An explanation of the noncorrespondence between assessment methods of cyclosporin

Abstract. Various methods of determining cyclosporin (CyA) levels in patients after kidney transplantation were compared. These included polyclonal antibody (pcAb-), specific and nonspecific monoclonal antibody (S-and NmcAb-) radioimmu-noassays (RIA), and high performance liquid chromatography (HPLC). The results obtained by the various methods when compared showed some correlation but did not correspond. A probable explanation for part of this noncorrespondence is the presence of monodonaily crossreactive metabolites (CyA-M). Another reason was that the concentration of CyA in the standards supplied with the RIA kits was found to be higher than stated.     

Effect of reduced cyclosporin dosage on long-term renal allograft histology

The effect of different doses of cyclosporin (CyA) on the occurrence of histological lesions in renal allograft biopsies was investigated 2 years after transplantation. Biopsy findings were compared in three different groups of patients. In group 1, patients were immunosuppressed with CyA and prednisolone according to an early, high-dosage schedule (initial CyA dose 15–17.5 g/kg body weight); in group 2, they were treated with a medium CyA dose (initial dose 12 mg/kg), together with prednisolone; and in group 3, patients were given triple drug therapy consisting of low doses of CyA (initial dose 8 mg/kg), together with both azathioprine and prednisolone. Interstitial fibrosis and tubular atrophy were common findings in all groups, and on the basis of all biopsies, no difference could be found between the groups with respect to the relative volume of the renal cortical interstitium, which was used as a quantitative parameter for interstitial fibrosis. Likewise, no difference was found with respect to serum creatinine levels. When grafts, that showed signs of rejection (usually vascular rejection) in the biopsy were excluded (two in group 1, six in group 2, and ten in group 3), the mean interstitial volume was significantly lower in group 3 (triple drug therapy) than in the other groups. The serum creatinine levels were also significantly lower in group 3 than in group 1. Thus, chronic renal lesions could be ameliorated when CyA doses were lowered, but this appeared to entail an increased risk of acute or chronic vascular rejection.     

Low-dose cyclosporin A therapy in cadaver renal transplantation in children

Fifty-one pediatric patients undergoing a first cadaveric kidney transplantation were followed for at least 2 years after grafting. They were divided into two groups: those treated with methylprednisolone plus azathioprine (AZA) and those treated with methylprednisolone plus low-dose cyclosporin A (CyA; median dose 109 mg/m² per day ≙ 3.4 mg/kg per day after 1 year). The steroid dosage given was significantly lower in the second group. The 4-year graft survival rate was 68% for the AZA group and 78% for the CyA group. Renal function did not differ significantly in the two groups; after 1, 2, and 3 years, the median 24-h creatinine clearance was 79, 69, and 51 ml/min/1.73 m², respectively, for the AZA group and 78, 63, and 68 ml/min/1.73 m², respectively, for the CyA group. Linear growth was similar in the two groups. We conclude that in pediatric patients the results of low-dose CyA immunosuppression do not differ significantly from those obtained with AZA in terms of graft survival, renal function, or growth.     

Contribution of cyclosporin metabolites to immunosuppression in liver-transplanted patients with severe graft dysfunction

The aim of this study was to analyse the immunosuppressive contribution of cyclosporin metabolites in liver-grafted patients. Therefore the immunosuppressive potency of 17 metabolites, alone and in combination, was tested in human mixed lymphocyte cultures, and the results were correlated with metabolite blood levels in liver-grafted patients. Of the 17 metabolites tested only six highly lipophilic metabolites showed a detectable immunosuppressive activity of up to 10% of the activity of cyclosporin; the effect of combining metabolites was additive. For calculation of the in vivo activity, blood levels of seven major cyclosporin metabolites were determined in liver-grafted patients with normal liver function (group A, 43 episodes) and with severe hyperbilirubinaemia (group B, 66 episodes). Both patient groups had comparable levels of parent drug (122.9±17.4 vs. 111.1±23.5 ng/ml by HPLC) and similar blood levels of the highly lipophilic metabolites 17, 1 and 18. By contrast, blood levels of the less lipophilic metabolites 8, 9, 26 and 203–218 were substantially increased in group B (P<0.05). High overall metabolite blood levels in group B were also indicated by a non-specific monoclonal RIA (520±199 ng/ml for group A vs. 1318±407 ng/ml for group B). Despite the very high levels in group B, however, the overall contribution of the metabolites to immunosuppression was similar in both groups (12.6±5.0% for group A vs. 13.8±5.6% for group B). These findings indicate that, despite a marked accumulation of cyclosporin metabolites in patients with severe cholestatic liver dysfunction, their immunosuppressive contribution remains low. This suggests that for assessment of the immunosuppressive potency of cyclosporin therapy monitoring of parent drug levels is necessary and sufficient. Since a variety of non-immunological effects of high metabolite levels cannot be excluded, however, additional non-specific measurements may, nevertheless, be useful in patients with severely disturbed liver graft function.     

A pharmacokinetic comparison of cyclosporin oral solution and cyclosporin capsules in heart and lung transplant recipients

Pharmacokinetic profiles were obtained for 16 heart or lung recipients following the administration of identical doses of cyclosporin as oral solution and capsules on consecutive days. A comparison of pharmacokinetic parameters (AUC, C_max, C_min and t_max) showed that there were no significant differences between the two formulations except for the t_max, which was significantly longer for the capsules. The mean variation in day-to-day trough levels produced by the two different forms was 25.6%. A retrospective study was carried out of consecutive cyclosporin levels in patients at steady state on oral solution. The mean variation in day-to-day trough levels was 32.3%. This was not significantly different from the variation in consecutive trough levels seen in the oral solution/capsule comparison. This study shows that cyclosporin capsules can be substituted for oral solution without causing acute changes in cyclosporin blood levels, and that the pharmacokinetics of the two formulations are similar.This work was carried out in partial fulfillment of the requirements for the Master of Science Degree in Clinical Pharmacy, University of London     

Low-dose cyclosporin A therapy in cadaver renal transplantation in children

Abstract. Fifty-one pediatric patients undergoing a first cadaveric kidney transplantation were followed for at least 2 years after grafting. They were divided into two groups: those treated with methylprednisolone plus azathioprine (AZA) and those treated with methylprednisolone plus low-dose cyclosporin A (CyA; median dose 109 mg/m²per day ± 3. 4 mg/kg per day after 1 year). The steroid dosage given was significantly lower in the second group. The 4-year graft survival rate was 68% for the AZA group and 78% for the CyA group. Renal function did not differ significantly in the two groups; after 1, 2, and 3 years, the median 24-h creatinine clearance was 79, 69, and 51 ml/min/1. 73 m² respectively, for the AZA group and 78, 63, and 68 ml/min/1. 73 m² respectively, for the CyA group. Linear growth was similar in the two groups. We conclude that in pediatric patients the results of low-dose CyA immuno-suppression do not differ significantly from those obtained with AZA in terms of graft survival, renal function, or growth.     

Renal graft rejection or cyclosporin toxicity? Early diagnosis by a combination of Papanicolaou and immunocytochemical staining of urinary cytology specimens

A method is described for distinguishing between graft rejection and cyclosporin nephrotoxicity in renal allograft recipients by analyzing fresh morning urine samples. The technique combines classic Papanicolaou with immunocytochemical staining and was performed in urine specimens from a series of 42 patients. Early-stage cyclosporin toxicity was usually associated with increased numbers of proximal tubular cells only, whereas in rejection and late-stage toxicity there were increases in both tubular cells and in lymphocytes and monocytes (>2000 cells/ml urine). Differentiation between these two clinical conditions was achieved by immunostaining, which revealed that increased numbers of CD25⁺ and CD8⁺ cells, as well as an increase in the HLA-DR/Lu5 ratio, were typical of rejection. CD25 positivity proved to be the best indicator of rejection, with a sensitivity and specificity of more than 90%. A cytodiagnostic algorithm is presented that is based on cell numbers and types, including immunophenotypes. The proposed method has the advantage of being noninvasive and appears to represent a reliable and rapid adjunct for the monitoring of graft function, especially in high-risk patients on cyclosporin immunosuppression.     

Glomerular filtration rate after liver transplantation with a low-dose cyclosporin protocol

Cyclosporin nephrotoxicity is a well-known complication in organ transplantation. In successful liver transplantation, a moderate degree of renal impairment is accepted. Whether this impairment is continuously progressive, stabilizes with time, or is reversible is not known. We have prospectively evaluated the glomerular filtration rate (GFR) using ⁵¹CrEDTA plasma clearance in 29 liver transplant patients (11 males and 18 females) with a mean age of 49 years (range 22–62 years). The ⁵¹CrEDTA plasma clearance measurements were performed preoperatively and at 3, 6, 12, 24, and 36 months after the liver transplantation. All but six patients were given sequential, quadruple drug therapy with antithymocyte globulin, azathioprine, steroids, and cyclosporin. Intravenous cyclosporin was avoided and oral cyclosporin started when renal function was stable. Cyclosporin was started in a dose of 8 mg/kg body weight, aiming at whole blood trough levels (specific monoclonal technique) of 200 g/l in the postoperative period; thereafter, the dosage was rapidly tapered down, aiming at whole blood trough levels of less than 100 g/l at 3 months (1.5–2 mg/kg body weight). From a mean preoperative GFR of 89±3 ml/min per 1.73 m², all patients declined in renal function after transplantation to a mean of 64±4 ml/min per 1.73 m² 3 months after transplantation, and starting in the 3rd month the renal function was stable at about 70% of the preoperative value. No correlations were found between cyclosporin weak level or accumulated cyclosporin dose and renal impairment. We conclude that liver transplantation with cyclosporin immunosuppression will induce renal impairment even if cyclosporin blood levels are carefully monitored and kept low. However, with a low-dose regimen, a progressive decline can be avoided.     

Impact of early cyclosporin average blood concentration on early kidney transplant failure

This retrospective study served to examine the correlation between the degree of cyclosporin (CyA) exposure, as estimated by a single pharmacokinetic (PK) profile performed at 1 week post-transplant, and the outcome of 290 consecutive renal transplants performed over a 6-year period. For this retrospective analysis patients were stratified into four historical groups based on 12- versus 24-h PK studies and on the use of radioimmunoassay versus fluorescence polarization immunoassay methods for estimates of CyA concentrations. Four PK measures – trough concentration (C₀), average concentration values (C_av; i. e., the dosing interval-corrected area under the concentration-time curve), maximum concentration (C_max), and time to maximum concentration (t_max) – were examined as predictors of patient, graft, and rejection-free survival rates for each of the four groups individually and for all groups combined. Patients with an initial C_av≥ 550 ng/ml had higher 1-year (88 %) and 6-year (66 %) graft survival rates than patients with C_av < 550 ng/ml, who had 1- and 6-year graft survival rates of 80 % and 59 %, respectively (P = NS). Statistically significant differences were observed in graft survival rates between patients with C_av < 550 versus C_av≥ 550 ng/ml at 30 (88 % vs 96 %; P < 0.02), 60 (85 % vs 94 %; P < 0.007), 90 (85 % vs 94 %; P < 0.02), and 180 (83 % vs 92 %; P < 0.05) days. Moreover, patients with C_av < 550 ng/ml displayed more severe rejection episodes, as judged by Banff classification, than patients who displayed C_av≥ 550 ng/ml (grades II and III; 71 % vs 50 %; P = 0.036). In contrast, the C₀, C_max, and t_max values did not correlate with patient, graft, or rejection-free survival rates. The pharmacokinetic parameter of C_av correlated strongly with early graft survival and may, therefore, be a useful predictor of those renal transplant patients who may require more intensive post-transplant monitoring of CyA concentrations by serial PK studies to improve graft survival. Received: 27 May 1997 Received after revision: 8 August 1997 Accepted: 21 August 1997     

Acute effect of cyclosporin on renal function following the initial changeover to a microemulsion formulation in stable kidney transplant patients

Potential differences in the acute effect of cyclosporin on renal function when dosed orally as the current market formulation or following a milligram-to-milligram conversion to a new microemulsion formulation were investigated in 14 stable kidney transplant patients. The study consisted of three sequential periods of 2 weeks duration each. Patients entered (period I) and completed (period III) the investigation with the market formulation and received the microemulsion formulation in period II; individualized cyclosporin doses remained unchanged throughout the study. Over one steady-state dosing interval at the end of each study period, whole blood cyclosprin pharmacokinetic profiles were assessed in parallel with endogenous creatinine clearances over sequential 1-to 2-h intervals. The rate and extent of cyclosporin absorption were significantly greater (P<0.01) from the microemulsion formulation with average increases of 73% in peak concentration and 44% in area under the curve compared to the market formulation. Sequential creatinine clearances exhibited a transient decrease with the nadir occurring on average between 4 and 6h post dose followed by a rapid return to baseline. Specifically in period I on the market formulation, clearances decreased from a baseline of 71.7±20.6 to a minimum of 51.1±17.9 ml/min per 1.73 m² (similar values in period III) and from 76.8±24.8 to 53.5±17.5 ml/min per 1.73 m² in period II on the microemulsion. Neither the baseline nor minimum clearances were significantly different among the study periods. Hence, the pharmacokinetic differences between the formulations did not acutely influence the pattern of glomerular filtration rate following the initial milligramto-milligram changeover in stable renal transplant patients.     

Polyarteritis nodosa type vasculitis in a patient with familial Mediterranean fever treated with cyclosporin A

Patients with amyloidosis secondary to familial Mediterranean fever (FMF) are known to tolerate cyclosporin A poorly. We report a case of severe cyclosporin toxicity in a patient with FMF amyloidosis who underwent kidney transplantation. The clinical syndrome consisted of severe gastrointestinal, neuromuscular, and psychiatric disturbances. Histological examination of the transplanted kidney revealed vasculitis of the polyarteritis nodosa type. We hypothesize that FMF patients are more vulnerable to the acute vascular toxicity of cyclosporin due to defective inhibition of complement activation, leading to a widespread vasculitis of the polyarteritis nodosa type.     

Post-transplant conversion from cyclosporin to azathioprine: effect on cardiovascular risk profile

The benefits of long-term cyclosporin (CyA) therapy are not yet established and must be weighed against its toxicity. We studied cardiovascular risk factors in 25 patients who received a kidney transplant between 1985 and 1989 and in whom CyA was discontinued. The protocol for discontinuing CyA involved starting azathioprine (Aza) and then weaning CyA over 6 weeks without changing the prednisone dose. Parameters collected from the patients' charts 3 months before (pre) and 3 months after conversion (post) and at the most current follow-up (cur) included serum creatinine, cholesterol, blood pressure, and anti-hypertensive medication. The severity of the hypertension was graded, based on a hypertension index reflecting the nature and dose of the anti-hypertensive medication. Of the 25 patients in whom CyA was discontinued, 2 experienced a rejection episode during conversion and were switched back to CyA; 1 patient had a rejection episode after conversion but remained on Aza. Converted patients demonstrated improved renal function (1/Cr pre 0.69±0.20, post 0.84±0.23, P<0.05), lower serum cholesterol levels (pre 6.8±1.0, post 5.8±1.2, P<0.05), lower mean arterial pressure (pre 111±14, post 102±8, P<0.05) and a lower hypertension index (pre 2.45±2.77, curr 1.62±1.70, P<0.05). Although conversion may carry some risk of acute rejection, it improves graft function and the cardiovascular risk profile significantly.     

Is there an optimal time for the first cyclosporin dose in renal transplantation?

It is customary for patients undergoing kidney transplantation to receive their first dose of cyclosporin either just before or during the transplant operation. This ensures the early establishment of good levels of immuno-suppression but might depress early graft function and contribute towards the development of acute tubular necrosis. In a controlled clinical trial, we have studied the effects of withholding cyclosporin for 12 h in patients undergoing cadaveric renal transplantation. Consecutive adult recipients of a cadaveric renal transplant were randomised to receive their first dose of cyclosporin (10 mg/kg p. o.) 6 h prior to transplant surgery or 12 h afterwards. All patients received azathioprine (1.5 mg/kg i.v.) and methylprednisolone (0.5 gi.v) in addition during surgery. From the 2nd day onwards both groups were treated with an identical triple immunosuppressive regimen. The 27 patients who received their first dose of cyclosporin post-operatively had significantly better immediate and subsequent function than did the 26 patients who received their cyclosporin at the time of surgery. The delayed dosing was associated with improved graft survival and no increase in the frequency of rejection episodes. This regimen is recommended for all patients receiving triple therapy.     

Renal fibrosis in cyclosporin A-treated renal allograft recipients: morphological findings in relation to renal hemodynamics

Nineteen nondiabetic kidney graft patients treated with cyclosporin A for 2 years underwent percutaneous renal allograft biopsy as well as renal hemodynamic examination. Renal allograft fibrosis was quantitatively evaluated as the relative volume of the renal cortical interstitium (V_v%) and as the intersttium/tubuli ratio (I/T ratio). The histological changes were then classified into four groups, depending on the degree of interstitial fibrosis. The glomerular filtration rate (GFR), renal plasma flow (RPF), renal blood flow (RBF), filtration fraction (FF), and fractional clearance of sodium, potassium, phosphate, chloride, osmoles, and free water clearance were determined in all patients and in 13 healthy controls. Kidney graft recipients had significantly lower GFR, lower RPF, and lower RBF than the healthy controls (P<0.001 for all comparisons) while FF was similar in patients and controls. Transplant recipients had a significantly higher fractional excretion of sodium, potassium, chloride, and phosphate than controls. All except one patients had clearly increased V_v values, indicating increased interstitial fibrosis. The mean V_v in renal allograft patients was 35%±10% (normal <16%±5%) and the I/T ratio was 1.07±0.60 (normal <0.24±0.08). No correlation was found between the quantitative or semiquantitative biopsy analysis and any renal hemodynamic parameter measured. We conclude that renal function is significantly decreased in kidney graft recipients, but that adaptive tubular changes occur in the graft. Interstitial renal fibrosis was common but did not correlate to any renal functional parameter.     

Effect of cyclosporin on lung diffusing capacity in renal transplant patients

A prospective lung function study pre- and postrenal transplantation was performed on 21 patients in order to evaluate whether cyclosporin decreased the lung diffusing capacity due to lung toxicity. Initial inclusion criteria were absence of respiratory symptoms and normal findings in both chest X-ray and pulmonary function tests. Participants had to be nonsmokers. We determined spirometry including lung volumes, arterial blood gases, carbon monoxide diffusing capacity by the single breath method (D_LCO_SB), and rate of CO uptake per unit of lung volume (KCO) before and 3, 6, and 12 months after transplantation. Immunosuppression consisted of prednisone and cyclosporin, maintaining total blood levels between 100 and 250 ng/ml. Spirometric and blood gases data remained within reference levels during the follow-up. Hemoglobin (Hb) pretransplant concentrations remained low, returning to their normal levels posttransplantation. Pretransplant D_LCO_SB levels were slightly decreased but fell within the therapeutic range after correction for Hb concentration, unlike the mean KCO levels which remained slightly diminished despite their correction. In post-transplant controls, the values obtained for both D_LCO_SB and KCO were significantly higher at the different post-transplant intervals (P<0.005) than pretransplantation but only when compared without Hb correction. No significant differences for D_LCO_SB were found when corrected values were compared, and an improvement in the KCO appeared to be significant at 12 months posttransplantation. Based on these findings, we feel that when serum levels are within the therapeutic range, cyclosporin fails to alter the respiratory function or the pulmonary diffusing capacity of the lung.     

FK 506 versus cyclosporin in the prevention of renal allograft rejection — European pilot study: six-week results

FK 506 was compared with cyclosporin in a randomised trial in good-risk cadaveric renal transplant recipients. The objective was to evaluate whether oral FK 506 dosing was viable and whether blood concentrations in the range 10–20 ng/ml would prove to be practical. Thirty-one adult patients were randomised to FK 506 and 16 to cyclosporin. Both groups received an identical regimen of azathioprine and corticosteroids. Serum creatinine concentrations decreased rapidly in both groups with mean values below 200 mol/l within 2 weeks. One graft in the cyclosporin group was lost due to renal vein thrombosis. During the 6-week study period, 19.4% of patients on FK 506 and 31.3% on cyclosporin experienced acute rejection. One patient in each group experienced corticosteroidresistant rejection that responded to anti-lymphocyte therapy. Infections were reported in 51.6% of the FK 506 group compared with 37.5% of the cyclosporin group. The spectrum of adverse events was similar in both groups. However, minor neurological disorders were more common in the FK 506 group (54.8% versus 6.3%) whereas hypertension was less common (48.8% versus 75.0%). The results indicate that oral FK 506 rapidly achieves therapeutic blood concentrations and is an effective immunosuppressant for the initial treatment of renal allograft recipients.     

Long-term renal allograft function under maintenance immunosuppression with cyclosporin A or azathioprine

In order to evaluate long-term renal graft function, 149 cyclosporin A and prednisolone (CyA/P)-treated renal transplant recipients were compared with 119 azathioprine and prednisolone (Aza/P)-treated patients. Only patients who had a functioning graft for at least 1 year and who were maintained on their initial immunosuppressive protocol were included. The minimum follow-up period was 4 years. Renal graft function was estimated by yearly determinations of serum creatinine and creatinine clearance. The CyA/P-treated patients had a significantly higher serum creatinine and a significantly lower creatinine clearance at every point in time posttransplantation than Aza/P-treated patients (P<0.001). The evolution of renal graft function, as reflected in the line of regression for serum creatinine and creatinine clearance versus time, was estimated for each individual patient. There was an almost stable renal function, as assessed by the median of the slopes of the regression line for serum creatinine versus time in both groups. The median increase in serum creatinine was only 1.4 mol/l per year for Aza/P-treated patients and 2.4 mol/l per year for CyA/P-treated patients (difference NS). The median decline in creatinine clearance was 2.18 ml/min per 1.73 m²/year in the Aza/P group and 1.07 ml/min per 1.73 m²/year in the CyA/P group (P=0.05). In patients with a functioning graft for at least 5 years, creatinine clearance remained unchanged in both groups during the study period. In conclusion, renal graft function, as assessed by measurements of serum creatinine and creatinine clearance, remained essentially unchanged for at least 5 years after transplantation, regardless of the immunosuppressive protocol used. Thus, these data do not indicate a progression with time of the nephrotoxicity observed in CyA-treated patients.     

Vasoconstrictor effect of cyclosporin on the mesenteric artery in the dog

To evaluate the effect of cyclosporin (CyA) on the mesenteric arterial bed, studies were performed on the isolated mesenteric artery perfused at a constant flow in 20 dogs. Changes in mesenteric perfusion pressure reflected variations in vascular resistance. Pure powder CyA was dissolved in autologous blood and injected at doses of 5, 10, 20 and 40 mg. Infusions of 5 and 10 mg CyA caused nonsignificant mean increases of 3±2 mm Hg [95% confidence interval (CI)-2 to +7; P>0.05] and 3±3 mm Hg (95% CI-3 to +9; P>0.05) in mesenteric perfusion pressure, with CyA blood levels in the mesenteric vein averaging 466±153 and 692±130 nmol/l, respectively, at the end of the injections. Infusions of 20 and 40 mg CyA caused significant increases in mesenteric perfusion pressure averaging 11±3 mm Hg (95% CI 3–18; P<0.05) and 26±4 mm Hg (95 % CI 16–34; P<0.05), respectively. CyA blood levels at the end of infusion averaged 806±85 and 1118±89 nmol/l, respectively, in the mesenteric vein. Blockade of alpha-adrenergic receptors with phentolamine abolished the CyA vasoconstriction of the mesenteric artery, with the increase in perfusion pressure averaging 16±4 mm Hg before and 3±3 mm Hg after phentolamine (P<0.05). Thus, in the dog, CyA causes an acute vasoconstriction of the mesenteric artery through stimulation of alpha-adrenergic receptors.     

Improving the therapeutic monitoring of cyclosporin A

The narrow therapeutic window of cyclosporin A (CsA) and the variable pharmacokinetics of the traditional preparation, CsA-SIM (Sandimmune), have made it difficult to establish its optimal use. The introduction of a microemulsion preparation, CsA-ME (Neoral), with less variable pharmacokinetics, has made it possible to attempt to define its use more closely. One hundred and one renal allograft recipients were converted from CsA-SIM to CsA-ME. Absorption was monitored using a standard pharmacokinetic 'profile' measuring 'whole blood' CsA levels at several time points following drug administration. Areas under the resulting time-versus-CsA concentration curve (AUC) were calculated. Surprisingly, many patients showed very little fluctuation in 'whole blood' levels after administration of the conventional preparation: 31% had a difference between trough (to) and maximal levels of < 100 micrograms/L. On microemulsion cyclosporin, there was much better correlation between AUC and several parameters incorporating elements of trough and peak values. The best correlation was with t0 + (t1/4), where t1 represents the concentration at 1 h following administration, (r2 = 0.779 for microemulsion cyclosporin). The use of this parameter is a practical possibility in an out-patient setting. The very common, but under-recognised, pattern of almost flat absorption profiles in patients on conventional CsA suggests that the use of CsA in numerous clinical contexts should be reviewed, since CsA immunosuppression may previously have been inadequately monitored.     

Dissolving intravenous cyclosporin A in a fat emulsion carrier prevents acute renal side effects in the rat

Cyclosporin A (CyA)-induced nephrotoxicity is still a serious clinical problem. The nephrotoxicity seems to be more pronounced when CyA (solubilized in water with Cremophore EL, as in Sandimmun) is given intravenously than when it is given orally. Using soybean oil in which CyA was dissolved, we prepared an intravenous fat emulsion without an artificial detergent, such as Cremophore EL. The renal effects of our new formula were compared with those of Sandimmun and Cremophore EL in a rat model. CyA in the fat emulsion did not significantly affect the glomerular filtration rate (GFR). Both Sandimmun and Cremophore EL significantly reduced the GFR. These results suggest that a change in the vehicle may obviate the acute nephrotoxic side effects caused by intravenous administration of CyA solubilized by Cremophore EL.