Continuing Education Activity

Calcineurin inhibitors are immunosuppressants used to manage autoimmune conditions including but not limited to lupus nephritis, idiopathic inflammatory myositis, interstitial lung disease, atopic dermatitis, and many more. In addition, they are used as mainstays for immunosuppression in solid organ transplants. This activity describes the indications, mechanism of action, contraindications to the use of calcineurin inhibitors. We will elaborate on the role of the drug as a valuable agent in all the conditions they are used for. This activity will also highlight the key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for health care team members in different specialties in their everyday practice.

Objectives:

• To elaborate on the mechanism of action of the four drugs that belong to the category of CNIs and appreciate the differences between them.
• To appreciate the utility of the drugs in our day-to-day practice.
• To have a thorough understanding of the toxicity profiles of the drugs so that patients can be counseled on the potential adverse effects.
• Establish very clear and concise monitoring guidelines and parameters while using CNI drugs.

Indications

Calcineurin inhibitors are immunosuppressants used in the management of autoimmune conditions such as lupus nephritis, idiopathic inflammatory myositis, interstitial lung disease, atopic dermatitis, and many more. In addition, they are used as mainstays for immunosuppression in solid organ transplants. 

Cyclosporine

• The most common FDA-approved indication is its role as an adjuvant to glucocorticoids in the treatment and prevention of allogeneic post-organ transplant rejection in patients who undergo kidney, heart, liver, and bone marrow transplantation.[1]
• Cyclosporine modified formulations are FDA-approved for treating patients with severe and active rheumatoid arthritis when the disease hasn’t adequately responded to methotrexate. It could be combined with methotrexate in patients with rheumatoid arthritis who do not respond adequately to methotrexate alone.[2]
• Cyclosporine modified formulations are also indicated for treating adult, nonimmunocompromised patients with severe and recalcitrant plaque psoriasis when they have failed to respond to at least one systemic therapy (e.g., retinoids, PUVA, or methotrexate) or when other systemic therapies can’t be tolerated or contraindicated.
• The ophthalmic formulation of cyclosporin is FDA-approved to increase tear production in patients diagnosed with keratoconjunctivitis sicca due to ocular inflammation and is also used in vernal keratoconjunctivitis.
• Non-FDA-approved indications include its role in the treatment of allergic conjunctivitis, alopecia, chronic urticaria, aplastic anemia, and interstitial cystitis. It is used off-labeled for several autoimmune diseases, including ulcerative colitis, systemic lupus erythematosus, Sjogren disease. It is also used in many glomerular diseases, including lupus nephritis, focal segmental glomerulosclerosis, minimal change disease, membranous nephropathy, and idiopathic nephrotic syndrome, particularly the steroid-resistant variety. It is used as prophylactic therapy for the prevention of graft vs. host disease.

Tacrolimus

• It is approved by the FDA in its oral formulation for the prevention of allogeneic post-organ transplant rejection in combination with other immunosuppressants like azathioprine and mycophenolate mofetil in patients undergoing kidney, liver, or heart transplants. In addition, IV formulation is offered for the same indications for patients who cannot take the drug orally.[3][4]
• The topical form of tacrolimus comes in 2 concentrations: 0.03% for children aged 2 to 15 years and 0.1% for adults. It is approved for use as a second-line treatment of moderate to severe atopic dermatitis in children who are nonresponsive to other topical treatments and in adults with a very severe disease involving a large body surface area. 
• Non-FDA-approved uses that have been reported for tacrolimus include its use as a prophylactic agent for the prevention of graft vs. host disease, prophylaxis for prevention of corneal, pancreatic, renal, and small intestine transplant rejection, induction therapy of lupus nephritis, treatment of Crohn disease, membranous glomerulonephritis, and myasthenia gravis, and to reduce the incidence of pancreatitis in patients undergoing liver transplantation after endoscopic retrograde cholangiopancreatography.

Pimecrolimus

• It is approved as a 1% topical formulation and is FDA-approved for the treatment of mild to moderate atopic dermatitis. It has many non-FDA-approved uses, including oral lichen planus, psoriasis on the face and intertriginous areas, vitiligo, lichen sclerosis of the vulva, and seborrheic dermatitis.[5]

Voclosporin

• It is a novel drug of the class and got FDA approval in 2021 in its oral form to be used with other immunosuppressants for the treatment of active lupus nephritis in adults.[6][7]

Mechanism of Action

Calcineurin is a complex of phosphatases composed of a 61-kDa calmodulin-binding catalytic subunit (calcineurin-A) and a 19-kDa calcium-binding regulatory subunit (calcineurin-B). This protein participates in a wide range of cellular processes and calcium-dependent signal transduction pathways, including T cell activation.[8] 

In general, calcineurin inhibitors bind with high affinity to specific cytoplasmic receptors termed immunophilins, including cyclophilin and FK binding protein.[9] This drug-receptor complex specifically and competitively inhibits calcineurin's activity, which is activated by the intracellular calcium released after T cell receptor engagement and co-stimulation from antigen-presenting cells. This process then inhibits the translocation of a family of transcription factors (NF-AT), leading to reduced transcriptional activation of cytokine genes for interleukin (IL)-2, tumor necrosis factor (TNF)-alpha, IL-3, IL-4, CD40L, granulocyte-macrophage colony-stimulating factor, and interferon-gamma.[10] By selectively inhibiting calcineurin, they impair the transcription of interleukin-2 and other cytokines in T lymphocytes and hence interfere with T cell activation, proliferation, and differentiation.[11] They primarily act on T-helper cells but also in the process inhibit T suppressor and T cytotoxic cells. In addition to being immunosuppressants, they also exert direct protective effects on podocytes, such as inhibiting calcineurin-induced dephosphorylation of synaptopodin, a critical protein that regulates actin filaments of the podocyte cytoskeleton. The drugs improve the viability of podocytes and reduce their migratory activity.

Cyclosporine acts by binding to cyclophilin-1 inside the cells to form the cyclosporine-cyclophilin complex. Subsequently, this complex inhibits calcineurin, which stops the activation and dephosphorylation of NF-AT, which is responsible for causing inflammatory reactions.[12] Tacrolimus and pimecrolimus share the same mechanism of action, and they both bind to FK binding protein and subsequently inhibit calcineurin.

Voclosporin is similar to cyclosporine in its chemical structure with a difference in one amino acid, making it more effective in calcineurin inhibition. Moreover, voclosporin inhibits calcineurin and inhibits p-glycoprotein, organic anion transporting polypeptide 1B1, and organic anion transporting polypeptide 1B3. All of these actions make voclosporin a promising immunosuppressant.

Administration

Cyclosporine

It is approved by the Food and Drug Administration (FDA) in its oral, intravenous injection, and ophthalmic formulations.

• Oral formulation: It is available in non-modified and modified formulations and is not bioequivalent. Capsules are available in 10 mg, 25 mg, 50 mg, and 100 mg strengths, and oral solution in 50 mg/ml strength. The oral form of cyclosporine should be administered in two divided doses. Patients should be consistent in administering the drug to their meals and plan to space the two doses exactly 12 hours apart. It is best to avoid grapefruit and grapefruit juice since it affects the drug's metabolism and increase blood levels of the drug.[1][2]

  • Cyclosporine non-modified formulation: The drug depends on bile for absorption, hence having varying absorption percentages in the gastrointestinal tract.
  • Cyclosporine modified formulation: It is available as a microemulsion formulation that does not depend on bile salts to get absorbed; hence it has good bioavailability.

• Intravenous formulation: IV cyclosporin is reserved for patients who cannot take the drug orally. Concentrated cyclosporin is available in 5 mL ampules, and each ml contains 50 mg cyclosporine.

• Ophthalmic formulation:  It is available as cyclosporine 0.05 %, 0.1% ophthalmic emulsion. Special instructions have to be given to patients before they use the drug. They should invert the unit dose several times, get a uniform white opaque emulsion, and be used concomitantly with artificial tears. It is available in 0.09% ophthalmic solution.

  • Keratoconjunctivitis sicca: Cyclosporin emulsion 0.05 %  and cyclosporin solution 0.09% is dosed one drop instilled two times per day 12 hours apart in each eye.
  • Vernal keratoconjunctivitis: Cyclosporin 0.1% ophthalmic emulsion is dosed one drop four times per day in affected eyes until signs and symptoms are resolved in patients age four years or older. In the case of vernal keratoconjunctivitis recurrence, it can be initiated again. Cyclosporin emulsion 0.05 % is dosed one drop four times per day in patients between 5 and 14 years of age.

Tacrolimus

It is approved by the Food and Drug Administration (FDA) in its oral, intravenous injection, and topical formulations.[3][4]

• Oral formulation: It is available as immediate-release capsules and extended-release capsules.

  • Tacrolimus immediate-release capsules: The oral formulation is available as 0.5 mg, 1 mg, and 5 mg immediate-release capsules. It is administered in 2 divided doses as follows: 0.2 mg/kg/day for adult patients post kidney transplant who are taking the drug in combination with azathioprine, 0.1 mg/kg/day if taken in combination with mycophenolate mofetil/IL-2 receptor antagonist, 0.1-0.15 mg/kg/day for adults post-liver transplant, 0.15-0.2 mg/kg/day for pediatric patients post-liver transplant, and 0.075 mg/kg/day for adults post heart transplant. Patients with hepatic or renal impairment should only use the lowest recommended value of the doses suggested. Grapefruit and grapefruit juices should be avoided for the reasons mentioned above.
  • Tacrolimus extended-release capsules: Extended-release tacrolimus capsules are available in 0.5 mg, 1 mg, and 5 mg. Capsules should not be crushed and chewed. They are a modified-release formulation that allows slow release of the drug by controlling water penetration and forming a protective polymer gel layer around the drug. Extended-release tablets come in 0.75 mg, 1 mg, and 4 mg strengths and use a drug delivery technology that improves drug bioavailability with low water solubility. Immediate release and extended-release formulations are not interchangeable.

• Intravenous formulation:  IV formulation is available as a 5 mg/mL concentrate in 5 mL ampules. Due to its increased toxicity, the IV form is reserved for patients who can't take the oral forms.

• Topical formulation: The topical formulation is available as an ointment of 0.03% or 0.1% concentrations and is found in 30 g and 60 g tubes.

Pimecrolimus

• Topical formulation: It is available in 1% concentration topical cream. It is not indicated for usage in children aged less than two years. A thin layer of the cream is applied to the skin twice daily. Its administration should be limited to the sites of atopic dermatitis in addition to the avoidance of its long-term use. 

Voclosporin

• Oral formulation: It is available as 7.9 mg capsules, and patients should be cautioned to take it on an empty stomach consistently as close to a 12-hour schedule. The recommended dose is 23.7 mg twice daily with mycophenolate mofetil and/or corticosteroids. Before initiating the drug, an accurate glomerular filtration(GFR) rate baseline should be established. The dose of the voclosporin should be adjusted based on GFR.

Adverse Effects

The side effects of cyclosporine and tacrolimus are very similar. Side effects of the two drugs include nephrotoxicity that manifests as an acute increase in the plasma creatinine and is reversible by dose reduction. It occasionally progresses to chronic kidney disease with permanent kidney damage, which can be irreversible despite stopping the drug.[13] 

• Hypertension is another significant side effect. It is caused by renal vasoconstriction and sodium retention and requires either dose reduction or the use of antihypertensives to reduce blood pressures.[14] 
• Neurotoxicity is manifested as tremors, headaches, seizures, and rarely encephalopathy, in addition to CNI pain syndrome.[15][16][17]
• Metabolic abnormalities include hyperlipidemia, hyperkalemia, hyperuricemia, gout, hypomagnesemia, and glucose intolerance.[18][19][20][21] 
• Hepatotoxicity is caused by the two drugs but could be avoided by quercetin.[22]
• Life-threatening bacterial, viral, and fungal infections resulting from immune system suppression are also reported.[23] 
• Malignancies include squamous cell cancers and benign and malignant lymphoproliferative disorders.[24] 
• Hirsutism (cyclosporine only), gum hyperplasia (cyclosporine only), and gastrointestinal disturbances of anorexia, nausea, vomiting, diarrhea, and abdominal discomfort are reported.[21] Tacrolimus and cyclosporine share all the side effects, but it is noteworthy that gastrointestinal disturbances and hyperglycemia are more frequently associated with tacrolimus. Tacrolimus differs from cyclosporine in that its use can result in alopecia, and the drug does not cause hirsutism or gingival hyperplasia, which is more commonly reported with cyclosporine.[25][26] 

Pimecrolimus causes adverse effects like erythema, irritation, burning and stinging at the site of application, headache, fever, influenza-like illness, infections, respiratory symptoms including sinusitis, tonsillitis, nasopharyngitis, cough, bronchitis, and upper respiratory tract infections, acne, folliculitis, gastrointestinal symptoms of gastroenteritis, diarrhea, abdominal pain, vomiting, nausea, and constipation, arthralgia, infections in the ear and conjunctiva, allergy and anaphylaxis, epistaxis, asthma exacerbation, lymphadenopathy, and malignancies including squamous/basal cell carcinomas, malignant melanoma, and lymphoma.[27][28]

Voclosporin has been reported to cause hypertension, headache, dizziness, hypoesthesia, migraine, paresthesia, seizure, alopecia, hypertrichosis, acute kidney injury, anemia, tremors, gastrointestinal tract disturbances including diarrhea, abdominal pain, decreased appetite, dyspepsia, gingivitis, and upper abdominal pain, cough, urinary tract infection, malignancies including lymphomas and skin cancer, infections, and chorioretinitis.[6][7][29]

Drug-drug Interactions

Cyclosporine, tacrolimus, and voclosporin are extensively metabolized by CYP3A4 and have numerous drug interactions with other medicines which are metabolized via the same pathway. CYP3A4 inhibitors like azole antifungals, macrolides, diltiazem, verapamil, amiodarone, colchicine, and oral contraceptives can increase the plasma concentration of these medicines. CYP3A4 inducers like phenytoin, carbamazepine, and orlistat can result in a subtherapeutic level of CNIs and may decrease its effectiveness. Concomitant use of cyclosporine with NSAIDs, azole antifungals, ciprofloxacin, gentamycin, vancomycin, and drugs having renal toxicity, may exhibit synergistic or additive renal impairment potential. Therefore, close monitoring of renal function (particularly serum creatinine) should be performed while using these medicines.

US Box warning

Cyclosporine

• Only clinicians experienced in the immunosuppressive treatment and managing organ transplant patients should prescribe cyclosporine non-modified capsules. Patients receiving immunosuppressive drugs should be managed in clinics staffed and equipped with adequate laboratory and supportive medical resources. The physician taking responsibility for maintenance therapy should have thorough information required for the follow-up of the patients.
• Cyclosporine non-modified capsules should be administered with adrenal corticosteroids but not in combination with additional immunosuppressive agents. There is an increased risk of infection and lymphoma resulting from immunosuppression.
• Since modified and non-modified formulations are not bioequivalent, they can’t be interchanged without clinician supervision.
• When non-modified capsules are administered chronically, the absorption was found to be variable. Therefore, clinicians should monitor patients taking non-modified capsules over at regular intervals for cyclosporine blood concentrations, and subsequent dose titrations should be made to avoid toxicity resulting from high blood concentrations or possible organ rejection resulting from low absorption cyclosporine, especially in patients with liver transplants.

Tacrolimus

• Malignancies and serious infection: There is an increased risk of developing serious infections and malignancies with tacrolimus or other immunosuppressants, leading to hospitalization or death. 
• Mortality in patients with liver transplantation: There is increased mortality in female patients taking Astagraf XL. Astagraf XL is not FDA-approved for use in liver transplantation.

Pimecrolimus

• The long-term safety of topical calcineurin inhibitor formulations has not been established. Therefore, continuous and long-term topical use of calcineurin inhibitors, including pimecrolimus, should be avoided, and if needed, the application should be limited to areas of involvement with atopic dermatitis. 
• Malignancy: There is no causal relationship, but rare reports of malignancy (e.g., lymphoma, skin malignancy) are documented in patients using pimecrolimus topical formulation.
• Pediatric Patients: Pimecrolimus is not FDA-approved for use in children younger than two years.

Voclosporin

• Malignancies and serious infections: There is an increased risk for developing malignancies and serious infections with voclosporin or other immunosuppressant use, leading to hospitalization or death.

Contraindications

Cyclosporine

Cyclosporine intravenous solution is contraindicated in patients with hypersensitivity to the drug or polyoxyethylated castor oil. In addition, cyclosporin is contraindicated in patients with rheumatoid arthritis and psoriasis with renal insufficiency, uncontrolled hypertension, or malignancies. Patients with psoriasis who are treated concomitantly with PUVA, UVB therapy, or other immunosuppressants and those receiving coal tar or radiation therapy should not be administered cyclosporin. Cyclosporin eyedrops should not be used topically during an active eye infection.[1][2]

Tacrolimus

Tacrolimus is only contraindicated if a previous hypersensitivity history to the drug or polyxyl 60 hydrogenated castor oil (HCO-60) is found.

Pimecrolimus

Pimecrolimus is contraindicated when a patient has hypersensitivity to the drug or excipients.

Voclosporine

Voclosporine is contraindicated in patients with a previous history of hypersensitivity to the drug and in patients concomitantly treated with strong CYP3A4 inhibitors, including ketoconazole itraconazole, and clarithromycin. This is due to the risk of acute and chronic nephrotoxicity by increasing the plasma concentration of the drug.[6]

Finally, there are some relative contraindications to CNIs that are important to mention, including concurrent malignancies, poorly-controlled hypertension, and infections.

Monitoring

Cyclosporine

The drug is metabolized in the liver, and hepatic dysfunction has been reported; periodic monitoring of liver function tests is recommended. Hypertension is another common side effect hence blood pressure monitoring is warranted. The recommendation is to prescribe an antihypertensive drug that is not a potassium-sparing diuretic to avoid life-threatening hyperkalemia.

When non-modified capsules are administered chronically, the absorption is variable. Therefore, clinicians should monitor patients taking non-modified capsules over at regular intervals for cyclosporine blood concentrations and make subsequent dose titrations to avoid toxicity or therapeutic failure, especially in patients with liver transplants. Numerous new assays are being developed to measure cyclosporine blood concentration. Therefore, clinicians should validate when comparing concentrations in the published literature to patient concentrations using new assay methods employed.[30][31]

Tacrolimus 

CYP3A enzymes metabolize tacrolimus; hence frequent monitoring of the drug levels is indicated when patients are on concomitant medications that activate and inhibit these enzymes. African Americans need higher drug dosage to reach the comparable plasma concentration trough values. Patients with renal and hepatic impairment should receive the lowest doses of the initial oral dosing range.

Pimecrolimus

The drug undergoes metabolism via the CYP3A enzyme pathway. FDA recommends that patients who use this drug avoid tanning beds, sun lamps, UV light therapy. Patients should not wear bandages or dressings covering the skin but rather regular clothes.

Voclosporin 

It is recommended to establish a baseline for the glomerular filtration rate and measure it every two weeks for the first month and every four weeks after that. Also, measuring urinary protein excretion as clinically indicated is recommended. Blood pressure monitoring at baseline and every two weeks for the first month is mandatory. In addition, EKG and serial potassium monitoring are of significant importance.

Toxicity

Generally, in case of overdosage, forced vomiting and gastric lavage would be valuable for up to two hours after administration. Transient hepatotoxicity and nephrotoxicity could occur and should resolve after drug withdrawal. 

• Oral doses of cyclosporine up to 10 grams (about 150 mg/kg) have been reported to be tolerable, with relatively mild symptoms including but not limited to drowsiness, headache, and tachycardia. However, moderate to severe reversible renal impairment has been reported as well. In premature neonates, accidental overdosage can happen when the drug is administered intramuscularly. Management for cyclosporine overdosage is mostly supportive and symptomatic.
• Tacrolimus is considered to be an overdose when it exceeds the regular dose by thirty times. Almost all patients recover completely. Adverse reactions include tremors, abnormal renal function, high blood pressure, and peripheral edema. Lethargy and transient urticaria have been reported in the acute setting. Management is largely supportive and symptomatic treatment as the drug cannot be dialyzed. Charcoal hemoperfusion to remove the drug is not well reported. The use of activated charcoal in an acute overdose is recommended with insufficient evidence.[32]
• There have been no reported cases of pimecrolimus overdosage as well as there are no reports of accidental oral intake. However, if oral ingestion occurs, the patient should seek medical intervention.
• Voclosporin is a relatively newer drug; hence there is no literature about its toxicity.

Enhancing Healthcare Team Outcomes

A multidisciplinary approach is needed to manage chronic conditions and enhance patient medication adherence to pharmacotherapy, a cornerstone of successful disease treatment. Medication adherence needs the highest level of participation by a patient. Compliance improves with the better physician-patient relationship and, in turn, improves long-term patient-reported efficacy and safety outcomes. A thorough understanding of a drug, its mechanism of action, its applications, toxicity, and monitoring guide are crucial tools to help the clinician counsel the patient. Prescribing a drug entails a multidisciplinary approach and requires all healthcare providers to participate in patient care to understand the drug and its pharmacokinetics better. Nurses can verify the dose before administering medicine and examine patient records for possible adverse reactions. In addition to patient education and behavioral interventions, pharmacists can perform medication reconciliation and report any issues to prescribers.

CNIs, when used, are the best friends in a wide variety of immune-mediated conditions but could be foes when overdosed. An interprofessional team approach can improve patient outcomes and reduce the adverse effects of calcineurin inhibitors. [Level 5]

Review Questions

• Access free multiple choice questions on this topic.
• Comment on this article.

References

1.

Colombo D, Ammirati E. Cyclosporine in transplantation - a history of converging timelines. J Biol Regul Homeost Agents. 2011 Oct-Dec;25(4):493-504. [PubMed: 22217983]

2.

Dijkmans BA, van Rijthoven AW, Goei Thè HS, Boers M, Cats A. Cyclosporine in rheumatoid arthritis. Semin Arthritis Rheum. 1992 Aug;22(1):30-6. [PubMed: 1411580]

3.

Shrestha BM. Two Decades of Tacrolimus in Renal Transplant: Basic Science and Clinical Evidences. Exp Clin Transplant. 2017 Feb;15(1):1-9. [PubMed: 27938316]

4.

Thiruvengadam NR, Forde KA, Chandrasekhara V, Ahmad NA, Ginsberg GG, Khungar V, Kochman ML. Tacrolimus and Indomethacin Are Safe and Effective at Reducing Pancreatitis After Endoscopic Retrograde Cholangiopancreatography in Patients Who Have Undergone Liver Transplantation. Clin Gastroenterol Hepatol. 2020 May;18(5):1224-1232.e1. [PubMed: 31622734]

5.

Ayer J, Young HS. Pimecrolimus for psoriasis. Expert Opin Pharmacother. 2013 Apr;14(6):767-74. [PubMed: 23461536]

6.

Rovin BH, Teng YKO, Ginzler EM, Arriens C, Caster DJ, Romero-Diaz J, Gibson K, Kaplan J, Lisk L, Navarra S, Parikh SV, Randhawa S, Solomons N, Huizinga RB. Efficacy and safety of voclosporin versus placebo for lupus nephritis (AURORA 1): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2021 May 29;397(10289):2070-2080. [PubMed: 33971155]

7.

Ponticelli C, Reggiani F, Moroni G. Old and New Calcineurin Inhibitors in Lupus Nephritis. J Clin Med. 2021 Oct 21;10(21) [PMC free article: PMC8584552] [PubMed: 34768354]

8.

Yilmaz DE, Kirschner K, Demirci H, Himmerkus N, Bachmann S, Mutig K. Immunosuppressive calcineurin inhibitor cyclosporine A induces proapoptotic endoplasmic reticulum stress in renal tubular cells. J Biol Chem. 2022 Mar;298(3):101589. [PMC free article: PMC8857494] [PubMed: 35033536]

9.

Schreiber SL, Crabtree GR. The mechanism of action of cyclosporin A and FK506. Immunol Today. 1992 Apr;13(4):136-42. [PubMed: 1374612]

10.

Mochizuki M, Masuda K, Sakane T, Ito K, Kogure M, Sugino N, Usui M, Mizushima Y, Ohno S, Inaba G. A clinical trial of FK506 in refractory uveitis. Am J Ophthalmol. 1993 Jun 15;115(6):763-9. [PubMed: 7685147]

11.

Jegasothy BV, Ackerman CD, Todo S, Fung JJ, Abu-Elmagd K, Starzl TE. Tacrolimus (FK 506)--a new therapeutic agent for severe recalcitrant psoriasis. Arch Dermatol. 1992 Jun;128(6):781-5. [PMC free article: PMC3208344] [PubMed: 1376102]

12.

Russell G, Graveley R, Seid J, al-Humidan AK, Skjodt H. Mechanisms of action of cyclosporine and effects on connective tissues. Semin Arthritis Rheum. 1992 Jun;21(6 Suppl 3):16-22. [PubMed: 1502562]

13.

Chen WR, Zhou YJ, Yang JQ, Liu F, Zhao YX, Sha Y. Melatonin Attenuates β-Glycerophosphate-Induced Calcification of Vascular Smooth Muscle Cells via a Wnt1/β-Catenin Signaling Pathway. Biomed Res Int. 2019;2019:3139496. [PMC free article: PMC6927024] [PubMed: 31886199]

14.

Sugianto RI, Schmidt BMW, Memaran N, Duzova A, Topaloglu R, Seeman T, König S, Dello Strologo L, Murer L, Özçakar ZB, Bald M, Shenoy M, Buescher A, Hoyer PF, Pohl M, Billing H, Oh J, Staude H, Pohl M, Genc G, Klaus G, Alparslan C, Grenda R, Rubik J, Krupka K, Tönshoff B, Wühl E, Melk A. Sex and age as determinants for high blood pressure in pediatric renal transplant recipients: a longitudinal analysis of the CERTAIN Registry. Pediatr Nephrol. 2020 Mar;35(3):415-426. [PubMed: 31811541]

15.

Prommer E. Calcineurin-inhibitor pain syndrome. Clin J Pain. 2012 Jul;28(6):556-9. [PubMed: 22673490]

16.

Schwartz RB, Bravo SM, Klufas RA, Hsu L, Barnes PD, Robson CD, Antin JH. Cyclosporine neurotoxicity and its relationship to hypertensive encephalopathy: CT and MR findings in 16 cases. AJR Am J Roentgenol. 1995 Sep;165(3):627-31. [PubMed: 7645483]

17.

Eidelman BH, Abu-Elmagd K, Wilson J, Fung JJ, Alessiani M, Jain A, Takaya S, Todo SN, Tzakis A, Van Thiel D. Neurologic complications of FK 506. Transplant Proc. 1991 Dec;23(6):3175-8. [PMC free article: PMC2964000] [PubMed: 1721398]

18.

Borda B, Nemes A, Lengyel C, Várkonyi T, Rárosi F, Keresztes C, Ottlakán A, Lázár G. [Risk factors for deterioration of liver functions after successful kidney transplantation]. Orv Hetil. 2019 Feb;160(5):186-190. [PubMed: 30686033]

19.

Saburi M, Kohashi S, Kato J, Koda Y, Sakurai M, Toyama T, Kikuchi T, Karigane D, Yuda S, Yamane Y, Hashida R, Abe R, Nakazato T, Hirahashi J, Ogata M, Okamoto S, Mori T. Effects of calcineurin inhibitors on sodium excretion in recipients of allogeneic hematopoietic stem cell transplantation. Int J Hematol. 2017 Sep;106(3):431-435. [PubMed: 28516402]

20.

Lopes PC, Fuhrmann A, Carvalho F, Sereno J, Santos MR, Pereira MJ, Eriksson JW, Reis F, Carvalho E. Cyclosporine A enhances gluconeogenesis while sirolimus impairs insulin signaling in peripheral tissues after 3 weeks of treatment. Biochem Pharmacol. 2014 Sep 01;91(1):61-73. [PubMed: 24960264]

21.

Song YH, Cai GY, Xiao YF, Wang YP, Yuan BS, Xia YY, Wang SY, Chen P, Liu SW, Chen XM. Efficacy and safety of calcineurin inhibitor treatment for IgA nephropathy: a meta-analysis. BMC Nephrol. 2017 Feb 13;18(1):61. [PMC free article: PMC5307812] [PubMed: 28193247]

22.

Pingili RB, Challa SR, Pawar AK, Toleti V, Kodali T, Koppula S. A systematic review on hepatoprotective activity of quercetin against various drugs and toxic agents: Evidence from preclinical studies. Phytother Res. 2020 Jan;34(1):5-32. [PubMed: 31617262]

23.

Zheng Q, Yang H, Liu W, Sun W, Zhao Q, Zhang X, Jin H, Sun L. Comparative efficacy of 13 immunosuppressive agents for idiopathic membranous nephropathy in adults with nephrotic syndrome: a systematic review and network meta-analysis. BMJ Open. 2019 Sep 11;9(9):e030919. [PMC free article: PMC6738938] [PubMed: 31511292]

24.

Abe S, Katsushima H, Fujishima F, Nomura J, Kameoka J, Ichinohasama R. A case study of t(14;22)(q32;q11) involving immunoglobulin heavy and light chain in follicular lymphoma. Int J Clin Exp Pathol. 2018;11(1):448-454. [PMC free article: PMC6957971] [PubMed: 31938130]

25.

Li HY, Zhang X, Zhou T, Zhong Z, Zhong H. Efficacy and safety of cyclosporine a for patients with steroid-resistant nephrotic syndrome: a meta-analysis. BMC Nephrol. 2019 Oct 23;20(1):384. [PMC free article: PMC6813125] [PubMed: 31646979]

26.

U.S. Multicenter FK506 Liver Study Group. A comparison of tacrolimus (FK 506) and cyclosporine for immunosuppression in liver transplantation. N Engl J Med. 1994 Oct 27;331(17):1110-5. [PubMed: 7523946]

27.

Ahn D, Robinson CA. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Oct 3, 2022. Pimecrolimus. [PubMed: 31424719]

28.

Wan XC, Dimov V. Pharmacokinetic evaluation of topical calcineurin inhibitors for treatment of allergic conjunctivitis. Expert Opin Drug Metab Toxicol. 2014 Apr;10(4):543-9. [PubMed: 24490943]

29.

Fontana F, Alfano G, Cappelli G. [The treatment of lupus nephritis, between consolidated strategies and new therapeutic options: a narrative review]. G Ital Nefrol. 2021 Aug 30;38(4) [PubMed: 34469086]

30.

Burckart GJ, Canafax DM, Yee GC. Cyclosporine monitoring. Drug Intell Clin Pharm. 1986 Sep;20(9):649-52. [PubMed: 3530679]

31.

Jensen SA, Dalhoff KP. Cyclosporine therapeutic drug monitoring. Transplant Proc. 2001 Sep;33(6):3003-5. [PubMed: 11543826]

32.

Su M, Hoffman RS, Nelson LS. Acute tacrolimus overdose without significant toxicity. J Toxicol Clin Toxicol. 2002;40(2):205-6. [PubMed: 12126198]

33.

Menter A, Gelfand JM, Connor C, Armstrong AW, Cordoro KM, Davis DMR, Elewski BE, Gordon KB, Gottlieb AB, Kaplan DH, Kavanaugh A, Kiselica M, Kivelevitch D, Korman NJ, Kroshinsky D, Lebwohl M, Leonardi CL, Lichten J, Lim HW, Mehta NN, Paller AS, Parra SL, Pathy AL, Prater EF, Rahimi RS, Rupani RN, Siegel M, Stoff B, Strober BE, Tapper EB, Wong EB, Wu JJ, Hariharan V, Elmets CA. Joint American Academy of Dermatology-National Psoriasis Foundation guidelines of care for the management of psoriasis with systemic nonbiologic therapies. J Am Acad Dermatol. 2020 Jun;82(6):1445-1486. [PubMed: 32119894]

Disclosure: Omar Safarini declares no relevant financial relationships with ineligible companies.

Disclosure: Chandana Keshavamurthy declares no relevant financial relationships with ineligible companies.

Disclosure: Preeti Patel declares no relevant financial relationships with ineligible companies.