Plasma Cyclosporin A Research Articles

Optimal sampling time‑point for cyclosporin A concentration monitoring in heart transplant recipients

The present study was performed to determine an optimal time-point for monitoring the concentration of the immunosuppressive drug cyclosporin A (CsA) in heart transplant patients and its efficacy in the prevention of transplant rejection. A total of 32 transplant recipients were randomly assigned for three treatment approaches. Recipients in groups A (n=11), B (n=13) and C (n=8) received oral administration of CsA at doses of 3.2, 3.5 and 4.4 mg/kg, respectively. The plasma CsA concentrations were examined at 2 h intervals over 12 h. Furthermore, their correlation with the 4 h pharmacokinetic profiles as the area under the plasma CsA concentration vs. time curve (AUC0-4 h) were calculated The efficacy of CsA in inhibiting cardiac allograft rejection was assessed at 2 h after oral CsA intake (C2) and adverse events of the drug were examined in the C2-monitored recipients. The plasma CsA concentration rapidly increased in most recipients with a peak level detected at ~2 h after dosing. Regression analysis revealed that among all time-points assessed, the CsA had the highest correlation with the AUC0-4 h at C2. At C2, increasing CsA doses exhibited a positive association with the measure of AUC0-4 h. The efficacy of increasing CsA target levels at C2 in preventing heart transplant rejection was comparable, as the survival rate was 100% in all of the treatment groups. However, the proportion of recipients with side effects in group A was obviously lower than that in the other two groups. In conclusion, C2 is an ideal time-point for monitoring plasma CsA levels with a utility for individualising the next scheduled dose for each patient to ensure that target levels are maintained and achieve a high efficacy and safety of CsA therapy in heart transplant recipients (clinical trial no. 12002610).

Cyclosporine-induced immune suppression alters establishment of HTLV-1 infection in a rabbit model

AbstractHuman T-lymphotropic virus type 1 (HTLV-1) infection causes adult T-cell leukemia and several lymphocyte-mediated inflammatory diseases. Persistent HTLV-1 infection is determined by a balance between host immune responses and virus spread. Immunomodulatory therapy involving HTLV-1–infected patients occurs in a variety of clinical settings. Knowledge of how these treatments influence host-virus relationships is not understood. In this study, we examined the effects of cyclosporine A (CsA)–induced immune suppression during early infection of HTLV-1. Twenty-four New Zealand white rabbits were split into 4 groups. Three groups were treated with either 10 or 20 mg/kg CsA or saline before infection. The fourth group was treated with 20 mg/kg CsA 1 week after infection. Immune suppression, plasma CsA concentration, ex vivo lymphocyte HTLV-1 p19 production, anti–HTLV-1 serologic responses, and proviral load levels were measured during infection. Our data indicated that CsA treatment before HTLV-1 infection enhanced early viral expression compared with untreated HTLV-1–infected rabbits, and altered long-term viral expression parameters. However, CsA treatment 1 week after infection diminished HTLV-1 expression throughout the 10-week study course. Collectively, these data indicate immunologic control is a key determinant of early HTLV-1 spread and have important implications for therapeutic intervention during HTLV-1–associated diseases.

In vitro and in vivo characterization on amorphous solid dispersion of cyclosporine A for inhalation therapy

Cyclosporine A (CsA) has been clinically used as immunosuppressant, and new application for airway inflammation was also proposed. However, the clinical use of CsA was limited due to severe adverse effects after systemic exposure and the poor solubility. In the present investigation, novel respirable powder (RP) of CsA was developed for pulmonary administration with use of solid dispersion of wet-milled CsA (WM/CsA), and the physicochemical and pharmacological properties of the WM/CsA and its RP formulation were characterized. CsA in the solid dispersion was found to be amorphous by X-ray powder diffraction and differential scanning calorimetry. It exhibited the improved dissolution behavior as compared to active pharmaceutical ingredients. Laser diffraction and cascade impactor analysis of newly developed WM/CsA-RP, consisting of jet-milled WM/CsA and lactose carriers, suggested high dispersion and deposition in the respiratory organs with the emitted dose and the fine particle fraction of 96 and 54%, respectively. Intratracheal administration of WM/CsA-RP (100 µg CsA) in experimental inflammatory rats led to 71 and 85% reduction of granulocyte recruitment in bronchoalveolar lavage fluids and lung tissues, respectively, with showing ca 10 2-fold reduced AUC and C max values of plasma CsA as compared to the oral dosage form of CsA at toxic concentration (10 mg/kg). Upon these findings, WM/CsA-RP would be efficacious dosage form for clinical treatment of airway inflammations with minimal systemic side effects.

Vascular endothelial growth factor in children with nephrotic syndrome treated with cyclosporine A

To assess the effect of cyclosporine A (CyA) on the level of vascular endothelial growth factor (VEGF) in the plasma and urine of nephrotic syndrome children. The study material consisted of 15 children (F 6, M 9; group I) who were subjected to the following examinations: A) at the time of proteinuria relapse, before treatment with CyA, B) after 3 mo, C) after 6 mo, and D) after 12 mo of CyA administration with prednisone and convertase inhibitor. The control group (II) contained 20 healthy children. The immunoenzymatic ELISA method (R&D Quantikine) was used to determine plasma and urinary VEGF levels, while the immunofluorescence method was applied to assess CyA concentration in the plasma. The statistical program Statistica 6.0 was used for statistical analysis of the results. In the present study, plasma VEGF level in examination A was higher than in the control group (p<0.01). After proteinuria regression (B), it did not differ from the level observed in healthy children (p>0.05). After 6 and 12 mo of CyA administration, VEGF concentration increased and was higher than in the control group (p<0.05). In all the examinations, urinary excretion of VEGF was higher than in the control group, increasing proportionally with the duration of treatment and plasma CyA level. A positive correlation was observed between plasma and urinary VEGF levels and between VEGF and CyA concentrations in the plasma. Long-term CyA treatment of nephrotic syndrome children leads to an increase in plasma and urinary VEGF.

Vascular endothelial growth factor in children with nephrotic syndrome treated with cyclosporine A

Abstract Aim: To assess the effect of cyclosporine A (CyA) on the level of vascular endothelial growth factor (VEGF) in the plasma and urine of nephrotic syndrome children. Methods: The study material consisted of 15 children (F 6, M 9; group I) who were subjected to the following examinations: A) at the time of proteinuria relapse, before treatment with CyA, B) after 3 mo, C) after 6 mo, and D) after 12 mo of CyA administration with prednisone and convertase inhibitor. The control group (II) contained 20 healthy children. The immunoenzymatic ELISA method (R&amp;D Quantikine) was used to determine plasma and urinary VEGF levels, while the immunofluorescence method was applied to assess CyA concentration in the plasma. The statistical program Statistica 6.0 was used for statistical analysis of the results. Results: In the present study, plasma VEGF level in examination A was higher than in the control group (p&lt;0.01). After proteinuria regression (B), it did not differ from the level observed in healthy children (p&gt;0.05). After 6 and 12 mo of CyA administration, VEGF concentration increased and was higher than in the control group (p&lt;0.05). In all the examinations, urinary excretion of VEGF was higher than in the control group, increasing proportionally with the duration of treatment and plasma CyA level. A positive correlation was observed between plasma and urinary VEGF levels and between VEGF and CyA concentrations in the plasma. Conclusion: Long‐term CyA treatment of nephrotic syndrome children leads to an increase in plasma and urinary VEGF.

The effect of cyclosporin A on the level of big endothelin in patients one year after orthotopic heart transplantation

Abstract Orthotopic heart transplantation (OHTx) is currently an established method for the treatment of end-stage heart failure. Persistent elevated plasma endothelin-1 (ET-1) levels have been reported after successful OHTx, the etiology of which is not yet fully understood. Immunosuppressive therapy is assumed to be one of the possible factors affecting ET-1 levels in the body. The present study evaluated the effect of cyclosporin A (CyA) on big ET-1 levels (a precursor of ET-1) in patients 1 year after successful OHTx. The study population comprised 34 patients after OHTx (28 males, 6 females, mean age 49.56±11.83 years) divided into two groups according to immunosuppressive protocol (17 patients on cyclosporine–azathioprine–prednisone and 17 patients on cyclosporine-mycophenolate mofetilprednisone therapy). Plasma levels of big ET-1 and CyA were available for all patients. The control groups consisted of 10 healthy individuals (8 males, 2 females, mean age 41.1±11.55 years) and 20 patients with severe heart failure (15 males. 5 females, mean age 54.45±8.49 years), respectively. Big ET-1 plasma levels were found to be elevated in OHTx patients in comparison with healthy controls (13.63±11.3 fmol ml vs 2.99±1.98 fmol/ml. P=0.005). Big ET-1 plasma levels correlated with plasma CyA levels in patients treated with cyclosporineazathioprine–prednisone (r= 0.53. P=0.03). This was not the case in either in the OHTx patients as a whole or in the subgroup of patients on cyclosporine–mycophenolate mofetil–prednisone therapy. The plasma levels of big ET-1 are dependent on CyA plasma levels 1 year after successful OHTx in patients treated with the immunosuppressive combination of cyclosporine, azathioprine, and prednisone. As this finding was not observed in the mycophenolate group of patients, mycophenolate mofetil might affect the alteration of the endothelin metabolism.

The effect of cyclosporin A on the level of big endothelin in patients one year after orthotopic heart transplantation.

Orthotopic heart transplantation (OHTx) is currently an established method for the treatment of end-stage heart failure. Persistent elevated plasma endothelin-1 (ET-1) levels have been reported after successful OHTx, the etiology of which is not yet fully understood. Immunosuppressive therapy is assumed to be one of the possible factors affecting ET-1 levels in the body. The present study evaluated the effect of cyclosporin A (CyA) on big ET-1 levels (a precursor of ET-1) in patients 1 year after successful OHTx. The study population comprised 34 patients after OHTx (28 males, 6 females, mean age 49.56+/-11.83 years) divided into two groups according to immunosuppressive protocol (17 patients on cyclosporine-azathioprine-prednisone and 17 patients on cyclosporine-mycophenolate mofetil-prednisone therapy). Plasma levels of big ET-1 and CyA were available for all patients. The control groups consisted of 10 healthy individuals (8 males, 2 females, mean age 41.1+/-11.55 years) and 20 patients with severe heart failure (15 males, 5 females, mean age 54.45+/-8.49 years), respectively. Big ET-1 plasma levels were found to be elevated in OHTx patients in comparison with healthy controls (13.63+/-11.3 fmol/ml vs 2.99+/-1.98 fmol/ml, P=0.005). Big ET-1 plasma levels correlated with plasma CyA levels in patients treated with cyclosporine-azathioprine-prednisone ( r=0.53, P=0.03). This was not the case in either in the OHTx patients as a whole or in the subgroup of patients on cyclosporine-mycophenolate mofetil-prednisone therapy. The plasma levels of big ET-1 are dependent on CyA plasma levels 1 year after successful OHTx in patients treated with the immunosuppressive combination of cyclosporine, azathioprine, and prednisone. As this finding was not observed in the mycophenolate group of patients, mycophenolate mofetil might affect the alteration of the endothelin metabolism.

GASTRIC EMPTYING TIME IN RENAL TRANSPLANT RECIPIENTS TREATED WITH CYCLOSPORINE‐A

Gastric emptying time (GET) appears to be a rate‐limiting factor in the absorption of cyclosporine‐A (CsA), and may be responsible for intra‐ and interpatient variabilities of CsA bioavailability. Few studies have assessed gastric motility after renal transplantation. The purpose of this study was to evaluate gastric emptying of semisolid material in stable renal transplant patients, and to assess whether it is associated with blood CsA levels. Gastric emptying time of semisolids (GET1/2: half emptying time) was measured in 16 transplant recipients who were taking CsA (Neoral®), prednisolone and azathioprine (or mycophenolate mofetil). None of the subjects had a history of gastrointestinal, metabolic, or systemic disease or surgery, and none was taking any drugs at the time of the study that affect gastrointestinal motility. Gastric emptying time (t=1/2) was measured by radionuclide methods. Data concerning the daily CsA dose, plasma levels of CsA (C0), and serum creatinine levels were also recorded. The mean GET (t=1/2) was 89.1±26.4 min. Twelve of the patients exhibited delayed gastric emptying. The mean plasma CsA level for the group was 171.8±56 ng/ml, and the mean CsA dose was 4.1±1.1 mg/kg/day. Gastric emptying time (t=1/2) was not significantly correlated with the serum creatinine levels, the time since transplantation, or the plasma levels of CsA. There was a weak‐positive, but statistically insignificant, correlation between the mean daily CsA dose and the GET (t=1/2; r=0.33, P=0.2). In conclusion, we cannot speculate whether a higher dose of CsA causes delayed gastric emptying or whether patients with delayed emptying require higher doses of CsA. However, we believe that determining GET after transplantation is important for adjusting the immunosuppressant dosage.

消失相自動認識能力を有するＶｉｓｕａｌ ＢＡＳＩＣによるノンコンパートメント薬物動態速度論解析用プログラム“ＷｉｎＨＡＲＭＯＮＹ”の開発と評価

A new Visual BASIC (ver. 4.0) program “WinHARMONY”, which operates withWindows 95, has been developed for the pharmacokinetic analysis of drugs. This pro gram uses the noncompartmental analysis method, where the recognition of the terminal elimination phase has an important role in the total analysis of the data. Three statistical methods for the automatic identification of the terminal elimination phase have been implemented and evaluated using two kinds of plasma drug concentrationtime data: 1) Plasma cyclosporin A (CyA) concentration-time data in 13 healthy human subjects, and 2) as an example of drugs having short and long half-lives, triazolam was selected and its plasma concentration-time data in 9 healthy human subjects under the single adminis tration and the coadministration with either ketoconazole or itraconazole were analyzed with this program. Among the three methods, an algorithm which performs an automatic identification of the terminal elimination phase based on two factors of linear regression analysis, i. e., an error variance and a confidence interval, gave the estimated value of the terminal elimination rate constant, λz, of 0.064 (mean) ±0.031 (SD) hr. This estimated value was not significantly different from the estimated value, 0.067±0.027 hr, of Grevel et al. who used a nonlinear regression analysis by assuming a two-compartment open model to describe the plasma CyA concentration-time data. Moreover, this program was found to work well even in the case of a drug with a long half-life such as triazolam under the coadministration with either ketoconazole or itraconazole. Since analytical results are shown on the CRT display and can be printed out, visual inspection of the analytical results is possible. Basically, the pharmacokinetic data are manually input and are saved at once in a data file. Prior to the analysis, each data set is read out from the data file. To improve upon a shortcoming of Visual BASIC where “DATA” command cannot be accepted, two optional data input modes are included in the program, i. e., a data file made by the format type of text file and data input by means of a spread sheet program. As this program is written in Visual BASIC, it runs on almost all personal computers except Macintosh and is thought to be useful for the analysis of pharmacokinetic data both in preclinical and clinical pharmacokinetic studies.

The Dosing-Ttme Dependent Influence of Chronic Cyclosporin a Treatment on Daily Profiles of Plasma Glucose and Insulin in the Wistar Rat

The dosing-time dependent effects of cyclosporin A (CsA) on glucose and insulin plasma levels were evaluated in the light of possible alterations of their biological rhythms. Male Wistar rats weighing 200–250 g were habituated to a 12:12h light-dark cycle. At the beginning of the experiments, on day DO (before any treatment), significant rhythms were obtained for plasma glucose and immunoreactive insulin (IRI). The plasma glucose showed a 12h periodicity and the plasma IRI a more pronounced rhythm, with both 12h and 24h significant components. Plasma glucose and IRI were then determined in drug-treated (20 mg CsA/kg b.wt/day; dosing time point: T01, T07, T13, or T20) and control rats during and after a 21-day treatment period. The CsA-treated rats developed hyperglycemia and a marked enhancement of the amplitude of the daily glucose rhythm. The magnitude of these effects differed among the groups (p < 0.001). Most pronounced alterations were observed on day 21 (D21) in group T07: M - 22.5 ± 4.0 mmol/l; A = 9.2 ± 6.0 mmol/l. The mean plasma insulin showed little though significant (p<0.01) decreases. For instance, on D21 in group T01, M = 28.5 ±3.6 μU/ml, and in group T07, M = 28.7 ±2.5 (μU/ml. In parallel, plasma CsA levels increased during the 21-day period and differed among groups (p < 0.01). The highest levels (4–5 mg/l) were obtained in T07 and T19 on D21. After drug cessation, the levels of plasma glucose were reduced, but stayed higher than control values. Body weights were monitored; the rate of growth was lower (p < 0.01) in CsA-treated rats than in controls (2.93 ±0.11 versus 5.1 ±0.11 g/day, respectively). (Chronobiology International, 14(3), 275–285, 1997)

Liposomal formulations of cyclosporin A: influence of lipid type and dose on pharmacokinetics.

Liposomal formulations of Cyclosporin A (CyA)3 have been described in more than 30 publications to substitute Cremophor EL (CrEL), a triricinoleate ester of ethoxylated glycerol, as drug carrier. However, conflicting reports did not allow to draw consistent conclusions about the influence of liposomes on CyA pharmacokinetics (PK) and pharmacodynamics. A series of liposomal CyA-formulations with varying liposome composition and lipid dose but constant CyA dose was compared in rats. Data were analysed with a PK-model taking into account the varying volume of distribution with the varying lipid concentration in blood. Surface properties and lipid type of liposomes are not important PK predictors of liposomal CyA, at least for small dosages of liposomes. Rather, the absolute lipid amount and the lipophilicity of cyclosporins are critical factors influencing the PK of liposomal CyA. The higher the concentration of lipid in blood and the greater the lipophilicity of cyclosporin is, the higher are the concentrations of CyA in blood. These relations may explain the inconsistent literature results. Together with earlier observations from our group the above findings indicate, that CyA is not caged in the liposomal membranes. Reports in literature, which claim lower clearance and a lower volume of distribution of CyA in obese rats compared to lean rats, support our assumption about the involved mechanisms. A semi-quantitative model of CyA distribution is presented, which points to the variable free fraction of CyA in plasma as the crucial factor for all previously reported phenomena in liposomal CyA formulations.

Cyclosporin A and cyclosporin SDZ PSC 833 enhance anti-CD5 ricin A- chain immunotoxins in human leukemic T cells

Recent studies have shown that cyclosporin A (CsA) may affect ricin A- chain immunotoxin (RTA-IT) therapy. In this study, we evaluated the ability of CsA and its nonimmunosuppressive analog, SDZ PSC 833, to enhance anti-CD5 T101 RTA-ITs in vitro. Both 4 mumol/L CsA and 4 mumol/L SDZ PSC 833 significantly and specifically enhanced the cytotoxic activity of T101 RTA-IT on the human lymphoblastic T-cell line, CEM III (101-fold and 105-fold, respectively). Furthermore, these Cs also enhanced the cytotoxicity of the more potent T101 F(ab')2 RTA- IT (ninefold and eightfold, respectively). The effect of human plasma, originating from four patients enrolled in a phase I high-dose CsA regimen, was examined on T101 RTA-IT cytotoxicity on CEM III cells. In each case, with plasma CsA levels between 3,090 and 4,860 ng/mL (2.5 to 4 mumol/L), a significant increase in T101 RTA-IT-mediated cytotoxicity was observed ranging from 31% to 60%. Neither CsA nor SDZ PSC 833 affected the rate of RTA-IT binding, internalization, intracellular trafficking, or degradation. Analysis of internalized T101 RTA-IT molecules showed that these were essentially intact, which suggests that these enhancers may act only on a small population of RTA-ITs that escapes present investigational techniques. In conclusion, because the concentrations used are clinically achievable, Cs appear to be promising agents for in vivo enhancement of RTA-ITs.

Cyclosporin A and Cyclosporin SDZ PSC 833 Enhance Anti-CD5 Ricin A-Chain Immunotoxins in Human Leukemic T Cells

AbstractRecent studies have shown that cyclosporin A (CsA) may affect ricin A-chain immunotoxin (RTA-IT) therapy. In this study, we evaluated the ability of CsA and its nonimmuno-suppressive analog. SDZ PSC 833, to enhance anti-CD5 T101 RTA-ITs in vitro. Both 4 µmol/L CsA and 4 µmol/L SDZ PSC 833 significantly and specifically enhanced the cytotoxic activity of T101 RTA-IT on the human lymphoblastic T-cell line, CEM III (101-fold and 105-fold, respectively). Furthermore, these Cs also enhanced the cytotoxicity of the more potent T101 F(ab)2 RTA-IT (ninefold and eightfold, respectively). The effect of human plasma, originating from four patients enrolled in a phase I high-dose CsA regimen, was examined on T101 RTA-IT cytotoxicity on CEM III cells. In each case, with plasma CsA levels between 3,090 and 4,860 ng/mL (2.5 to 4 μmol/L). a significant increase in T101 RTA-IT-mediated cytotoxicity was observed ranging from 31 % to 60%. Neither CsA nor SDZ PSC 833 affected the rate of RTA-IT binding, internalization, intracellular trafficking, or degradation. Analysis of internalized T101 RTA-IT molecules showed that these were essentially intact, which suggests that these enhancers may act only on a small population of RTA-ITs that escapes present investigational techniques. In conclusion, because the concentrations used are clinically achievable, Cs appear to be promising agents for in vivo enhancement of RTA-ITs.

In vivo characterization of the anti-inflammatory effect of cyclosporin A on human basophils.

We investigated whether cyclosporin A (CsA) in vivo exerts anti-inflammatory effects by inhibiting IgE- and non-IgE-dependent mediator release from human basophils. Six healthy volunteers were given oral CsA (5 mg/kg twice daily) or placebo for 5 days. Plasma CsA and basophil releasability in response to anti-IgE, FMLP, and A23187 were monitored 1 day before treatment, on alternate days during the treatment course, and 1 and 8 days after cessation of treatment. A constant plasma level of approximately 250 ng/ml CsA was obtained during CsA treatment. Basophil releasability in response to anti-IgE, FMLP, and A23187 was diminished by 20 to 60% throughout the course of CsA treatment. Placebo had no effect on basophil releasability. There was a significant correlation between plasma CsA and the decrease of histamine release induced by anti-IgE (rs = -0.66; p < 0.0005), FMLP (rs = -0.59; p < 0.001) and A23187 (rs = -0.68; p < 0.0001). In a second study, eight normal volunteers were given a single oral dose of CsA (7 mg/kg) or placebo, and plasma CsA and basophil releasability were monitored at different times thereafter. A rapid and significant reduction of histamine release induced by anti-IgE, FMLP, and A23187 paralleled a sharp increase of CsA plasma levels, which peaked at 5 h and lasted approximately 13 h. This study indicates that oral administration of CsA in normal subjects causes a rapid and significant inhibition of histamine release from basophils. This is the first evidence that in vivo administration of CsA can modulate the release of proinflammatory mediators from basophils obtained ex vivo.

Short-term effect of various doses of cyclosporin A on plasma lipoproteins and its distribution in blood: an experimental study.

Hyperlipidaemia commonly develops in both transplant recipients and experimental animals receiving cyclosporin A (CsA). However, the threshold of CsA induced-changes on lipoproteins and the role of parenteral vehicle (cremophor) has not been defined. Male Wistar rats were classified into five groups of six animals each and received CsA in cremophor vehicle at doses of 5, 10 or 20 mg kg-1 d-1, s.c., vehicle alone or saline for 7 d. Blood was obtained 24 h after the last dose and plasma was analysed. Plasma very low density lipoprotein (VLDL), low density lipoprotein (LDL), and high density lipoprotein subfractions (HDL-2, HDL-3) were isolated by sequential ultracentrifugation and their content of cholesterol, triglyceride and phospholipid was determined. Whole blood and trough plasma CsA levels were measured by monoclonal radioimmunoassay. Plasma lipids did not differ significantly among the five groups. At a dose of 20 mg kg-1 d-1 of CsA VLDL cholesterol rose significantly (P < 0.05). Administration of either CsA or cremophor vehicle increased HDL-2 phospholipids (P < 0.05) and decreased HDL-3 cholesterol. There was not a linear relationship between whole blood and plasma CsA levels and increasing CsA doses. Short-term treatment with low doses of CsA have little influence on lipid profile in the rat. Changes on lipoprotein composition can be attributed mainly to cremophor vehicle, conceivably due to its ethanol content.

Acute Cyclosporin a Renal Dysfunction in Dogs Reversed by Calcium Antagonists and Antiplatelet Agents

The aim of this study was to assess the effect of nifedipine and piracetam alone or in combination in the protection of renal function and morphology after cyclosporin A (CyA) administration. Thirty healthy mongrel dogs with a mean body weight of 15 kg were sacrificed. Six animals (group C) were given CyA 20 mg/kg body weight per os, while the remaining groups (8 animals each) were given concomitantly 20 mg nifedipine (group CN) or 4 g of piracetam (group CP), or both drugs in combination (group CNP). After 5 days of drug administration the animals were anesthetized, both kidneys were exposed, and functional tests were performed. Then the kidneys were removed for histological study. The mean plasma CyA levels in the four groups were 1765 +/- 685 ng/mL, 1300 +/- 324 ng/mL, 1116 +/- 491 ng/mL and 1600 +/- 290 ng/mL, respectively. Urine volume, creatinine, urea, and osmolar clearances were significantly higher in the groups CN, CP, and CNP compared to the control group C (p < 0.01). Urine sodium concentration was significantly higher (p < 0.05 or p < 0.01) in nifedipine groups than in the other two groups of animals, while the fractional excretion of sodium (FENa%) was significantly higher (p < 0.01) in all treated groups compared to controls. Plasma thromboxane-B2 levels were significantly reduced by each drug alone or in combination (p < 0.01). Morphological lesions, similar in all groups, did not correlate with the functional improvement.(ABSTRACT TRUNCATED AT 250 WORDS)

Reflex sympathetic dystrophy syndrome of the lower limbs in renal transplant patients treated with cyclosporin A

In a 36-month period, 240 patients at our institution received kidney transplants from cadaver donors. Cyclosporin A (CsA) was used as the initial immunosuppressive therapy. Seven patients (5 men and 2 women) developed severe pain, periarticular soft tissue swelling with no effusion, and vasomotor changes in affected areas. Although articular mobility was conserved, most of the patients had great difficulty in walking. A patchy osteoporotic pattern was seen radiographically and increased uptake of 99mtechnetium with a periarticular distribution in the clinically affected areas were found. All of these symptoms and radiographic and scintigraphic signs are compatible with definite reflex sympathetic dystrophy syndrome (RSDS). Articular symptoms began within 3 months after kidney transplantation in all patients; all but 1 patient had plasma CsA levels greater than 200 ng/ml at that time. When the dosage of CsA was reduced, there was concomitant improvement in the RSDS, which appeared when the plasma CsA levels declined to less than 200 ng/ml. The mean duration of the clinical symptoms of RSDS was 8 months. We believe RSDS should be added to the list of complications that may appear in kidney transplant patients who receive CsA treatment.

SUCCESSFUL CYCLOSPORIN A TREATMENT OF APLASTIC ANAEMIA IN SHWACHMAN‐DIAMOND SYNDROME

We present a 17-year-old mentally retarded female diagnosed with SDS. Cyclosporin A (CsA) was initiated at a dose of 10 mg/kg/d p.o. CsA was ajusted according to serum creatinine, bilirubin and plasma CsA levels

Effects of temperature and endogenous factors in blood on concentrations of cyclosporin in plasma measured by high-performance liquid chromatography.

The effects of temperature, hematocrit (Hct), lipid level in plasma and cyclosporin A (CyA) level in whole blood on the concentration of CyA in plasma measured by high-performance liquid chromatography were studied in vitro. With rise in blood storage temperature before cells were removed, the concentration of CyA in plasma was increased in the temperature range between 10 degrees C and 37 degrees C, but was decreased between 4 degrees C and 10 degrees C. With rise in Hct, the concentration of CyA in plasma was decreased, and it was more markedly decreased at the blood storage temperature of 4 degrees C than at 37 degrees C. A lipid supplementation study showed that the concentration of CyA in plasma was increased with rise in plasma triglyceride level and in plasma cholesterol level at the storage temperature of 4 degrees C but not at 37 degrees C. Studies of the effect of CyA concentration in blood on the CyA distribution in blood demonstrated that the cellular/plasma concentration (C/P) ratio at low levels (less than 200 micrograms/ml) of plasma CyA ranged from 4 to 10 and was about 2 times higher than that at higher concentrations at 4 degrees C, but the ratio was relatively constant at 37 degrees C. The saturation capacity of the cellular fraction for CyA showed considerable individual variations, but there was no difference between the capacities at 4 degrees C and 37 degrees C. The separation of plasma after equilibration at 37 degrees C made it possible to avoid the variations in the distribution of CyA in whole blood associated with changes in Hct, lipid level in plasma and CyA level in whole blood, and to obtain a measurement reflecting the physiologically significant concentration of CyA in plasma.

Increased systemic availability of cyclosporin A by formulation design: pharmacokinetic consideration on its transport

The systemic availability of cyclosporin A (CyA) from two different oral formulations was investigated in rats in relation to the lymphatic transport of CyA. The two test oral CyA formulations were a well-solubilized solution with a pharmaceutical additive, polyoxy 60 caster oil (HCO-60), and an olive oil formation. Each formulation was administered orally to two groups of 4 rats. After oral administration of the HCO-60 formulation, 7 mg/kg, the peak plasma CyA level and the area under the curve (AUC) were 1.5 times higher than obtained from the olive oil formulation. To clarify the contribution of the two absorption routes, portal and lymphatic, on the systemic availability of CyA, a pharmacokinetic study was performed by administering CyA to two more groups of 3 rats by two different administration routes, intraportal (i.p.) infusion and intravenous (i.v.) injection. The mean AUC after i.p. infusion, 7 mg/kg, was 11.32 ± 0.85(S.E.M.) μg · h/ml and after i.v. injection, 3.5 mg/kg, was 8.74 ± 0.85 (S.E.M.) μg · h/ml. By analyzing these results with a physiologic pharmacokinetic model containing the liver and gastrointestinal (GI) tissue as metabolic eliminating organs for CyA, the increased systemic availability of CyA by formulation design was revealed to be due to increased absorption from the GI tract and the main transport route after being absorbed into the GI cells was revealed to be the portal venous system.