Cyclosporine

Brand Names: Sandimmune, Neoral

Clinical Names: Cyclosporine

Summary

generic name: Cyclosporine

trade name: Sandimmune®, Neoral®

type of drug: Immunosuppressant.

used to treat: Prevention of graft rejection following solid organ transplantation and treatment of transplant rejection in patients previously receiving other immunosuppressive agents.

overview of interactions:
• nutrient affected by drug and affecting drug toxicity: Magnesium

• nutrient affecting drug performance: Vitamin E

• nutrient affecting drug toxicity: Arginine

• nutrient affecting drug toxicity: DHA and EPA (Omega-3 Fish Oil)

• herb affecting drug toxicity: Ginkgo biloba (Ginkgo)

• herb affecting drug toxicity: Silybum marianum (Milk Thistle)

• nutrient affecting drug performance and toxicity: Grapefruit Juice



Interactions

nutrient affected by drug and affecting drug toxicity: Magnesium

• mechanism: Cyclosporine has been linked to reduced serum levels of magnesium.

• adverse drug effects: This systemic depletion of magnesium produces a high risk of seizures due to cyclosporine-induced toxicity to the nervous system.

• testing: Individuals undergoing cyclosporine therapy should have their magnesium levels tested regularly. Nutritionally-oriented physicians generally find that monitoring red blood cell magnesium levels, rather than serum magnesium, is the most accurate method for diagnosing a deficiency.

• nutritional support: Magnesium supplementation prevents magnesium deficiency and subsequent neurotoxicity. In the event of cyclosporine-induced depletion, the prescribing physician should be consulted before starting any form of magnesium supplementation.
(Toffaletti J. Analyt Chem 1994 63(12):192R-194R; Pere AK, et al. Nephrol Dial Transplant 1998 Apr;13(4):904-910; Rob PM. Fortschr Med 1996 Apr 10;114(10):125-126; Thompson CB, et al. Lancet 1984;ii:1116.)

nutrient affecting drug performance: Vitamin E

• mechanism: Several studies have found that 25 mg/kg of "water-soluble" d-a Vitamin E increases the absorption of cyclosporine and may decrease the needed dose of cyclosporine by 40-72% without reducing its effectiveness.
(Chang T, et al. Clin Pharmacol Ther 1996 Mar;59(3):297-303; Sokol RI et al. Lancet 1991;338:212-215; Pan SH, et al. Pharmacotherapy 1996 Jan;16(1):59-65.)

• nutritional synergy: Supplementing 25 IU of Vitamin E per 2.2 pounds of body weight is an appropriate dosage as indicated by the research. However, since supplementation with Vitamin E will effect the drug's potency and dosage, any such usage should be done in consultation with the prescribing doctor, and preferably in collaboration with a nutritionally-oriented physician. Apart from some potential for reduced toxicity, the most obvious value in this increased absorption derives from the reduced cost of the therapy as cyclosporine is very expensive.

nutrient affecting drug toxicity: Arginine

• research: Studies involving rats indicate that oral supplementation of L-arginine can prevent chronic cyclosporine nephrotoxicity.
(Yang CW, et al. Exp Nephrol 1998 Jan;6(1):50-56; Alexander JW, et al. JPEN J Parenter Enteral Nutr 1998 May;22(3):152-155; Andoh TF, et al. Transplantation 1997 Nov 15;64(9):1236-1240.)

• mechanism: Nitric oxide (NO) decreases cyclosporine nephrotoxicity and arginine is a nitric oxide substrate. Nitric oxide can also have both effector (cytotoxic) and regulatory roles in immune function.

• nutritional support: Given the preliminary state of the research involved, supplementation with L-arginine cannot be suggested as offering definite benefit. However, other research with animals indicates that arginine may inhibit tumor growth by activating macrophage cytotoxic effects.
(Marcinkiewicz J, et al. Eur J Immunol 1995 Apr;25(4):947-951.)

nutrients affecting drug toxicity: DHA and EPA (Omega-3 Fish Oil)

• research: Several studies have found that large doses of omega-3 fish oil (6 g per day) over three month period reduced cyclosporine-induced kidney toxicity and the resultant decline in glomerular filtration rate by more than 50%.
(Kooijmans-Coutinho MF, et al. J Am Soc Nephrol 1996 Mar;7(3):513-518; Bilo HJK, et al. Nephron 1991;57:385-393: Badalamenti S, et al. Hepatology 1995 Dec;22(6):1695-1671; Alexander JW, et al. JPEN J Parenter Enteral Nutr 1998 May;22(3):152-155.)

• nutritional support: Reaching the levels found to be effective in studies could be difficult using standard supplementation. EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) together constitute the omega-3 fraction of fish oil. 20,000 mg of fish oil would be necessary to obtain 6,000 mg of the omega-3 fraction. Thus obtaining the required dosage would involve consuming twenty pills per day at 500 mg of omega-3 oil per pill.

herb affecting drug toxicity: Ginkgo biloba (Ginkgo)

• research: Additionally, test tube research involving human liver microsomes found that Ginkgo exercised some protective function against lipid peroxidation in liver cells caused by cyclosporin A. Other animal studies indicate that Ginkgo could prevent cyclosporine-induced kidney toxicity.
(Barth SA, et al. Biochem Pharmacol 1991;41:1521-1526; Pirotzky E, et al. Transplant Proceed 1988;20(suppl 3):665-669.)

• herbal support: Ginkgo biloba can function as a powerful antioxidant that may have beneficial effects against many disease processes. However, as of yet, no clinical studies involving humans have confirmed that Ginkgo specifically protects against the severe side effects of cyclosporine. Ginkgo biloba extract is usually standardized to contain 24% flavone glycosides and 6% terpene lactones. A typical preventive dosage for an individual taking cyclosporine might be in the range of 160-240 mg, two to three times per day. Ginkgo is essentially non-toxic and can be taken for long durations without known risk for most individuals. However, it may need to be taken for several weeks before it begins to exert the desired therapeutic effects.

herb affecting drug toxicity: Silybum marianum (Milk Thistle)

• research: Silymarin is an extract of milk thistle, and silibinin is a key component of this plant extract. Cyclosporine A (CsA) is metabolized in the liver by cytochrome P-450 IIIA. In one study on rats, silibinin, decreased cyclosporine-induced lipid peroxidation but did not exert a protective effect on glomerular filtration rate in the kidneys. Administration of Cyclosporine A in conjunction with Silibinin increased the specific content of cytochrome P-450 in liver microsomes. Another rat study found that silibinin protects the exocrine pancreas from Cyclosporine toxicity. Silibinin and CiA had an additive inhibitory effect on insulin secretion, but silibinin attenuated CiA-induced inhibition of amylase secretion.
(Zima T, et al. Ren Fail 1998 May;20(3):471-479; von Schonfeld J, et al. Cell Mol Life Sci 1997 Dec;53(11-12):917-920.)

nutrient affecting drug performance and toxicity: Grapefruit Juice

• mechanism: Grapefruit juice increases blood concentrations of some dihydropyridine calcium-channel blockers, which are metabolized by the P450 enzymes that also metabolize cyclosporine. Thus concurrent administration of grapefruit juice with cyclosporine will delay the absorption of the cyclosporine and increase the drug exposure of cyclosporine without changing peak concentration.

• research: Ioannides-Demos et al conducted a randomized crossover study with nine patients comparing the effects of grapefruit juice and water on steady state blood concentrations of cyclosporine and metabolites in patients with autoimmune diseases. They found that over a period of ten days, the relatively large amount of grapefruit juice involved, five ounces twice daily, produced a significant increases in predose cyclosporine concentrations and total metabolite concentrations when taken at the same time as the cyclosporine. One patient complained of abdominal pain and nausea as well as significant neurological side effects including tremor and lightheadedness.
(Ioannides-Demos LL, et al. J Rheumatol 1997;24:49-54.)

• potential nutritional synergy and risk: Lower doses of cyclosporine could potentially be used to achieve the desired levels in the body when administered in conjunction with a typical 8 oz. serving of grapefruit juice. Thus grapefruit juice might be used to provide a non-toxic and inexpensive alternative to drugs that are used to reduce cyclosporin dose. However, at this time clinical use of such a therapeutic approach would be wholly speculative. In the meantime physicians and pharmacists might caution patients taking cyclosporine against drinking grapefruit juice while taking cyclosporine to prevent any alterations in the effects of the medicine. No such effect has been reported with consumption of grapefruits as a food.
(Yee GC, et al. Lancet 1995 Apr 15;345(8955):955-956; Min DI, et al. Transplantation 1996 Jul 15;62(1):123-125.)

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Do not rely solely on the information in this article.

References

Alexander JW, Levy A, Custer D, Valente JF, Babcock G, Ogle CK, Schroeder TJ. Arginine, fish oil, and donor-specific transfusions independently improve cardiac allograft survival in rats given subtherapeutic doses of cyclosporin. JPEN J Parenter Enteral Nutr 1998 May;22(3):152-155.

Andoh TF, Gardner MP, Bennett WM. Protective effects of dietary L-arginine supplementation on chronic cyclosporine nephrotoxicity. Transplantation 1997 Nov 15;64(9):1236-1240.

Assis SM, Monteiro JL, Seguro AC. L-Arginine and allopurinol protect against cyclosporine nephrotoxicity. Transplantation 1997 Apr 27;63(8):1070-1073.
Abstract: The role of nitric oxide (NO) and oxygen free radicals in cyclosporine (CsA) nephrotoxicity was investigated using L-arginine, an NO substrate, and allopurinol, a xanthine oxidase inhibitor (involved in the formation of oxygen radicals) in an experimental model with Wistar rats. CsA, administered at 15 mg/kg/body weight (BW) subcutaneously for 10 days, caused a decrease in glomerular filtration rate, with inulin clearance of 0.33+/-0.04 vs. 1.11+/-0.06 ml/min/100 g BW (P<0.01 vs. control). L-Arginine, 1.5% in drinking water 5 days before and during CsA administration, partially protected the animals against this fall in glomerular filtration rate, with inulin clearance of 0.68+/-0.03 ml/min/100 g BW (P<0.01 vs. CsA). Allopurinol, at 10 mg/kg/BW by gavage, also had a protective action, with inulin clearance of 0.54+/-0.04 ml/min/100 g (P<0.01 vs. CsA). CsA caused an elevation in NO production, as assessed by urinary excretion of its metabolites, nitrite and nitrate (NO2 and NO3; 0.836+/-0.358 vs. 0.107+/-0.019 nmol/microg creatinine). NO production was as much as threefold higher in the L-arginine group (1.853+/-0.206 nmol/g creatinine). This CsA effect is probably related to its vasoconstrictive stimulus. Supplementation with L-arginine, which provides more substrate for NO formation, may enhance vasodilatation and consequently reduce the impairment of renal function. The protection provided by allopurinol may be related to the reduced formation of oxygen radicals, preventing the deleterious effects of lipid peroxidation.

Badalamenti S, Salerno F, Lorenzano E, Paone G, Como G, Finazzi S, Sacchetta AC, Rimola A, Graziani G, Galmarini D, et al. Renal effects of dietary supplementation with fish oil in cyclosporine-treated liver transplant recipients. Hepatology 1995 Dec;22(6):1695-1671.
Abstract: Nephrotoxicity is the main untoward effect of cyclosporine (CsA) treatment. Experimental and clinical data suggest that dietary supplementation with fish oil may lessen cyclosporine nephrotoxicity, possibly by lowering renal thromboxane (Tx) production. We have studied the renal effects of a daily supplementation for 2 months of 12 g fish oil (18% C20:5 n-3 eicosapentaenoic acid [EPA] and 12% C22:6 n-3 docosahexanoic acid [DHA]) in a placebo-controlled (12 g corn oil), prospective, randomized, double-blind study of stable CsA-treated liver transplant recipients. Thirteen patients ingested corn oil capsules and 13 fish oil. Compliance with dietary regimen was confirmed by fatty acid chromatography that showed increased plasma concentrations of EPA (from 0.4 +/- 0.02% to 4.6 +/- 0.5%, P < .0001) and DHA (from 1.8 +/- 0.2% to 3.9 +/- 0.1%, P < .0001) in the fish oil group and increased plasma concentration of linoleic acid (C18:2 n-6) in the corn oil group (from 25 +/- 2% to 28.4 +/- 2%, P < .001). At the end of the 2 months of the study, in the fish oil group the effective renal plasma flow increased by 22% (P = .012), the glomerular filtration rate increased by 33% (P = .057), the renal blood flow increased by 17% (P = .024), and the calculated total renal vascular resistances decreased by 20% (P = .034). In contrast, none of these parameters changed in the corn oil group. The renal functional reserve determined during L-arginine infusion, plasma renin activity (PRA), and plasma aldosterone (PA) remained unchanged during the study in either group.

Barth SA, Inselmann G, Engemann R, Heidemann HT. Influences of Ginkgo biloba on cyclosporine A included lipid peroxidation in human liver microsomes in comparison to vitamin E, glutathione and N-acetylcysteine. Biochem Pharmacol 1991 May 15;41(10):1521-1526.
Abstract: The in vitro effect of cyclosporin A (CsA) on lipid peroxidation in human liver microsomes was investigated, and efforts were made to prevent the resulting toxic effect of CsA. Microsomes were prepared from human liver resection material and incubated with CsA (0, 10, 30, 100, 300, 1000 micrograms/mL) for one hour (pH 7.4, 37 degrees, 95% O2, 5% CO2). Subsequently the resulting concentrations of malondialdehyde equivalents (MDA) were determined, a breakdown product of lipid peroxidation. Furthermore the duration of incubation was varied (0, 15, 30, 60, 90 min) using a CsA concentration of 300 micrograms/mL. CsA was shown to stimulate MDA-formation to up to 10-fold of the control value in both a time and concentration dependent manner. The dosage dependent experiment stated above was repeated, adding alpha-tocopherol (vitamin E, 1 mM), reduced glutathione (GSH, 1 mM), N-acetylcysteine (0.1, 0.3, 1, 3 mM), and Ginkgo biloba extract (Gbe, 15, 50, 150 micrograms/mL), respectively, to the medium of incubation. Vitamin E, a potent radical scavenger, proved to inhibit lipid peroxidation almost totally. Both GSH and N-acetylcysteine were also able to prevent lipid peroxidation, suggesting that the antioxidant effect of GSH might be caused by its thiol group and does not depend on the integrity of the whole molecule. Gbe inhibited CsA induced lipid peroxidation in a concentration dependent manner. This effect of Gbe was diminished yet not totally abolished when FeCl3 was added to the medium of incubation, whereas N-acetylcysteine even slightly enhanced CsA stimulated lipid peroxidation in the presence of iron. These results suggest that Gbe might be able to prevent radical mediated damage to human membranes caused by CsA.

Bilo HJ, Homan van der Heide JJ, Gans RO, Donker AJ. Omega-3 polyunsaturated fatty acids in chronic renal insufficiency. Nephron 1991;57(4):385-393. (Editorial; Review)

Chang T, Benet LZ, Hebert MF. The effect of water-soluble vitamin E on cyclosporine pharmacokinetics in healthy volunteers. Clin Pharmacol Ther 1996 Mar;59(3):297-303.
Abstract: We evaluated the effect of water-soluble vitamin E (d-alpha-tocopheryl polyethylene glycol 1000 succinate [TPGS]; Liqui-E) on the oral pharmacokinetics of the cyclosporine, a poorly available (approximately 30%) drug, in healthy volunteers. Ten healthy subjects were given two doses of oral cyclosporine (10mg/kg) separated by a 7-day washout period. Oral TPGS (2.6 IU/kg) was administered concomitantly with one of the cyclosporine doses in a randomized order. A significant increase was observed in area under the blood concentration-time curve (AUC;mean +/ SD) with concomitant TPGS administration (3908 +/- 2601 versus 6296 +/- 5102 ng x hr/ml). Significant decreases were observed in apparent oral clearance (0.24 +/- 0.14 versus 0.15 +/- 0.08 L/hr/kg) and apparent oral steady-state volume of distribution (1.57 +/- 0.95 versus 1.07 +/- 0.73 L/kg). No significant changes were observed in the ratios of metabolites to parent drug AUC values. The comparable relative decreases in apparent oral clearance (38%) and apparent oral steady-state volume of distribution (30%) with TPGS are most likely explained by enhanced absorption, decreased counter transport back into the intestine by P-glycoprotein, or some unknown mechanism by which cyclosporine is protected from metabolism in the gut, thereby increasing bioavailability.

Emilia G, Longo G, Bertesi M, Gandini G, Ferrara L, Valenti C. Clinical interaction between grapefruit juice and cyclosporine: is there any interest for the hematologists? Blood 1998 Jan 1;91(1):362-363. (Letter)

Ioannides-Demos LL, Christophidis N, Ryan P, Angelis P, Liolios L, McLean AJ. Dosing implications of a clinical interaction between grapefruit juice and cyclosporine and metabolite concentrations in patients with autoimmune diseases. J Rheumatol 1997 Jan;24(1):49-54.
Abstract: OBJECTIVE: To determine the effect of chronic grapefruit juice administration on steady state blood concentrations of cyclosporine and metabolites in patients with autoimmune diseases. METHODS: 9 patients stabilized on administration of cyclosporine (range 0.7-6.7 mg/kg/day) were given either grapefruit juice or water using randomized crossover design. Whole blood samples were collected before the morning cyclosporine dose and during the 12 h interdose interval. Cyclosporine concentrations were measured using a relatively specific assay (Emit) and total metabolite concentrations were estimated using a nonspecific assay (polyclonal Abbott-TDx). RESULTS: Exposure to grapefruit juice produced significant increases in predose cyclosporine concentrations (p < 0.01) and total metabolite concentrations (p = 0.03) and the area under the cyclosporine and metabolite blood concentration-time curves (p = 0.005, p = 0.001, respectively). One patient developed significant neurological side effects associated with a 68.9 and 214% increase in predose cyclosporine and metabolite concentrations, respectively, during grapefruit juice co-administration. CONCLUSION: Grapefruit juice causes an increase in both parent and metabolite profiles, indicating an alteration in the disposition of cyclosporine and metabolites. This interaction is of potential clinical importance in terms of mechanism, side effects, and dosing.

Kooijmans-Coutinho MF, Rischen-Vos J, Hermans J, Arndt JW, van der Woude FJ. Dietary fish oil in renal transplant recipients treated with cyclosporin-A: no beneficial effects shown. J Am Soc Nephrol 1996 Mar;7(3):513-518.
Abstract: This study aimed to determine whether dietary supplementation with fish oil has a beneficial effect on graft function and the incidence of rejection in renal allograft recipients treated with cyclosporin A (CsA). Renal function, blood pressure, the incidence of acute rejection episodes, graft survival, and renal histology and immunochemistry were investigated. In a randomized, placebo-controlled, double-blind trial, groups of 25 recipients of primary cadaveric renal allografts who had been treated with CsA took fish oil (30% C20:5 omega-3 and 20% C22:6 omega-3) or coconut oil (63% C8:0 and 36% C10:0) at 6 g/day for 3 months. There were no differences between the two patient groups with regard to HLA matching, panel-reactive antibody titers, or the demographic characteristics of donors or recipients. The GFR and effective RPF were determined at 1, 3, and 12 months after transplantation by simultaneous measurement of (125I-)iothalamate and (131I) hippuran clearances. At 1 yr after transplantation, patients treated with fish oil showed better renal function than did the control patients, but this difference was not statistically significant. Blood pressure and antihypertensive drug use were similar in both groups. The number of rejection episodes was also similar, and renal histopathological and immunohistochemical studies showed no significant differences between the fish-oil group and the control patients. It is concluded that fish oil, at a dose of 6 g/day, has no beneficial effect after renal transplantation within the time scale of the study.

Marcinkiewicz J, Grabowska A, Chain B. Nitric oxide up-regulates the release of inflammatory mediators by mouse macrophages. Eur J Immunol 1995 Apr;25(4):947-951.

Min DI, Ku YM, Perry PJ, Ukah FO, Ashton K, Martin MF, Hunsicker LG. Effect of grapefruit juice on cyclosporine pharmacokinetics in renal transplant patients. Transplantation 1996 Jul 15;62(1):123-125.
Abstract: This study investigated the effect of grapefruit juice on cyclosporine A (CsA) bioavailability in 10 renal transplant patients. Under CsA steady state conditions, patients were randomly administered their usual dose of CsA with either 8 ounces of grapefruit juice or 8 ounces of water. Using a crossover design, a 12-hr pharmacokinetic study was then conducted. Grapefruit juice increased the area under the concentration versus time curve (4218+/-1497 ng x hr/ml [grapefruit juice] vs. 3415+/-1288 ng x hr/ml [water], P=0.029) and 12-hr trough (244+/-214 ng x ml [grapefruit juice] vs. 132+/-56 ng x ml [water], P=0.09), but it did not change peak concentration (734+/-290 ng x ml [grapefruit juice] vs. 708+/-305 ng x ml [water], P=0.76). In addition, grapefruit juice delayed the time to peak concentration compared with water (5.4+/-3.0 hr [grapefruit juice] vs. 2.8+/-0.8 hr [water], P=0.025). These data suggest that concurrent administration of grapefruit juice with CsA will delay the absorption of CsA and increase the drug exposure of CsA without changing peak concentration.

Pan SH, Lopez RR Jr, Sher LS, Hoffman AL, Podesta LG, Makowka L, Rosenthal P. Enhanced oral cyclosporine absorption with water-soluble vitamin E early after liver transplantation.  Pharmacotherapy 1996 Jan;16(1):59-65.
Abstract: We evaluated the effect of Liqui-E, a water-soluble vitamin E preparation, on cyclosporin A (CyA) whole blood concentration in liver transplant recipients, and its impact on the cost of CyA. Patients were 26 liver transplant recipients (19 adults, 7 children) who were unable to achieve and maintain therapeutic CyA whole blood concentrations with the standard recommended oral daily dose in the early post-transplant period. Liqui-E 6.25 IU/kg orally was administered with CyA every 12 hours (median time of starting Liqui-E day 14.5). With Liqui-E, the daily oral CyA requirements (mean +/- SD) were decreased in adults from 22.6 +/- 8.9 to 16.2 +/- 7.3 mg/kg/day (p < 0.001) and in children from 78.6 +/- 34.1 to 53.7 +/- 35.0 mg/kg/day (p < 0.02); intravenous administration of CyA was unnecessary. The CyA trough concentrations (mean +/- SD) before and after Liqui-E were 670 +/- 186 and 1012 +/- 216 ng/ml, respectively, in adults (p < 0.001) and 732+/- 187 and 1052 +/- 166 ng/ml, respectively, in children (p < 0.01). When given with Liqui-E, the daily cost of CyA decreased by 26% in both adults and children. No clinical or biochemical evidence of Liqui-E toxicity was observed. Thus its administration in the early post-transplantation period can enhance CyA absorption in adults and children who are unable to achieve adequate whole blood concentrations with the usual recommended oral dosages. In addition, a significant cost saving can be realized by coadministration.

Pere AK, Krogerus L, Mervaala EM, Laakso J, Karppanen H, Inkinen K, Pere P, Ahonen J, Vapaatalo H, Lindgren L. Detrimental effect of dietary sodium and beneficial effect of dietary magnesium on glomerular changes in cyclosporin-A-treated spontaneously hypertensive rats. Nephrol Dial Transplant 1998 Apr;13(4):904-910.

Pirotzky E, Colliez P, Guilmard C, Schaeverbeke J, Braquet P. Cyclosporine-induced nephrotoxicity: Preventive effect of a PAF-acether antagonist, BN 52063. Transplant Proc 1988 Jun;20(3 Suppl 3):665-669.

Rob PM. [Magnesium deficiency after kidney transplantation and cyclosporine therapy]. Fortschr Med 1996 Apr 10;114(10):125-126. [Article in German]

Rong Y, Geng Z, Lau BH. Ginkgo biloba attenuates oxidative stress in macrophages and endothelial cells. Free Radic Biol Med 1996;20(1):121-127.

Sokol RI et al. Improvement of cyclosporine absorption in children after liver transplantation by means of water-soluble vitamin E. Lancet 1991;338:212-215.

Stoof TJ, Korstanje MJ, Bilo HJ, Starink TM, Hulsmans RF, Donker AJ. Does fish oil protect renal function in cyclosporine-treated psoriasis patients? J Intern Med 1989 Dec;226(6):437-441.
Abstract: In order to study the influence of fish oil on CyA-induced renal dysfunction, 13 patients with psoriasis (CyA group) received cyclosporin A (CyA) alone, and seven patients (CyA/EPA + DHA group) received a combination of cyclosporin A and fish oil (6g eicosapentaenoic acid, C20:5 omega-3, and docosahexaenoic acid, C22:6 omega-3, daily) for 3 months. The glomerular filtration rate fell by 18.0 +/- 9.6% in the CyA group compared with 8.7 +/- 6.8% in the CyA/EPA + DHA group (mean +/- SD, P less than 0.05). The effective renal plasma flow fell by 10.6 +/- 8.9% in the CyA group and did not change in the CyA/EPA + DHA group (P less than 0.05). The calculated total renal vascular resistance increased by 19.8 +/- 14.5% in the CyA group and did not change in the CyA/EPA + DHA group (P less than 0.01). The results of this pilot study suggest that fish oil can reduce CyA-associated renal dysfunction in psoriasis patients.

Thompson CB, et al. Association between cyclosporine neurotoxicity and hypomagnesemia. Lancet 1984;ii:1116.

Toffaletti J. Electrolytes, divalent cations, and blood gases (magnesium). Analyt Chem 1994 63(12):192R-194R.

Van Rensburg CE, Joone G, Anderson R. Alpha-tocopherol antagonizes the multidrug-resistance-reversal activity of cyclosporin A, verapamil, GF120918, clofazimine and B669. Cancer Lett 1998 May 15;127(1-2):107-112.
Abstract: The effects of the membrane-stabilizing agent, alpha-tocopherol (25 microg/ml), on the chemosensitizing interactions of cyclosporin A (5 microg/ml), verapamil (2 microg/ml), clofazimine (1 microg/ml), B669 (0.5 microg/ml) and GF120918 (0.015 microg/ml) with a P-glycoprotein-expressing human lung cancer cell line (H69/LX4) have been investigated in vitro. In an assay of cell proliferation, all the chemosensitizing agents restored the sensitivity of H69/LX4 cells to doxorubicin and vinblastine. The inclusion of alpha-tocopherol (25 microg/ml) antagonized the multidrug-resistance (MDR)-modifying activity of all five chemosensitizing agents, effectively preventing restoration of sensitivity to both doxorubicin and vinblastine in H69/LX4 cells.

von Schonfeld J, Weisbrod B, Muller MK. Silibinin, a plant extract with antioxidant and membrane stabilizing properties, protects exocrine pancreas from cyclosporin A toxicity. Cell Mol Life Sci 1997 Dec;53(11-12):917-920.
Abstract: Silymarin can be extracted from the milk thistle, and silibinin is the main component of the plant extract. Possibly due to their antioxidant and membrane-stabilizing properties, the compounds have been shown to protect different organs and cells against a number of insults. Thus liver, kidney, erythrocytes and platelets have been protected from the toxic effects of ethanol, carbon tetrachloride, cold ischemia and drugs, respectively. The effect of silibinin on endocrine and exocrine pancreas, however, has not been studied. We therefore investigated whether silibinin treatment attenuates cyclosporin A (CiA) toxicity on rat endocrine and exocrine pancreas. Groups of 15 male Wistar rats were treated for 8 days with CiA and/or silibinin. On day 9, endocrine and exocrine pancreatic functions were tested in vitro. At the end of the treatment period, blood glucose levels in vivo were significantly higher in rats treated with CiA while silibinin did not affect glucose levels. In vitro, insulin secretion was inhibited after treatment with silibinin, but amylase secretion was not affected. After treatment with CiA both insulin and amylase secretion were reduced. Silibinin and CiA had an additive inhibitory effect on insulin secretion, but silibinin attenuated CiA-induced inhibition of amylase secretion. Despite CiA treatment, amylase secretion was in fact restored to normal with the highest dose of silibinin. Thus silibinin inhibits glucose-stimulated insulin release in vitro, while not affecting blood glucose concentration in vivo. This combination of effects could be useful in the treatment of non-insulin-dependent diabetes mellitus. Furthermore, silibinin protects the exocrine pancreas from CiA toxicity. As this inhibitory effect is probably unspecific, silibinin may also protect the exocrine pancreas against other insult principles, such as alcohol.

Yang CW, Kim YS, Kim J, Kim YO, Min SY, Choi EJ, Bang BK. Oral supplementation of L-arginine prevents chronic cyclosporine nephrotoxicity in rats. Exp Nephrol 1998 Jan;6(1):50-56.
Abstract: This study was performed to evaluate the effect of L-arginine (L-Arg) on the prevention of chronic cyclosporine (CsA) nephrotoxicity in rats. Rats pair-fed a low-salt diet (0.05%) were given CsA (15 mg/kg/day s.c.), CsA and L-Arg (L-Arg group, 1.25 g/l water), CsA and N-nitro-L-arginine methyl ester (L-NAME group, 70 mg/l water) or vehicle. After 28 days, the L-Arg group had a higher glomerular filtration rate compared to the CsA (0.42 +/- 0.05 vs. 0.31 +/- 0.06 ml/min/100 g, p < 0.05) and the L-NAME groups (vs. 0.19 +/- 0.04 ml/min/100 g, p < 0.05) and a significantly lower serum creatinine level compared to the CsA (0.70 +/- 0.06 vs. 0.92 +/- 0.12 mg/dl, p < 0.05) and the L-NAME groups (vs. 1.21 +/- 0.17 mg/dl, p < 0.05). The L-Arg group had less fibrosis, tubular injury (TI), and arteriolopathy than the CsA (fibrosis 0.39 +/- 0.14 vs. 0.74 +/- 0.15; TI 1.3 +/- 0.3 vs. 2.0 +/- 0.1; arteriolopathy 33 +/- 7 vs. 48 +/- 17, p < 0.05, respectively) and the L-NAME groups (fibrosis vs. 1.67 +/- 0.32, TI vs. 2.6 +/- 0.3, arteriolopathy vs. 63 +/- 10, p < 0.05, respectively). Plasma renin activity in the L-Arg group was less than in the CsA (18 +/- 2 vs. 23 +/- 3 ng Ang I/ml/h, p < 0.05) and the L-NAME groups (vs. 30 +/- 3 ng Ang I/ml/h, p < 0.05). Nitric oxide production in L-Arg group was higher than in the CsA (24.2 +/- 1.7 vs. 11.1 +/- 1.5 mumol/24 h, p < 0.05) and the L-NAME groups (vs. 8.4 +/- 1.0 mumol/24 h, p < 0.05). In conclusion, the nitric oxide pathway is associated with the pathogenesis of chronic CsA nephrotoxicity, and exogenous L-Arg supplementation is effective in reducing chronic CsA nephrotoxicity in rats.

Yee GC, Stanley DL, Pessa LJ, Dalla Costa T, Beltz SE, Ruiz J, Lowenthal DT. Effect of grapefruit juice on blood cyclosporin concentration. Lancet 1995 Apr 15;345(8955):955-956.
Abstract: Grapefruit juice increases blood concentrations of some dihydropyridine calcium-channel blockers, which are metabolised by the P450 enzymes that also metabolise cyclosporin. We evaluated, in a randomised cross-over study, the effect of grapefruit juice on blood cyclosporin concentrations in 14 healthy adults. Each subject was given oral cyclosporin 300 mg with 250 mL grapefruit juice, orange juice, or water. Area-under-the-curve (AUC) was significantly higher with grapefruit juice than with water or orange juice (means 7057, 4871, and 4932 ng h/mL, respectively; p < 0.0001). Thus grapefruit juice may provide a non-toxic and inexpensive alternative to drugs that are used to reduce cyclosporin dose.

Zima T, Kamenikova L, Janebova M, Buchar E, Crkovska J, Tesar V. The effect of silibinin on experimental cyclosporine nephrotoxicity. Ren Fail 1998 May;20(3):471-479.
Abstract: The immunosuppressive drug cyclosporine A (CsA), is metabolized by cytochrome P-450 IIIA. It causes acute reversible as well as chronic largely irreversible nephrotoxic effects. This effect is bases on vasoconstriction of the afferent and efferent glomerular arterioles which leads to a reduction in glomerular plasma flow and glomerular filtration rate. The mechanisms of the vasoconstriction are unclear with a number of different pathways under discussion. Silibinin is the main constituent of silymarin. Silibinin inhibits lipid peroxidation on hepatic microsomes and mitochondria of rats and is also able to reduce the activity of various monooxygenases. Cyclosporin-induced lipid peroxidation and affected cytochrome P-450 may even contribute to cyclosporine nephrotoxicity. We examined the possibility that silibinin had a protective effect as a result of its radical scavenging properties. Silibinin, 5 mg/kg BW i.p., was administered 30 min before cyclosporine application at dose of 30 mg/kg BW daily i.p. The biochemical parameters, total malondialdehyde (MDA) in whole blood and kidney homogenates and specific content of cytochrome P-450 in microsomal liver suspension were estimated. Three groups were studied: controls (con), cyclosporine alone (CsA), and cyclosporine plus silibinin (CsA + Sili). Creatinine was significantly increased after 2 weeks in both cyclosporine treated groups compared to controls (CsA 60.2 +/- 10.6 versus 45.8 +/- 10.4 mumol/L, p < 0.05; and CsA + Sili 72.0 +/- 8.3 versus 45.8 +/ 10.4 mumol/L, p < 0.001) and glomerular filtration rate (GFR) was significantly decreased (p < 0.0001) in the same groups. Total MDA was elevated only in CsA rats (2.26 +/- 0.35 mumol/L, p < 0.05) in comparison with controls (1.60 +/- 0.44 mumol/L, p < 0.05) and with rats treated by CsA + Sili (1.65 +/- 0.27 mumol/L, p < 0.05). The specific content of cytochrome P-450 in microsomal liver suspension was increased in group CsA + Sili (1.179 +/- 0.115 nmol/mg prot) compared to control group (0.775 +/- 0.086 nmol/mg prot., p < 0.05) and also CsA group (0.806 +/- 0.098 nmol/mg prot., p < 0.05). In conclusion, silibinin decreased cyclosporine-induced lipid peroxidation without a protective effect on GFR. These data indicate that this pathway is not be important in cyclosporine-induced nephrotoxicity. Administration of both drugs (CsA + sili) increased the specific content of cytochrome P-450 in liver microsomes. This suggests that the effect of silibinin on cyclosporine biotransformation in the liver is via cytochrome P-450.