Cyclosporine: Immunology, pharmacology and therapeutic uses

doi:10.1016/0039-6257(86)90035-4

Survey of Ophthalmology

Volume 31, Issue 3, November–December 1986, Pages 159-169

https://doi.org/10.1016/0039-6257(86)90035-4 Get rights and content

Abstract

Human and animal investigations since the mid-1970s have demonstrated the effectiveness of cyclosporine (CsA) as an immunosuppressive agent. In the area of transplantation immunity, it has been shown to enhance success of renal, bone marrow, and liver transplantation. Moreover, certain models of autoimmune disease have been effectively treated with CsA, and a number of studies have reported encouraging results with CsA therapy for ocular inflammatory disorders, notably Behçet's disease. The most serious side effects of CsA are nephrotoxicity and hypertension; thus, conservative dosages of the drug and careful monitoring of renal function during treatment are recommended. The purpose of this review is to provide clinicians and researchers with a clear perspective of both the potential benefits and shortcomings of this agent.

References (103)

C Bolton et al.
Immunosuppression by Cyclosporin A of experimental allergic encephalomyelitis
J Neurol Sci
(1982)
R.Y. Calne et al.
Cyclosporin A in patients receiving renal allografts from cadaver donors
Lancet
(1978)
C.C. Chan et al.
Kinetics of T-lymphocyte subsets in the eyes of Lewis rats with experimental autoimmune uveitis
Cell Immunol
(1985)
D.J. Coster et al.
Prolonged survival of corneal allografts in rabbits treated with cyclosporin A
Lancet
(1979)
H Dieperink et al.
Ketoconazole and cyclosporin (letter)
Lancet
(1982)
R.M. Ferguson et al.
Cyclosporine (CsA) in renal transplantation: a single institution experience
Am J Kidney Dis
(1985)
C.J. Green et al.
Extensive prolongation of rabbit kidney allograft survival after short term Cyclosporin A treatment
Lancet
(1978)
E Langhoff et al.
Rapid metabolism of cyclosporine and prednisone in kidney transplant patients receiving tuberculostatic treatment (letter)
Lancet
(1983)
A Laupacis et al.
Cyclosporin prevents diabetes in BB Wistar rats
Lancet
(1983)
R.B. Nussenblatt et al.
Cyclosporin A therapy in the treatment of intraocular inflammatory disease resistant to systemic corticosteroids and cytotoxic agents
Am J Ophthalmol
(1983)

R.B. Nussenblatt et al.

Standardization of vitreal inflammatory activity in intermediate and posterior uveitis

Ophthalmology

(1985)

R.B. Nussenblatt et al.

Treatment of intraocular inflammatory discase with Cyclosporin A

Lancet

(1983)

A.G. Palestine et al.

Laser interferometry and visual prognosis in uveitis

Ophthalmology

(1985)

A.G. Palestine et al.

Cyclosporine penetration into the anterior chamber and cerebrospinal fluid

Am J Ophthalmol

(1985)

A.G. Palestine et al.

Side effects of systemic cyclosporine in patients not undergoing transplantation

Am J Med

(1984)

R.L. Powles et al.

Cyclosporin A to prevent graft-versus-host disease in man after allogeneic bone marrow transplantation

Lancet

(1980)

J. Wallwork et al.

Cyclosporin and intravenous sulphadimidine and trimethoprim therapy (letter)

Lancet

(1983)

B Amor et al.

Ciclosporin in rheumatoid arthritis. Open trials with different dosages

K Atkinson et al.

Blood and tissue distribution of cyclosporine in humans and mice

T.A.G. Bell et al.

A placebo-controlled blind trial of cyclosporine-A in prevention of corneal graft rejection in rabbits

Br J Ophthalmol

(1982)

K Bendtzen et al.

Mechanism of action of Cyclosporine A

Scand J Immunol

(1984)

T Beveridge

Pharmacokinetics and metabolism of Cyclosporin A

T Beveridge et al.

Cyclosporin A: Pharmacokinetics after a single dose in man and serum levels after multiple dosing in recipients of allogeneic bone-marrow grafts

Curr Ther Res

(1981)

T Beveridge et al.

Lymphomas and lymphoproliferative lesions developing under cyclosporin therapy

Lancet

(1980)

H.M. Boisjoly et al.

Prophylactic topical Cyclosporine in experimental herpetic stromal keratitis

Arch Ophthalmol

(1984)

C Bolton et al.

The effect of Cyclosporin A on the adoptive transfer of experimental encephalomyelitis in the Lewis rat

Clin Exp Immunol

(1982)

J.F. Borel et al.

Biological effects of Cyclosporin A: A new antilymphocytic agent

Agents and Actions

(1976)

J.F. Borel

The history of cyclosporine A and its significance

J.F. Borel et al.

Cyclosporine: Speculation about its mechanism of action

D Bunjes et al.

Cyclosporin A mediates immunosuppression of primary cytotoxic T-cell responses by impairing the release of interleukin 1 and interleukin 2

Eur J Immunol

(1981)

G.J. Burckart et al.

Cyclosporin A blood concentrations in a child after intravenous and oral therapy (abstracted)

Drug Intell Clin Pharm

(1983)

R.Y. Calne et al.

Cyclosporin A — A powerful immunosuppressant in dogs with renal allografts

IRCS Med Sci

(1977)

C.C. Chan et al.

Cyclosporine-induced alterations of humoral response in experimental autoimmune uveitis

Invest Ophthalmol Vis Sci

(1984)

G.A. DosReis et al.

Effect of Cyclosporin A on T-cell function in vitro: The mechanism of suppression of T cell proliferation depends on the nature of the T cell stimulus as well as the differentiation state of the responding T cell

J Immunol

(1982)

J Dupre et al.

Effects of Ciclosporin on insulin secretion in recent onset type 1 diabetes mellitus

J.F. Elliott et al.

Induction of interleukin 2 messenger RNA inhibited by Cyclosporin A

Science, Dec

(1984)

S.M. Flechner et al.

The nephrotoxicity of cyclosporine in renal transplant recipients

F.M. Graham et al.

Cyclosporin A in the treatment of posterior uveitis

Trans Ophthalmol Soc UK

(1985)

B.M. Hall et al.

Suppressor T cells in rats with prolonged cardiac allograft survival after treatment with Cyclosporine

Transplantation

(1984)

A.D. Hess et al.

Effect of Cyclosporin A on human lymphocyte responses in vitro. II. Induction of specific alloantigen unresponsiveness mediated by a nylon wool adherent suppressor cell

J Immunol

(1981)

P.C. Hiestand et al.

Comparison of the pharmacological profiles of cyclosporine, (NVA²)-cyclosporine and (VAL²) Dihydro-cyclosporine

Immunology

(1985)

F. Hoffmann et al.

Lokale Behandlung des hornhaut Transplantates beim Menscheu mit Cyclosporin A

Klin Monatsbl Augenheilkd

(1985)

P.A. Hunter et al.

Cyclosporin A applied topically to the recipient eye inhibits corneal graft rejection

Clin Exp Immunol

(1981)

I.F. Hutchinson et al.

Cyclosporin A spares selectively lymphocytes with donor specific suppressor characteristics

Transplantation

(1981)

M Jones et al.

Prolongation of life in female $NZB NZW$ (Fi) hybrid mice by ciclosporin A

Clin Exp Immunol

(1985)

J.S. Kana et al.

Rabbit corneal allograft survival following topical administration of cyclosporin A

Invest Ophthalmol Vis Sci

(1982)

Y Kaufman et al.

Mechanism of action of Cyclosporin A: Inhibition of lymphokine secretion studied with antigen-stimulated T-cell hybridomas

J Immunol

(1984)

M.S. Kennedy et al.

Acute renal toxicity with combined use of amphotericin B and cyclosporine after marrow transplantation

Transplantation

(1983)

P.A. Keown et al.

The effects and side effects of cyclosporine: Relationship to drug pharmacokinetics

Transplant Proc

(1982)

P.A. Keown et al.

The clinical relevance of cyclosporine blood levels as measured by radioimmunoassay

Transplant Proc

(1983)

Cited by (161)

Whitcup and Nussenblatt’s Uveitis: Fundamentals and Clinical Practice
2021, Whitcup and Nussenblatt's Uveitis: Fundamentals and Clinical Practice
Formulations and toxicologic in vivo studies of aqueous cyclosporin A eye drops with cyclodextrin nanoparticles
2017, International Journal of Pharmaceutics
Citation Excerpt :
Cyclosporin A (CyA) is an immunosuppressive peptide that has proved useful for patients with dry eye syndrome (DES) (Di Tommaso et al., 2012; Nussenblatt and Palestine, 1986; Tatlipinar and Akpek, 2005).
Cyclosporin A (CyA) is an immunosuppressive drug used topically to treat ocular inflammatory disorder such as dry eye disease (DES). It is a lipophilic cyclic peptide with molecular weight of 1202.6 Da. The aim of this study was to develop surfactant free aqueous 0.2% (w/v) CyA eye drops where the drug is present in an aqueous vehicle containing CyA/cyclodextrin (CyA/CD) nanoparticles and then do three-month toxicological testing in rabbits. Five formulations of different CD concentrations were studied, all of them contained 12.5% (w/v) of α-cyclodextrin (αCD) and various amounts of γ-cyclodextrin (γCD) (ranging from 0 to 12.5% w/v). αCD was used to solubilize the drug and γCD to promote formation of complex aggregates. CyA/CD complex aggregates were formed in all the formulations tested. However, the formulation containing 12.5% (w/v) αCD and 12.5% (w/v) γCD created more CyA/CD nanoparticles of suitable size and was therefore tested in vivo. The eye drops did not cause ocular irritation or toxic side effects upon topical administration to rabbits once or twice a day for three months.
Solvent-free protamine nanocapsules as carriers for mucosal delivery of therapeutics
2017, European Polymer Journal
Citation Excerpt :
Rational design and choice of excipients provided a nanosized carrier for efficient drug solubilization. Cyclosporin A is a calcineurin inhibitor that down-regulates interleukin-2 expression and T-cell activity and is frequently used to prevent rejection after organ transplantations as well as to treat a number of autoimmune disorders [32]. However, the low aqueous solubility is the main obstacle to the efficient CsA delivery, emphasizing the need for lipid-based dosage forms [33].
Local delivery of drugs and biopharmaceuticals for the treatment of inflammatory bowel disease remains a challenge. Innovative nanomedicines with appropriate properties raise the possibility of efficient drug targeting. Hence, the overall aim of this study was to develop and characterize a protamine-based nanosystem for topical delivery of therapeutics to inflamed intestinal mucosa following oral administration. Protamine nanocapsules with a new composition were for the first time prepared by a self-emulsifying process, without the use of organic solvents or heat. A model lipophilic anti-inflammatory agent, cyclosporin A (CsA), was encapsulated in the oily core of these nanocarriers. The CsA-loaded formulation was isolated from the free drug by gel filtration and the entrapment efficiency was determined using reverse phase high-performance liquid chromatography (HPLC). Protamine nanocapsules had sizes within the range of 160–180 nm, with low polydispersity index (0.2) and positive surface charge, together with high entrapment efficiency (95%) and drug loading capacity (5%). The nanocapsules exhibited good stability in storage both as an aqueous suspension and as a freeze-dried powder. Nanocapsules also preserved their colloidal stability in simulated intestinal media. In vitro studies performed with the Jurkat human T lymphocyte cell line showed that CsA-loaded protamine nanocapsules are more efficient than the commercial Sandimmune Neoral^® formulation at reducing IL-2 secretion (^γγp < 0.01). At the same time, nanocapsules showed no toxic effects on the cells. The results discussed herein indicate the feasibility of the developed nanosystem to serve as a potential carrier for cyclosporin A administration.
Topical cyclosporin A 0.05% eye drops for management of symptomatic acquired punctal stenosis: a prospective, controlled clinical study
2024, Orbit (London)
Cyclosporine A Delivery Platform for Veterinary Ophthalmology—A New Concept for Advanced Ophthalmology
2022, Biomolecules
Adamantiades-Behc¸et's Disease
2022, Albert and Jakobiec's Principles and Practice of Ophthalmology: Fourth Edition

View all citing articles on Scopus

View full text

Therapeutic reviewCyclosporine: Immunology, pharmacology and therapeutic uses

Abstract

J Neurol Sci

Lancet

Cell Immunol

Lancet

Lancet

Am J Kidney Dis

Lancet

Lancet

Lancet

Am J Ophthalmol

Ophthalmology

Lancet

Ophthalmology

Am J Ophthalmol

Am J Med

Lancet

Lancet

Ciclosporin in rheumatoid arthritis. Open trials with different dosages

Blood and tissue distribution of cyclosporine in humans and mice

A placebo-controlled blind trial of cyclosporine-A in prevention of corneal graft rejection in rabbits

Br J Ophthalmol

Mechanism of action of Cyclosporine A

Scand J Immunol

Pharmacokinetics and metabolism of Cyclosporin A

Cyclosporin A: Pharmacokinetics after a single dose in man and serum levels after multiple dosing in recipients of allogeneic bone-marrow grafts

Curr Ther Res

Lymphomas and lymphoproliferative lesions developing under cyclosporin therapy

Lancet

Prophylactic topical Cyclosporine in experimental herpetic stromal keratitis

Arch Ophthalmol

The effect of Cyclosporin A on the adoptive transfer of experimental encephalomyelitis in the Lewis rat

Clin Exp Immunol

Biological effects of Cyclosporin A: A new antilymphocytic agent

Agents and Actions

The history of cyclosporine A and its significance

Cyclosporine: Speculation about its mechanism of action

Cyclosporin A mediates immunosuppression of primary cytotoxic T-cell responses by impairing the release of interleukin 1 and interleukin 2

Eur J Immunol

Cyclosporin A blood concentrations in a child after intravenous and oral therapy (abstracted)

Drug Intell Clin Pharm

Cyclosporin A — A powerful immunosuppressant in dogs with renal allografts

IRCS Med Sci

Cyclosporine-induced alterations of humoral response in experimental autoimmune uveitis

Invest Ophthalmol Vis Sci

Effect of Cyclosporin A on T-cell function in vitro: The mechanism of suppression of T cell proliferation depends on the nature of the T cell stimulus as well as the differentiation state of the responding T cell

J Immunol

Effects of Ciclosporin on insulin secretion in recent onset type 1 diabetes mellitus

Induction of interleukin 2 messenger RNA inhibited by Cyclosporin A

Science, Dec

The nephrotoxicity of cyclosporine in renal transplant recipients

Cyclosporin A in the treatment of posterior uveitis

Trans Ophthalmol Soc UK

Suppressor T cells in rats with prolonged cardiac allograft survival after treatment with Cyclosporine

Transplantation

Effect of Cyclosporin A on human lymphocyte responses in vitro. II. Induction of specific alloantigen unresponsiveness mediated by a nylon wool adherent suppressor cell

J Immunol

Comparison of the pharmacological profiles of cyclosporine, (NVA2)-cyclosporine and (VAL2) Dihydro-cyclosporine

Immunology

Lokale Behandlung des hornhaut Transplantates beim Menscheu mit Cyclosporin A

Klin Monatsbl Augenheilkd

Cyclosporin A applied topically to the recipient eye inhibits corneal graft rejection

Clin Exp Immunol

Cyclosporin A spares selectively lymphocytes with donor specific suppressor characteristics

Transplantation

Prolongation of life in female NZBNZW (Fi) hybrid mice by ciclosporin A

Clin Exp Immunol

Rabbit corneal allograft survival following topical administration of cyclosporin A

Invest Ophthalmol Vis Sci

Mechanism of action of Cyclosporin A: Inhibition of lymphokine secretion studied with antigen-stimulated T-cell hybridomas

J Immunol

Acute renal toxicity with combined use of amphotericin B and cyclosporine after marrow transplantation

Transplantation

The effects and side effects of cyclosporine: Relationship to drug pharmacokinetics

Transplant Proc

The clinical relevance of cyclosporine blood levels as measured by radioimmunoassay

Transplant Proc

Therapeutic review
Cyclosporine: Immunology, pharmacology and therapeutic uses

Comparison of the pharmacological profiles of cyclosporine, (NVA²)-cyclosporine and (VAL²) Dihydro-cyclosporine

Prolongation of life in female $NZB NZW$ (Fi) hybrid mice by ciclosporin A