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The novel immunosuppressive drug O-hydroxyethyl-D(Ser)8-cyclosporine (SDZ IMM 125) and cyclosporine A (CyA) were compared in different in vitro models with respect to hepatocellular side effects. SDZ IMM 125 was less lipophilic than CyA and also decreased liposomal membrane anisotropy less. Furthermore, SDZ IMM 125 increased Na+ and Ca++ permeability across the liposomal membranes significantly more than CyA. The uptake of CyA and SDZ IMM 125 into freshly isolated rat hepatocytes was neither saturable, Na+ dependent or temperature sensitive, nor could it be inhibited vice versa, indicating passive diffusion. The diffusion coefficient of CyA was about two times higher than that of SDZ IMM 125, reflecting its higher lipophilicity. In primary hepatocyte monolayers the cellular concentrations of CyA were about two times higher than that of SDZ IMM 125. As an indicator of cholestasis the saturable uptake of cholyltaurine into isolated cells was found to be apparently competitively inhibited to the same extent by both compounds. In isolated perfused rat livers SDZ IMM 125 caused a significantly greater decrease in bile flow than did CyA. Release of lactate dehydrogenase from hepatocyte primary cultures and from isolated perfused livers were determined as parameter of cell damage. In both systems the cytotoxicity of SDZ IMM 125 was significantly higher than that of CyA. The data suggest that SDZ IMM 125 causes greater cholestatic and cytotoxic effects than CyA at equimolar cellular exposure.

This study compares the toxic effects of native cyclosporia A (CyA) with those of targeted CyA that is conjugated with the anti-rat-thymocyte antibody of rabbit origin via the N-(2-hydroxypropyl)methacrylamide (HPMA) carrier bearing digestible, reactive oligopeptide side chains. Ten toxic doses of native CyA (50 mg/kg i.p.) given to young adult rats in the course of 14 d produced a severe renal lesion-diffuse microvacuolization of the proximal tubules in the deep cortex, and hypergranulation of juxtaglomerular regions. Severe atrophy of the thymic medulla was documented by morphometry. In the cortex the epithelial reticular (but not deep interdigitating) cells showed ultrastructural signs of severe degeneration and lysis. The immature CD4+8+ double-positive cortical lymphocytes were preserved whereas the single-positive medullary thymocytes were greatly depleted; there was also a restriction of MHC class II antigen expression in the medulla. The number of medullary B cells was increased. The cytokeratin net was focally shrunken in the cortex and almost negative in the medulla, with loss of Hassall's corpuscles. After ten corresponding doses of antibody-targeted conjugated CyA no damage to the renal tubules and arterioles appeared and the antiGBM or immune-complex deposition was absent. The thymus had a normal medulla with numerous mature thymocytes and the cortical epithelial reticulum remained well preserved. Thus, the main toxic effects of CyA could be eliminated by targeting. The T-cell-targeted drug was tested for preserved immunosuppressive properties and non-toxic character of HPMA copolymer carrier.

OG 37-325 (nva-cyclosporine, cyclosporine G) is structurally similar to cyclosporine A (CsA). We hypothesized that OG 37-325 may, therefore, be metabolized by P450 3A, an enzyme recently shown to metabolize CsA. To test this hypothesis, we employed the erythromycin breath test (ERMBT) to measure P450 3A activity on multiple occasions in twenty OG 37-325-treated renal transplant recipients. When stable dosing was achieved, there was a measured 6-fold variation in the ratio of 12-hr whole-blood parent compound trough concentration (ng/ml, HPLC) to daily OG 37-325 dose (mg/kg) ([OG 37-325]/dose). In support of our hypothesis, there was an inverse correlation between the ERMBT result and the [OG 37-325]/dose ratio (r = -0.71, P < 0.001, n = 20); that is, patients with higher P450 3A activity generally required higher OG 37-325 doses to attain target blood levels. We also found that intrapatient variation in the [OG 37-325]/dose ratio observed over the course of the study correlated with changes in the ERMBT results (r = -0.67, P = 0.002). Inter- and intrapatient differences in [OG 37-325]/dose ratio were not predicted by patient age, serum cholesterol, blood hematocrit, or traditional liver chemistries. We conclude that P450 3A is generally rate limiting in the elimination of OG 37-325 in adult renal transplant recipients. Therefore, most drug interactions observed with CsA should also be expected with OG 37-325. We also conclude that intrapatient changes in OG 37-325 dosing requirements largely result from changes in P450 3A activity. The ERMBT may therefore provide useful information concerning patient compliance and may also serve as a useful guide to OG 37-325 dosing adjustments.

Cyclosporin G (CsG) is an analogue of cyclosporin A (CsA) with strong immunosuppressive activity. We compared these two drugs in a rat model in which salt depletion promotes irreversible renal interstitial fibrosis with renal dysfunction in animals given CsA for three weeks. When both drugs were given in the same dosage on a weight basis (15 mg/kg/day, subcutaneously), CsA blood levels were higher than CsG (3305 vs. 1824 ng/ml, P < 0.001). This could be explained by a higher CsG clearance (6.4 vs. 4.3 ml/min/kg in CsA, P < 0.0001) resulting in smaller CsG area under the curve. There was also lower renal and hepatic CsG tissue concentrations. CsA induced a dramatic decrease in GFR, 0.14 in CsA versus 0.67 ml/min/100 g in control, P < 0.001, and increased urinary excretion of N-acetyl beta-D-glucosaminidase (NAG), 21 in CsA versus 13 IU/gCr in control rats, P < 0.001. CsG-treated and control rats had similar GFR and urinary NAG. When CsA dosage was decreased to 7.5 mg/kg blood levels were similar to those found with CsG 15 mg/kg. CsA at this dose caused a reduced GFR (0.29 ml/min/100 g) and an increased urinary NAG (20 IU/gCr) (P < 0.01 vs. control for both). Both dosages of CsA induced considerable cortical and medullary injury (interstitial fibrosis and tubular atrophy), more severe than the histological damage found in CsG-treated rats. Neither drug promoted significant changes in liver function or histology.(ABSTRACT TRUNCATED AT 250 WORDS)

The immunosuppressive efficacy of CsA and its derivative SDZ IMM-125 was compared in highly mismatched mongrel dogs in receipt of renal allografts. At an equal dose of 15 mg/kg/day and in the same drug vehicle, SDZ IMM-125 was not superior to CsA in prolonging allograft survival. Whole blood levels of SDZ IMM-125 were lower than those achieved for CsA. No specific drug-related side effects were noticed in this model.

The pharmacological profiles of two new derivatives of the immunosuppressive drug, cyclosporine, is presented here. (Nva2)-CS has very similar properties to CS, but lacks the nephrotoxic side-effects. This derivative appears to be a potential successor to cyclosporine. (Val2)DH-CS seems to have a different spectrum of activities. It does not suppress humoral immunity and allograft rejection, but suppresses some types of cell-mediated immune responses. This derivative may prove useful in autoimmune situations where T cells are involved in the disease process.

The first preliminary clinical results with a new Cyclosporin derivative (Dihydrocyclosporin-D) are reported. The compound has no obvious nephrotoxic effect; but it exhibits a hepatotoxic effect, and frequently leads to hypertension. The clinical efficiency cannot yet be judged with certainty.

Acute cyclosporine nephrotoxicity is characterized by the dose-dependent reduction of glomerular filtration rate both in patients and experimental animals. Administration of a vasodilator agent such as PGE2 might prevent glomerular vasoconstriction and hence reduce cyclosporine nephrotoxicity. The results of the present investigation in spontaneously hypertensive rats indicate that a synthetic PGE2 prevents cyclosporine nephrotoxicity. Pharmacokinetic studies revealed that CSA plasma peak levels and area under the plasma concentration-time curve were significantly decreased in PGE2 treated rats, indicating reduced bioavailability of oral CSA. Furthermore, the immunosuppressive effect of CSA was completely abolished by concomitant PGE2 administration. In summary, the preventive effect of a synthetic PGE2 analogue on CSA nephrotoxicity in rats is most likely due to a reduced enteral absorption of CSA, resulting in insufficient immunosuppression.

Nephrotoxicity has limited the effectiveness of cyclosporine in transplantation therapy and has precipitated the need to develop a new immunosuppressive agent that lacks this nephrotoxicity or has a higher therapeutic index. Prior studies have suggested that cyclosporin G may be equally effective immunosuppressively, but less nephrotoxic than cyclosporine. To compare the immunosuppressive effects of the two agents, graft survival was analyzed in Lewis-Brown Norway rats, which received heterotopic ACl heart allografts and were treated orally with cyclosporin G or cyclosporine at 5 and 10 mg/kg/day. To compare nephrotoxicity the group of rats that had transplantations and an additional group of surgically intact Lewis-Brown Norway rats, treated orally with cyclosporin G or cyclosporine at dosages ranging from 10 to 50 mg/kg/day and for durations ranging from 50 to 180 days, were analyzed in terms of kidney morphology (fibrosis, glomerular damage, interstitial infiltrate, and tubular dilation) and kidney function (blood urea nitrogen and serum creatinine levels) in this model cyclosporin G was significantly less effective than cyclosporine in prolonging graft survival at 5 mg/kg/day but equally effective at 10 mg/kg/day. In addition, cyclosporin G was substantially less nephrotoxic both morphologically and functionally at low (10 mg/kg/day) and high (50 mg/kg/day) dosages. Further studies are indicated to determine the therapeutic index of cyclosporin G and to evaluate its use in combination with other immunosuppressive agents.

Between March 29, 1979, and March 1, 1985, 62 heart transplants were done in 61 patients at the University Medical Center, University of Arizona. There were two treatment groups with nearly equal numbers in each; conventional immunosuppression (1979 to 1982) and cyclosporine (1982 to the present). Comparison of actuarial survival, number of rejection episodes, number of fatal rejection episodes, number of infections, and number of "other complications" failed to reveal any significant difference between the two groups. The cyclosporine-treated patients had a documented increase in blood urea nitrogen and serum creatinine accompanied by an increase in diastolic blood pressure. The length of hospital stay of the cyclosporine group was approximately one half of that of the conventionally treated patients, and they required fewer rehospitalizations. The cost for initial hospitalization was not significantly different between the two groups. Therefore, in 1979 dollars, the cost for cyclosporine-treated patients has decreased. This difference in cost was only minimally diminished by the difference in expenditure for outpatient pharmaceuticals, which was four times higher in the cyclosporine group. We believe that cyclosporine is a potent immunosuppressive agent but that it has toxic, possibly irreversible effects on the kidney. In view of the minimal differences that we were able to demonstrate in survival rejection and infection, it seems prudent to reduce or modify present doses of cyclosporine in an attempt to avoid irreversible renal damage.

Five immunosuppressive and anti-inflammatory agents were tested for their effects on development of experimental autoimmune uveoretinitis (EAU) and immune responses to S-antigen in rats immunized with this retinal antigen. When administered daily from day 0-14 after immunization, cyclosporine at 5-20 mg/Kg was nontoxic and yet effective in inhibiting the development of EAU for at least 30 days. All other tested drugs were found toxic at their immunosuppressive doses. Of these drugs, only cyclophosphamide (at 5-20 mg/Kg) was capable of inhibiting EAU in some of the treated rats for up to 30 days. Other agents, bredinin (40-100 mg/Kg), dexamethasone (0.2-0.4 mg/Kg), or colchicine (0.5 mg/Kg) produced only a delay in the disease onset. Cyclosporine was also unique in its effect on the immune responses of the rats by selectively inhibiting only the specific T-cell-mediated responses to S-antigen (delayed skin response and lymphocyte response in culture), while having no negative effect on antibody production or the lymphocyte response to the polyclonal mitogen, concanavalin A. Other drugs, when effective, inhibited all types of immune response. In addition, cyclosporine was capable of preventing EAU even when given to rats as late as from day 7 after immunization. Only cyclophosphamide (at 20 mg/Kg/day) had a similar effect on 1/3 of the rats, while other drugs only delayed or had no effect on the disease onset when given by this late schedule.

Orthotopic hepatic transplantation was performed upon 29 dogs. Four dogs received no immunosuppressant, 12 received cyclosporine and 13 received azathioprine. Dogs treated with cyclosporine at a dose of 20 milligrams per kilogram yielded histologic and functional data indistinguishable from those of the dogs in the sham transplant group. Histologic evidence of rejection consistently appeared when the dose was decreased to 10 milligrams per kilogram but was reversed upon resuming the administration of the higher dosage. Serum levels of bilirubin and hepatic enzymes, serum glutamic-oxalacetic transaminase, serum glutamic-pyruvic transaminase and alkaline phosphatase did not correlate with the development or resolution of histologic evidence of rejection in dogs receiving cyclosporine. Dogs receiving cyclosporine for 60 days had a prolonged survival when the drug was stopped, whereas the dogs receiving such therapy for less than 60 days did not have a prolonged survival period.

Cyclosporin A-associated nephrotoxicity has precipitated the need to develop new immunosuppressive protocols or agents that have a higher therapeutic index than cyclosporin A. A new immunosuppressive agent, cyclosporin G or norvaline (Nva-2) cyclosporine, has been shown to be potent. The rat heterotopic transplant model (ACI to Lewis) and Lewis rats that had no operation were used to compare cyclosporin G with cyclosporin A (5 mg/kg/day per gavage) with and without azathioprine (5 to 10 mg/kg/day, intraperitoneally) in terms of immunosuppressive efficacy (graft survival), toxicity (mortality, renal histopathology, and serum creatinine and blood urea nitrogen values), and pharmacokinetics (trough whole blood cyclosporine levels as measured by radioimmunoassay on days 14 and 28 of treatment). In this model no statistically significant difference in immunosuppression was shown between the two cyclosporins both with and without azathioprine. Cyclosporin G, however, was associated with significantly less mortality when combination therapy with azathioprine was used. Both cyclosporins were associated with normal serum creatinine values and little histopathologic evidence of nephrotoxicity, except juxtaglomerular apparatus hyperplasia. Comparable cyclosporine levels were achieved when cyclosporin A or G was used as the sole immunosuppressive agent, but significantly higher cyclosporine levels were shown with cyclosporin A than with cyclosporin G when combination therapy with azathioprine was used. Further studies in humans are needed to evaluate whether cyclosporin G will be a clinically useful immunosuppressive agent either alone or combined with other immunosuppressive modalities.