, which compared well with the mean observed CyA level of 180 +/- 31 ng/ml. The system bias expressed as the mean percent error (MPE) for the training and test data sets were 7.1 +/- 5.4% (0.1% to 26.7%) and 8.0 +/- 6.7% (0.8% to 28.8%), respectively. The prediction accuracy ranged from 80% to 90%. The correlation coefficient between predicted and observed CyA concentration for the training data were 0.93 (p < 0.001) and for the test data were 0.85 (p < 0.001), respectively. The results of this study suggest that the use of evolutionary algorithms to identify pharmacokinetic models yields accurate prediction of cyclosporine whole blood levels in heart transplant recipients. This and other similar technologies should be considered as future clinical tools to reduce costs in our health systems.

Lack of effect of a single oral dose of cyclosporine on systemic blood pressure and on forearm blood flow and vascular resistance in humans

The acute hemodynamic effect of cyclosporine in man is controversial. A randomized, double blind, placebo-controlled, cross-over study was undertaken to evaluate the effect of a single oral dose of cyclosporine (20 mg/kg body weight) on mean blood pressure (MBP), heart rate (HR), forearm blood flow (FBF), and vascular resistance (FVR) in 16 healthy adult subjects. Subjects were studied twice, with an intervening period of 2 weeks, before and after the administration of either cyclosporine or the vehicle olive oil. Blood pressure was measured on brachial and digital arteries. After 30 min of rest, basal measurements were obtained and individuals were randomly assigned to receive either cyclosporine or the vehicle, and the same measurements were repeated 2 h later. Mean whole blood levels of cyclosporine were 1542 ± 387 ng/mL (range 1000 to 2550) 2 h after the administration of a single oral dose of cyclosporine. Cyclosporine did not cause any significant change in the hemodynamic parameters when compared with vehicle. Pre- and post–cyclosporine data were as follows (means ± SD): MBP (determined by Finapres on the digital artery), 92 ± 10 v 95 ± 11 mm Hg; HR, 66 ± 10 v 68 ± 11 beats/min; FBF, 3.9 ± 1.3 v 3.8 ± 1.8 mL/100 mL/min; and FVR, 28 ± 9 v 33 ± 18 units, respectively. For the vehicle the results were: MBP, 94 ± 9 v 94 ± 9; HR, 67 ± 9 v 67 ± 11; FBF, 3.3 ± 1.6 v 3.2 ± 2.0; FVR, 35 ± 14 v 37 ± 15, respectively. These figures did not differ from those obtained with the auscultatory method applied to the brachial artery among 10 selected subjects studied with Finapres. In conclusion, we found no evidence that at supratherapeutic doses cyclosporine causes acute increase in blood pressure or peripheral vasoconstriction in humans.

Decrease in lipoprotein(a) after renal transplantation is related to the glucocorticoid dose.

Serum lipoprotein(a) [Lp(a)] concentrations and apolipoprotein(a) phenotypes were determined in 46 patients with end-stage renal disease both before as well as 1 week and 1, 3 and 6 months after renal transplantation. Immunosuppressive therapy consisted of cyclosporin A, prednisone and azathioprine. Before transplantation median Lp(a) levels did not differ between the patients and a healthy control group. A highly significant decrease (P < 0.001) in Lp(a) levels was observed in both male and female patients 1 week after transplantation. This marked reduction in Lp(a) occurred at a time when patients were receiving the highest doses of corticosteroids. As steroid doses were gradually tapered, Lp(a) concentrations subsequently increased, although at 6 months levels were still significantly reduced (P < 0.01) in women. No significant correlation was observed between Lp(a) and whole-blood cyclosporin levels, nor was there any correlation with the azathioprine dose. The reduction in Lp(a) concentrations was seen for all apo(a) phenotypes observed in the study.

Acute vasodilatation in early dumping syndrome

The acute hemodynamic effect of cyclosporine in man is controversial. A randomized, double blind, placebo-controlled, cross-over study was undertaken to evaluate the effect of a single oral dose of cyclosporine (20 mg/kg body weight) on mean blood pressure (MBP), heart rate (HR), forearm blood flow (FBF), and vascular resistance (FVR) in 16 healthy adult subjects. Subjects were studied twice, with an intervening period of 2 weeks, before and after the administration of either cyclosporine or the vehicle olive oil. Blood pressure was measured on brachial and digital arteries. After 30 min of rest, basal measurements were obtained and individuals were randomly assigned to receive either cyclosporine or the vehicle, and the same measurements were repeated 2 h later. Mean whole blood levels of cyclosporine were 1542 ± 387 ng/mL (range 1000 to 2550) 2 h after the administration of a single oral dose of cyclosporine. Cyclosporine did not cause any significant change in the hemodynamic parameters when compared with vehicle. Pre- and post–cyclosporine data were as follows (means ± SD): MBP (determined by Finapres on the digital artery), 92 ± 10 v 95 ± 11 mm Hg; HR, 66 ± 10 v 68 ± 11 beats/min; FBF, 3.9 ± 1.3 v 3.8 ± 1.8 mL/100 mL/min; and FVR, 28 ± 9 v 33 ± 18 units, respectively. For the vehicle the results were: MBP, 94 ± 9 v 94 ± 9; HR, 67 ± 9 v 67 ± 11; FBF, 3.3 ± 1.6 v 3.2 ± 2.0; FVR, 35 ± 14 v 37 ± 15, respectively. These figures did not differ from those obtained with the auscultatory method applied to the brachial artery among 10 selected subjects studied with Finapres. In conclusion, we found no evidence that at supratherapeutic doses cyclosporine causes acute increase in blood pressure or peripheral vasoconstriction in humans.

Incidence of adverse reactions to cyclosporine after liver transplantation is predicted by the first blood level

Despite the availability of whole-blood cyclosporine assays, the different responses of individual patients to its administration after transplantation continue to pose clinical problems, particularly with respect to toxicity. Fifty-seven recipients of first orthotopic liver transplants were studied between January 1992 and July 1992. Initial immunosuppression was carried out with azathioprine, methylprednisolone and cyclosporine, at a dose of 1 mg/kg/day adjusted to achieve blood levels between 400 and 600 ng/ml. Cyclosporine levels were measured 12 hr after the start of intravenous administration and correlated with the occurrence of toxic complications. Twelve patients experienced toxic complications in the first 7 days after orthotopic liver transplantation. These were neurological in six patients (of whom four also had kidney failure) and renal complications in the other six patients. All complications were reversed by reducing or stopping administration of cyclosporine. We noted excellent correlation between the occurrence of complications and cyclosporine whole-blood levels (p < 0.0001) despite the fact that levels did not exceed the therapeutic range. However, no correlation was observed between toxicity and cumulative dosage. In this study we were able to demonstrate that a standardized dose of cyclosporine does not prevent the occurrence of toxic side effects even when cyclosporine whole-blood levels are subsequently maintained in the therapeutic range. This highlights the importance of the first dose of cyclosporine and consequent early postoperative blood levels and indicates that these problems are unlikely to be overcome until a method of predicting individual requirements can be established in clinical practice.

Incidence of adverse reactions to cyclosporine after liver transplantation is predicted by the first blood level

Despite the availability of whole-blood cyclosporine assays, the different responses of individual patients to its administration after transplantation continue to pose clinical problems, particularly with respect to toxicity. Fifty-seven recipients of first orthotopic liver transplants were studied between January 1992 and July 1992. Initial immunosuppression was carried out with azathioprine, methylprednisolone and cyclosporine, at a dose of 1 mg/kg/day adjusted to achieve blood levels between 400 and 600 ng/ml. Cyclosporine levels were measured 12 hr after the start of intravenous administration and correlated with the occurrence of toxic complications. Twelve patients experienced toxic complications in the first 7 days after orthotopic liver transplantation. These were neurological in six patients (of whom four also had kidney failure) and renal complications in the other six patients. All complications were reversed by reducing or stopping administration of cyclosporine. We noted excellent correlation between the occurrence of complications and cyclosporine whole-blood levels (p < 0.0001) despite the fact that levels did not exceed the therapeutic range. However, no correlation was observed between toxicity and cumulative dosage. In this study we were able to demonstrate that a standardized dose of cyclosporine does not prevent the occurrence of toxic side effects even when cyclosporine whole-blood levels are subsequently maintained in the therapeutic range. This highlights the importance of the first dose of cyclosporine and consequent early postoperative blood levels and indicates that these problems are unlikely to be overcome until a method of predicting individual requirements can be established in clinical practice. (HEPATOLOGY 1993;18:1123–1126.)

Thromboxane receptor blockade attenuates chronic cyclosporine nephrotoxicity and improves survival in rats with renal isograft.

The question of whether pharmacological inhibition of the thromboxane A2 activity prevents cyclosporine-induced chronic renal dysfunction in a Lewis rat model of renal isograft was addressed. Transplanted animals were given a daily oral dose of cyclosporine (20 mg/kg; N = 15), cyclosporine (20 mg/kg) and the thromboxane A2 receptor antagonist GR32191 (3 mg/kg twice daily, by gavage; N = 15), or the vehicle alone (N = 12). Treatments were started the day of kidney transplant, and animals were monitored for 1 year. Cyclosporine-treated animals developed renal insufficiency, as documented by serum creatinine levels of 0.49 +/- 0.09, 0.95 +/- 0.12, and 1.38 +/- 0.15 mg/dL before and after 6 and 12 months of observation, respectively. Cyclosporine and GR32191 used in combination partially but significantly prevented the deterioration of renal function (serum creatinine, basal, 0.52 +/- 0.06; month 6, 0.68 +/- 0.04; month 12, 0.93 +/- 0.10 mg/dL). At the end of the study, GFR, as insulin clearance, was significantly lower in rats given cyclosporine (0.28 +/- 0.09 mL/min/100 g) than in rats given cyclosporine plus GR32191 (0.45 +/- 0.05 mL/min/100 g) or than in vehicle-treated animals (0.56 +/- 0.07 mL/min/100 g). Similar results were obtained for the effective RPF, measured as p-aminohippurate clearance. At the same time points, comparable to whole-blood cyclosporine levels were found in rats receiving cyclosporine alone and in those given cyclosporine plus GR32191. More than 50% of the animals on cyclosporine alone died from uremia before the end of the observation period. By contrast, rats receiving cyclosporine in combination with GR32191 had a prolonged survival.(ABSTRACT TRUNCATED AT 250 WORDS)

PATHOLOGIC STUDIES OF ACUTE REJECTION OF MISMATCHED FELINE MUSCULOCUTANEOUS FLAPS

The gracilis musculocutaneous flap was developed as an allograft model to study acute rejection and immunosuppression in the cat. Twelve adult cats received a MLC incompatible flap. Six of the cats received cyclosporine oral solution and prednisolone (0.5 mg/kg/24 hr) for 100 days and six cats were not treated. Trough whole-blood levels of cyclosporine in the treatment group were maintained at approximately 750 ng/ml for 70 days, then 500 ng/ml for the remaining 30 days. Three flaps failed due to technical problems; 5 flaps were studied in the treatment group and 4 in the untreated group. All 5 flaps in the treatment group survived the 100 day treatment period and were rejected 30 +/- 26 days following cessation of treatment. Prior to discontinuation of treatment, with the exception of one cat, inflammatory changes associated with rejection were not observed in biopsy specimen. The flaps in the untreated group survived 13 +/- 1.5 days. Histopathologic examination of the flaps revealed little difference in the appearance of acute rejection and rejection after cessation of therapy. The most prominent lesion was a vasculitis with extensive perivascular lymphohistocytic inflammation. The lymphoid infiltrates consisted predominantly of T cells of both major classes (CD4 and CD8). Full-thickness epidermal necrosis and subsequent bacterial invasion followed vascular compromise.

GLOMERULOTUBULAR FUNCTION IN LONG-TERM RENAL ALLOGRAFT RECIPIENTS

Glomerular and tubular function were assessed, using a lithium clearance technique, in two groups of renal allograft recipients at least one year after transplantation. Group 1 comprised 14 patients receiving low-dose prednisolone and cyclosporine, and group 2, 14 patients receiving low-dose prednisolone and azathioprine. There were no significant differences in creatinine clearances between the two groups, although the clearances of lithium (which is absorbed almost exclusively from the proximal tubule) and sodium were significantly lower in the cyclosporine-treated group. Fractional lithium excretion was also significantly lower in group 1 than in group 2, but there was no significant difference in fractional sodium excretion. The absolute proximal reabsorption of sodium and water did not differ between the groups, although the fractional proximal reabsorption of sodium and water was significantly higher in group 1. In contrast, the distal reabsorption of sodium and of water was significantly lower in the cyclosporine-treated patients than in the azathioprine-treated patients; there were, however, no significant differences in the distal fractional reabsorptions of sodium and water between the two groups. In addition there was no correlation in group 1 between whole-blood cyclosporine levels or time since transplantation and any of the assessed parameters of renal function. These results indicate that tubular concentrating abnormalities in cyclosporine-treated renal allograft recipients are similar to those observed in rodent models of cyclosporine nephrotoxicity. They suggest that the pathogenesis of cyclosporine nephrotoxicity may be similar in renal allograft recipients to that in experimental models.

The Effect of Calcium Channel Blockers on the Cyclosporine Dose Requirement in Renal Transplant Recipients

Thirteen patients found to be hypertensive following renal transplantation were treated with either a calcium channel blocker or other antihypertensive therapy for control of blood pressure. Immunosuppression was either with cyclosporine and prednisone alone or with cyclosporine, azathioprine, and prednisone. Patients had weekly or biweekly cyclosporine whole-blood levels measured by radioimmunoassay drawn approximately 12 h after their last dose. Patients treated with cyclosporine and prednisone alone had their cyclosporine dosage adjusted to maintain their cyclosporine level between 400 and 900 ng/mL between 1 and 6 months following transplantation. Patients treated with cyclosporine, azathioprine, and prednisone had their cyclosporine level adjusted to be between 100 and 400 ng/mL during this same time period. Cyclosporine levels were significantly higher in verapamil-treated patients and significantly lower in nifedipine-treated patients as compared to controls. The dose of cyclosporine administered was significantly lower in the verapamil-treated patients and higher in the nifedipine-treated patients than controls. Normalizing the whole-blood cyclosporine level for the dose of cyclosporine, and verapamil-treated patients had a significantly greater, and the nifedipine-treated patients a significantly lower value than control patients. These data suggest the verapamil treatment results in significantly higher levels of cyclosporine whereas nifedipine therapy may actually result in lower cyclosporine levels for a given dose of cyclosporine than seen in patients not exposed to these drugs.

Effects of combination cyclosporine/mizoribine immunosuppression on canine renal allograft recipients.

Heterotopic renal allografts following bilateral nephrectomies were placed in 21 healthy mongrel dogs. One group of 11 dogs received cyclosporine (5 mg/kg/24 hr, orally), and 1 group of 10 dogs received cyclosporine and mizoribine (5 mg/kg and 3 mg/kg/24 hr, orally). Body weights, blood cell counts, serum chemistry profiles, serum electrolyte levels, urinalysis with cytology and culture, lymphocyte stimulation assays, immunoglobulin levels, whole blood levels of cyclosporine, and serum levels of mizoribine were followed. At the end of each survival period, necropsy and histopathologic examinations were performed. The mean survival time for the cyclosporine group was 12.8 +/- 7 days. The mean survival time for the cyclosporine/mizoribine group was 33.6 +/- 16.4 days, significantly longer (P = .0006) than the cyclosporine group. Death in the cyclosporine/mizoribine group was attributed to the combined effects of renal allograft rejection and development of a mizoribine-dependent enteritis. Serum levels of mizoribine were greater in the last half of the survival period due to compromised renal excretion of the drug. There were no complications due to infection, myelosuppression, or hepatotoxicity. Combination cyclosporine/mizoribine immunosuppression enhanced canine renal allograft survival in this study. Monitoring serum concentrations of mizoribine is imperative to determine toxic (enteritis) levels. Availability of an intravenous form of mizoribine would facilitate immunoregulation during periods of variable intestinal absorption or renal excretion.

MODIFICATION OF EXPERIMENTAL NEPHROTOXICITY WITH FISH OIL AS THE VEHICLE FOR CYCLOSPORINE

Cyclosporine-associated renal dysfunction is well recognized. While renal vasoconstriction appears to be a major pathogenic factor, the precise mechanism responsible for the altered hemodynamics is unclear. To investigate whether alterations in renal eicosanoid metabolism could be involved, we substituted fish oil rich in eicosapentaenoic acid (EPA), an inhibitor of cyclooxygenase metabolites, for the conventional olive oil cyclosporine vehicle. Male rats were pretreated with 1.0 cc fish oil or olive oil by gavage. After 14 days, cyclosporine (12.5 mg/cc vehicle) was added to the oil and animals received cyclosporine 50 mg/kg for an additional 14 days. Pair-fed control animals received fish oil or olive oil alone. Glomerular filtration rate (GFR) was severely reduced in the cyclosporine-in-olive-oil (CSA + OO) group (0.28 +/- .05 ml/min/100 g) vs. olive oil (OO) controls (0.70 +/- .04) (P less than 0.001). While GFR was reduced in the cyclosporine-in-fish oil group (CSA + FO) vs. fish oil (FO) controls (0.47 +/- .07 vs. 0.74 +/- .04), it was significantly higher than in the CSA + OO group (P less than 0.05). Trough whole-blood cyclosporine levels were not significantly different in the two groups. While CSA + OO appeared to elevate renal cortical content of thromboxane B2 (65.7 +/- 7.3 pg/mg tissue vs. 46.9 +/- 5.3 for OO), both the CSA + FO and FO groups had reduced levels (31.1 +/- 2.7 and 29.5 +/- 2.3, respectively). In addition, there was a striking reduction in proximal tubular vacuolar changes in the CSA +/- FO vs. CSA + OO group. We conclude that the use of EPA-rich fish oil as the vehicle for cyclosporine results in improved renal function and morphology and is associated with depressed renal cortical levels of vasoconstrictor thromboxane B2.

A COMPARATIVE TOXICOLOGICAL STUDY OF CYCLOSPORINE AND Nva2-CYCLOSPORINE IN SPRAGUE-DAWLEY RATS

Adult, male Sprague-Dawley rats were given 50 mg/kg cyclosporine (CsA), cyclosporine G (nor-valine2-cyclosporine [CsG], or drug vehicle by orogastric intubation every 24 hr for 14 days. Both drugs profoundly suppressed humoral immune responses. Similar trough whole-blood cyclosporine levels were recorded in each group at days 7 and 14. In CsA-treated animals, significant lymphopenia was evident on day 14, together with monocytosis and neutrophilia. Only the monocytosis was seen in the CsG group. CsA and CsG both caused significant impairment of renal function by day 7, although at this time the effect was less marked with CsG. In both drug-treated groups, there was evidence of further deterioration in glomerular filtration rate (GFR) by day 14. A significant rise in enzymuria was also recorded in each group. Typical cyclosporine-induced proximal straight tubular cell vacuolation was evident in four of the eight rats given CsG and in three of seven CsA-treated animals. Liver function was also significantly impaired in both CsA and CsG groups. These data show that, at the selected dose, CsG shares the nephrotoxic and hepatotoxic properties of CsA. The extent to which these effects of CsG are dose-related and the true clinical potential of this cyclosporine analogue have yet to be evaluated.