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Prog. Allergy, vol. 38, pp.9-18 (Karger, Basel 1986)
Editorial: Ciclosporin and Its Future
J.F. Borel
Preclinical Research, Sandoz Ltd., Basel, Switzerland
Das Närrische Ist, dass jeder glaubt,
überliefern zu müssen,
was man gewusst zu haben glaubt.
The strange thing is that everyone feels
obliged to pass on
what he believes he knows.
J.W. Goethe: Gedanken zur Naturforschung
When Prof. P. Kall s asked me to edit a comprehensive book on ciclosporin (CS) for the series Progress in Allergy, I felt rather reluctant to agree
to his request. Why should a further addition be made to the already much
too prolific and overabundant literature on this subject? However, while
drafting a letter of refusal, I came to realize a number of points which led to
a reconsideration of this decision.
Firstly, the book Cyclosporin A [ 1 ] resulting from the memorable symposium held at Cambridge (UK) in September 1981 is largely outdated.
Secondly, the more recent proceedings of the very successful First International Congress on Ciclosporin [2] held in Houston, Tex., in May 1983 contain an impressive wealth of information but, because they consist of progress report papers, an outside reader will have difficulty in obtaining an
overall view. Moreover, some important developments have occurred since
their publication. Thirdly, the number of publications per year — about 700
— is beyond the assimilation capacity of any individual (fig. 1). It becomes
increasingly difficult to select the relevant papers from this flood of literature
and to form a personal opinion from the many contradictory reports. The
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Why a New Book on Ciclosporin?
10
Borel
10000
-- 700
76 77 78 79 80 81 82 83 84
Number of publications pe year
spread of CS into widely different fields often causes information to be dispersed and incompletely accessible.
It is obvious that there are many ways to conceive a book on CS. The
concept of the present book is that it should be comprehensive, concise and
readable. Each chapter should review and summarize a major topic and cite
only the main references, in order to facilitate further reading. The editorial
policy was to seek the collaboration of highly qualified experts in their respective areas and to give them entire freedom; editorial activity being restricted
to answering queries and avoiding repetitious accounts. The authors were
urged to give a balanced view of the whole subject in a limited number of
pages. Each chapter, therefore, tries to inform the reader briefly and exhaustively about the present state of the art in his particular field. This is the type
of book that is needed most today.
It should be added that more specialized proceedings of the First International Symposium on Ciclosporin in Autoimmune Diseases organized by
Sandoz Ltd. in March 1985 in Basel [3], of the Workshop on the Management
of Cyclosporine-Induced Renal Dysfunction held in the same month in
Puerto Rico [4], and of an International Workshop on Experimental Ciclosporin Nephrotoxicity held in April 1985 in Basel [5] are in press.
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Fig. 1. The growing numbers of publications on cic!osporin over the years are represented
on a logarithmic scale. The first papers appeared in late 1976, i.e. 4 years after the discovery of
the immunosuppressive properties and more than 6 years after the soil sample was taken.
Ciclosporín and Its Future
11
Spelling of Generic Name
The spelling of the compound has unfortunately led to great confusion.
For many years the name cyclosporin A was used in the scientific literature.
Sandoz' original request to the World Health Organisation (WHO) for an
International Nonproprietary Name (INN) was for cyclosporin A. Sandoz
amended it to cyclosporin (first choice) and ciclosporin (second choice) when
it was learnt that the United States Adopted Name (USAN) Council had
proposed these two names, and the WHO refused to accept isolated letters
ín an INN. The WHO then decided on ciclosporin and the USAN Council
on cyclosporine. The British Pharmacopoeia (BP) Commission some months
later proposed cyclosporin as British Approved Name (BAN) and, in spite
of Sandoz' own request to change the name in order to make it identical to
either the INN or the USAN, refused to modify it. Moreover, the name is
spelt ciclosporine in French and ciclosporina in Spanish. Since this book is
being published in Europe, the generic name ciclosporin (CS) proposed by
WHO will be used. In the chapters dealing with chemistry and derivatives,
however, the original form cyclosporin, which is still used by Chemical
Abstracts, has been preferred.
Finally, the trade name worldwide is Sandimmun®, except for North
America where it is spelt Sandimmune®.
The tortuous history of CS, starting with the soil sample from the Hardanger Vidda in Norway (fig. 2) from which the CS-producing fungus was
grown, has attracted the attention of numerous journalists and writers. A first
personal version of our early experience with CS was presented at Cambridge
[6] and later an extended account of the `Historical Perspectives' appeared
as a separate chapter in the Houston Proceedings [7].
The first pharmacological paper on CS [8] was written by four authors
and was listed as a citation classic in Current Contents [9]. The chapter on the
`Historical Background' by Dr. H. Stahelin, one of the co-authors of the early
papers [8, 10], gives an exhaustive review of the development leading to the
discovery of CS. The Immunology Unit was part of the Cell Biology Section
of which he was the head. This chapter clearly demonstrates the pivotal role
played by scientists from Sandoz Ltd. in the development of CS until its reg-
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Historical Background
Borel
12
ístration as a drug, and justifies the writing of several chapters by specialists
from this firm.
It should also be mentioned here that CS was awarded two Prix Gallien
in 1984 (France and Belgium), the highest distinction a drug may receive.
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Fig. 2. The Hardanger Vidda is situated in the southern part of Norway, east of the Hardangerfjord. It forms the largest highland plateau in Europe, with an area of 7,500 km2 at an
altitude of 1,000-1,200 m. The Vidda is a vast and untouched primeval landscape, whose face
changes continually with the interplay of light and dark, sun and shadow, sky and rocks, lakes
and streams, mosses, lichens, and treeless grassland. Hills and a few mountains dominate the
plateau, which has neither dales nor glens. The gneiss boulders still lie where the glacier
deposited them aeons ago. Arrowheads and traps belonging to early hunters have been found
and dated back 7000 years (Photograph by Ernst Scagnet, Lucerne, Switzerland).
Ciclosporin and Its Future
13
The main interest in CS was at first almost exclusively focused on its
immunosuppressive effect and on its potential as a promising drug in organ
transplantation. Despite the fact that in the pre-cíclosporín era a few
transplantation centers were already achieving exceptional 1-year kidney
graft survival rates of 80% and more, it should be remembered that the overall
figure barely reached 50%. With other organs the results were so disappointing that they were either almost abandoned or considered as experimental
procedures (e.g. heart, liver, pancreas, lung). The long-term side effects of
corticosteroids and cytostatic drugs, the latter especially on hematopoietic tissues, were considerable and constituted a limiting factor for further advancement.
Because the surgical techniques of organ replacement had achieved
remarkable progress, the need for superior immunosuppressive measures
was desperately felt. While antilymphocyte serum, or later antithymocyte
globulin, proved to be highly effective in short-term prevention or reversal
of a rejection crisis, it is of limited value for long-term treatment because it
induces sensitization to foreign antibodies. With its selective and reversible
inhibition of the immunocompetent T lymphocyte, CS can be regarded as the
forerunner of a new generation of immunosuppressive drugs. This explains
its immediate impact in this field and perhaps the raising of disproportionate
hopes. Indeed, we are still in the process of evaluating its optimal use, debating its merits as a single drug or in combination with other compounds to
obtain synergistic effects and thereby to minimize undesirable side effects.
The benefit of switching patients from CS treatment to conventional
immunosuppression, i.e. mainly to azathioprine and steroids, or vice versa,
is still being discussed. The advent of CS has led to a revival in the field of
transplantation and, as a consequence, to an aggravation of the problem of
organ procurement.
Although CS has so far been registered in over 20 countries exclusively
for transplantation, its potential in autoimmune diseases as an investigational new drug is currently being assessed [11]. As mentioned above, the
proceedings of the First International Symposium on Ciclosporin in Autoimmune Diseases are due to appear soon [3]. It was felt, however, that a chapter,
written by Dr. M. Schmitz, which gives an overview of that symposium and
draws the main conclusions should be included here. Another comprehensive paper presenting CS as a new approach to therapy of autoimmune diseases, based mainly on experimental models, is in press [12]. Although the
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Α Novel Immunosuppressive Drug
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prospects are relatively encouraging, the events leading to autoimmunity are
so varied, and in most instances still poorly understood, that more controlled
and long-term clinical studies need to be performed before the usefulness of
CS can be firmly established in such conditions.
To assess the optimal use of a drug we need to know its mechanism of
action. Important progress has recently been achieved in unravelling the
molecular biology of lymphocyte activation, proliferation and maturation;
however, it is still far from being completely understood. Because of the
undeniable selectivity of CS for lymphocytes, the most promising approach
for uncovering its mode of action would focus on the cellular functions which
are peculiar to the lymphocyte and distinct from other more general events
occurring during cell activation. In spite of the many efforts which have substantially advanced our knowledge, large gaps still need to be filled before
we understand it satisfactorily [13]. This is the reason why several chapters
were devoted to this crucial topic.
Meanwhile, it turned out that CS itself ís a most valuable tool for investigating the events leading to an immune response as well as for studying the
role of T cells in a number of biological models. Numerous examples of this
compound being used both as a drug and as an immunological tool are given
in the Proceedings of the Houston Congress [2].
Of particular interest were the results obtained with CS in experimental
infectious models to assess the involvement of the T lymphocytes [for a
review, see ref. 7]. Unexpectedly, it was discovered that this agent had per se
a remarkable antiparasitic activity in animals infected with plasmodia [ 14,
15], schistosomes [16-18] and, very recently, leishmania [19] and strongyloides [19a]. Since it could additionally be shown that the antiparasitic effect
was apparently independent of immunosuppression, the role of T lymphocytes might be negligible. On the other hand, the use of CS demonstrated the
importance of T cells in trypanosomiasis, since the severity of parasitosis significantly-increased in the treated mice [20]. Other parasitic models are currently under investigation.
It is difficult to envisage the use of CS proper as an antiparasitic agent
in humans. However, some interesting conclusions can be drawn from the
Workshop on Antiparasitic Effects of CS and Its Analogues held in February
1985 in Basel. There is a direct inhibitory effect on Coccidioides immitis of
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A New Investigational Tool
Ciclosporin and Its Future
15
CS and certain congeners both in vitro and in vivo [21]. In malaria, schistosomiasis and leishmaniasis, however, there is convincing evidence that CS and
some of its derivatives exert a novel type of host-mediated action, which only
indirectly affects the parasites, and renders the drug-treated animals resistant
to later attempts at reinfection. Several laboratories around the world are
actively pursuing the study of this potential new antiparasitic mechanism.
To cut a long story short, let us speculate on what the future prospects
of CS research might be.
(1) CS has opened new perspectives in the field of transplantation. New
developments are often the target of bitter criticisms, but once successfully
performed, are soon accepted by the same critics as everyday practice. Heart
transplantation is such an example. The main efforts in transplantation surgery aim at demonstrating the feasibility of allogeneic limb and skin replacement, the latter in severely burned patients. Another indication may comprise the use of concordant xenogeneic organs in instances where a human
organ is unlikely to be available.
(2) Autoimmunity is a phenomenon characterized by the dysfunction of
the immune system; however, the causes leading to such an unbalanced state
are manifold. It can therefore reasonably be expected that CS might prove
of therapeutic value in at least some conditions among this heterogeneous
group of diseases. In a first step the indications in which an effect can be
shown should be listed and, in a second step, it should be conclusively
demonstrated that this effect is indeed beneficial. Long-term and controlled
clinical studies are needed.
(3) The optimal use of CS in transplantation as well as in autoimmunity
is still debated. It appears that unnecessarily high doses of the drug have often
been used in the past and that a number of side effects can today be decreased
by appropriately reducing the dosage. The development of monoclonal antibodies to CS will replace the radioimmunoassay for measuring drug blood
levels by a more specific test in which unchanged CS can be distinguished
from its metabolites. The combination of CS with other immunosuppressive
drugs or measures could elicit synergistic effects and further improve its
therapeutic prospects. However, caution must prevail since some drug
interactions may also induce deleterious effects due to altered drug metabolism, overimmunosuppression, etc.
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Future Prospects
16
(4) Like most potent drugs, CS is not devoid of side effects, the most worrying being nephrotoxicity. Acute nephrotoxicity in patients usually
responds to dose reduction. Moreover, this condition can be studied in
relevant animal models. The occasional chronic nephrotoxicity resulting in
irreversible interstitial fibrosis is, however, a serious problem, especially since
all attempts to create a reliable experimental model for assessing this type of
nephrotoxicity have consistently failed [5]. This handicap renders further
progress in the search either for new modalities or for a congener without
nephrotoxicity most difficult [22, 23]. Many years of hard work have resulted
in the development of (Ννα2)-CS (formally called cyclosporin G) [24, 25]
which will soon be undergoing clinical trials.
(5) Research is also being pursued in another direction, i.e. the search
for derivatives differing from CS in their pharmacological profile. Interesting
results have been obtained with (Va12)dihydro-CS [25, 26] which is currently
being investigated in a clinical pilot study in Basel. This compound exerts
marked anti-inflammatory effects in chronic inflammation and in some
autoimmune animal models. Its suppression of the cell-mediated response
seems to be confined to the hypersensitivity reaction, whilst the humoral
response is little affected. However, our experience in the search for more
specific congeners has been disappointing and indicates that these possibilities may be limited.
(6) The study of CS analogues possessing antiparasitic properties but
devoid of immunosuppressive activity is perhaps not of immediate practical
value. However, their indirect, i.e. host-mediated, antiparasitic effect might
uncover new insights into the body's defense mechanism against certain
parasites. The most promising analogues possess marked anti-inflammatory
activity in chronic inflammation but compared with CS very weak
immunosuppression in tests for antibody production and in various other
models for cellular immunity. The host-mediated antiparasitic action and the
resistance to later reinfection that they confer on the treated animals will be
the effects that deserve the most scientific attention.
(7) Finally, the ultimate goal of immunosuppression is to achieve antigen-specific tolerance. With possible exceptions (see chapters by Dr. C. Green
and Dr. Κ Lafferty et al.), CS itself does not fulfil this task nor is it likely to
restore a defective immune system in autoimmunity, although it might be
very useful as a palliative treatment. However, it should be borne in mind
that, in conjunction with future developments in immunopharmacology, CS
could become part of a more subtle and complex immunoregulatory protocol
through which tolerance or immune restoration might be achieved.
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Borel
Ciclosporin and Its Future
17
These loose speculations illustrate how diversified the scientific and clinical specialities using CS have become. During the editing of this book it was
suddenly realized that this could be the last attempt to cover the whole subject
in one volume. It is certainly the hope of all the authors that their efforts have
contributed to creating a practical and useful guide for several years to come
in the jungle of what might be called `ciclosporinology'.
Acknowledgements
Numerous people have participated in various ways in this volume on
CS. It has given me particular pleasure that no one who was asked for a contribution has refused his help. Because of their heavy workloads, many
authors could only fulfil their additional task by generously agreeing to make
an extra effort. I wish here to express to all contributors, in whatever way they
have responded to my requests, my sincere gratitude and appreciation of
their competence and unfailing enthusiasm. This rewarding undertaking,
which scared me a good deal to start with, has been brought to a happy end.
It is the wish of all of us that it will blossom for a long season, that it will attract
a wide readership, and that its reading may be both useful and enjoyable.
These are our hopes; the judgement will be the reader's.
1 White, D.J.G.: Cyclosporin A (Elsevier Biomedical Press, Amsterdam 1982).
2 Kahan, B.D.: Cyclosporine: Biological activity and clinical applications (Grune & Stratton, Orlando 1984).
3 Schindler, R. Ciclosporin in autoimmune diseases (Springer, Heidelberg, in press, 1985).
4 Kahan, B.D.; Bennet, W.: Cyclosporine-induced renal dysfunction. Transplant. Proc. (in
press, 1985).
5 Thiel, G.; Mihatsch, M.: International workshop on experimental ciclosporin nephrotoxicity. Clin. Nephrol. (in press).
6 Borel, J.F.: History of cyclosporin A and its significance in immunology; in White, Cyclosporin A, pp. 5-17 (Elsevier Biomedical Press, Amsterdam 1982).
7 Borel, J.F.: Cyclosporine: historical perspectives. Transplant. Proc. 15: suppl.1, pp.
2219-2229 (1983).
8 Borel, J.F.; Feurer, C.; Gubler, H.U.; Stähelin, H.: Biological effects of cyclosporin A: a
new antilymphocytic agent. Agents Actions 6: 468-475 (1976).
9 Anonymous: This week's citation classic. Curr. Cont. 27 6: 16 (1984).
10 Borel, J.F.; Feurer, C.; Magnée, C.; Stähelin, H.: Effects of the new anti-lymphocytic peptide cyclosporin A in animals. Immunology 32: 1017-1025 (1977).
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References
Borel
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Editorial: Cyclosporin in autoimmune disease. Lancet i: 909-911 (1985).
Borel, J.F.; Gunn, H.C.: Cyclosporine as a new approach to therapy of autoimmune diseases. Ann. N.Y. Acad. Sci. (in press).
13 Borel, J.F.; Ryffel, B.: The mechanism of action of ciclosporin - A continuing puzzle; in
Schindler, Ciclosporn in autoimmune diseases (Springer, Heidelberg, in press, 1985).
14 Thommen-Scott, K.: Antimalarial activity ofcyclosporin A. Agents Actions I1: 770-773
(1981).
I5 Nickell, S.P.; Scheibel, L.W.; Cole, G.A.: Inhibition by cyclosporin A of rodent malaria
in vivo and human malaria in vitro. Infect. Immunity 37: 1093-1100 (1982).
16 Bueding, B.E.; Hawkins, J.; Cha, Y.-Ν.: Antischistosomal effects ofcyclosporin A. Agents
Actions 11: 380-383 (1981).
17 Bout, D.T.; Deslee, D.; Capron, A.R.: Protection against schistosomiasis produced by
cyclosporin A. Am. J. trop. Med. Hyg. 33: 185-186 (1984).
18 Nilsson, L.-Å.; Lindblad, R.; Oiling, S.; Ouchterlony, Ö.: The effect of cyclosporin A on
the course of murine infection by Schistosoma monsoni. Parasite Immunol. 7: 19-27
(1985).
19 Behforouz, N.C.: Effect of cyclosporine and an analogue on Leishmania tropico in mice
(personal communication).
19a Schad, G.A.: Cyclosporine may eliminate the thread of overwhelming strongyloidosis in
immunosuppressed patients. Lancet (in submission).
20 Kierszenbaum, F.; Gottlieb, C.A.; Budzko, D.B.: Exacerbation of Trypanosome cruzi
infection in mice treated with the immunoregulatory agent cyclosporin A. Tropenmed.
Parasitol. 34: 4-6 (1983).
21 Kirkland, T.N.; Fierer, J.: Cyclosporin A inhibits Coccidioides immitis in vitro and in vivo.
Antimicrob. Agents Chemother. 24: 921-924 (1983).
22 Siegl, H.; Ryffel, B.; Petric, R.; Shoemaker, P.; Muller, A.; Donatsch, P.; Mihatsch, M.:
Cyclosporine, the renin-angiotensin-aldosterone system, and renal adverse reactions.
Transplant. Proc. 15: 2535-2537 (1983).
23 Ryffel, B.; Siegl, H.; Mueller, A.-M.; Hauser, R.; Mihatsch, M.J.: Nephrotoxicity of
cyclosporine ín spontaneously hypertensive rats. Transplant. Proc. 17: 1430-1431 (1985).
24 Hiestand, P.C.; Gunn, H.; Gale, J.; Siegl, H.; Ryffel, B.; Donatsch, P.; Borel, J.F.: The
immunosuppressive profile of a new natural cyclosporine analogue: (Ννα2)-cyclosporine.
Transplant. Proc. 17: 1362-1364 (1985).
25 Hiestand, P.C.; Gunn, H.C.; Gale, J.M.; Ryffel, B.; Borel, J.F.: Comparison of the pharmacological profiles of cyclosporine, (Νva2)-cyclosporine and (Va12)dihydro-cyclospοrine. Immunology 55: 249-255 (1985).
26 Borel, J.F.; Gubler, H.U.; Hiestand, P.C.; Wenger, R.M.: Immunological properties of
cyclosporine (Sandimmunea) and (Va12)dihydro-cyclosporine and their prospect in
chronic inflammation; in Adv. Inflammation Res. (in press).
Prof. J.F. Borel, Preclinical Research, Sandoz Ltd., CH-4002 Basel (Switzerland)
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