Ital J Gastroenterol 1992; 24 : 355-360
`EDITORIALS & REVIEWS
`
`FK 506: a new immunosuppressive agent for organ transplantation.
`Pharmacology, mechanism of action and clinical applications
`
`S FAGIUOLI 1, A GASBARRINI 2, A AZZARONE 3, A FRANCAVILLA 4, DH VAN THIEL
`Department of Surgery, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA
`
`Control of the immune response directed at the allograft is
`the ultimate goal of the immunosuppression utilized to
`achieve a successful organ transplant. The initial approach to
`immunosuppression was the use of high doses of glucocor-
`ticoids, often in combination with cytotoxic agents such as
`azathioprine and/or cyclophosphamide (1-3). In 1976, fol-
`lowing the discovery of the T cell specific immunosuppres-
`sant Cyclosporine A (CsA) (4), the immunosuppressive
`therapy utilized at transplant centers entered a new era. A
`large number of both basic and clinical studies demonstrated
`a dramatic improvement in the outcome of whole organ
`transplantation, both in terms of allograft survival and patient
`quality of life with such agents. Despite this major step for-
`ward, the failure to completely control the rejection process
`in some patients and the presence of side effects, such as
`nephrotoxicity (5), hypertension (6-8), hepatotoxicity (6-8),
`diabetogenicity (6-8), central nervous system dysfunction (6-
`8), have remained as troublesome problems associated with
`the use of immunosuppressive therapy required for continued
`organ engraftment. Since the introduction of CsA, many
`studies have been performed in an effort to identify new and
`more powerful immunosuppressive agents which would fur-
`ther improve allograft acceptance (tolerance) without induc-
`ing the toxic side effects of existing immunosuppressive
`agents.
`One of these new agents, FK 506, an hydrophobic antibiotic
`of the macrolide family (Fig. 1), was isolated in 1985, in
`Japan, by the Fujisawa Pharmaceutical Company from a fer-
`
`mentation broth of a soil organism, Streptomyces
`Tsukubaensis (9,10). Initial in vitro and in vivo studies
`demonstrated that FK 506 was effective in suppressing the
`immune response having an ED50 of approximately 0.1 nM,
`which is close to 100 times more active than Cyclosporine A
`in similar: assays (10-14).
`Subsequent studies have demonstrated that FK 506 success-
`fully inhibits hepatic (15,16), renal (17), small intestine (18)
`and cardiac (15,19) rejection in animal models of organ
`transplantation (20). Since these early studies were reported
`many additional biochemical and immunological studies
`have been perfOlmed to assess the clinical usefulness of this
`new drug (21). Beside the immunological activity, FK 506
`and CsA have shown powerful hepatotrophic properties both
`in "in vivo" and "in vitro" experiments (22,23).
`
`BIOCHEMICAL SITE OF ACTION
`FK 506, like CsA and Rapamycin (another new immunosup-
`pressive agent that also inhibits T cell activation at con-
`
`FK506
`
`12
`
`Address for correspondence: Dr. S Fagiuoli, Department of
`Surgery, School of Medicine, University of Pittsburgh, 3601 Fifth
`Avenue, Falk Clinic 5c, Pittsburgh, PA 15213, USA
`
`Me" "
`18
`
`1 Visiting Fellow from the Divisione di Gastroenterologia, Univer-
`sita di Padova, Italy
`2 Visiting Fellow from Patologia Medica, Universita di Bologna,
`Italy
`3 Visiting Fellow from the Divisione di Gastroenterologia, Univer-
`sita di Bari, Italy
`4 Visiting Professor from the Divisione di Gastroenterologia,
`Universita di Bari, Italy
`
`Accepted for publication: 30 March 1992
`
`Fig. 1. Structure of FK 506.
`
`Me
`
`Me
`
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`S FAGIUOL! et al : FK 506: a new immunosuppressive agent
`
`centrations comparable to those of FK 506), binds with high
`affinity to cytoplasmic receptors termed immunophillins (im-
`munosuppressant binding proteins). The predominant
`cytosolic FK 506 binding protein is termed FKBP. It has been
`isolated and structurally characterized by Schreiber et al (24).
`Like cyclophillin, the major cytosolic binding protein for
`CsA, FKBP has rotamase activity (folds peptide substrates).
`Despite their quite similar common enzymatic properties,
`these two immunophillins have very different primary struc-
`tures. The geometry of the immunophillin-drug complex has
`been invoked as a biological effector that inhibits T cell ac-
`tivation (24).
`
`IMMUNOMODULATING PROPERTIES OF FK 506
`FK 506 inhibits T cells activation by mechanisms similar to
`those identified for Cyclosporine A. Although structurally
`unrelated, CsA and FK 506 share several putative
`mechanisms of action at both the cellular and the molecular
`level. T lymphocyte activation occurs following a recogni-
`tion event that is initiated via the T-cell receptor/CD-3 com-
`plex combined with one or more additional signals provided
`by accessory cells and/or cytokines. In this process, a com-
`plex series of events takes place; these include an increase in
`intracellular free calcium, phosphorylation of cytosolic
`proteins, activation of protein kinase C and increased phos-
`phoinositide turnover (25). Neither FK 506 or CsA appear to
`affect these early events following T cell activation (26).
`Once initiated, these biochemical processes lead to the coor-
`dinate expression of a set of gene products critical for
`lymphocyte growth and differentiation.
`Current evidence suggests that both CsA and FK 506 inhibit
`the induction of a discrete set of lymphokine genes which in-
`clude IL-2, IL-3, IL-4, GM-CSF, TNFa and interferon y (27)
`at the transcriptional level. Both FK 506 and CsA have been
`shown to directly inhibit transcription of the IL-2R gene (28).
`Taken together, these data suggest that FK 506 and CsA in-
`hibit T cell receptor-mediated signal transduction pathways
`that are distal to the early membrane-associated events
`described above but that are proximal to regulatory nuclear
`transcriptional factors (29).
`
`HEPATOTROPHIC PROPERTIES OF FK 506
`Kim (30) and Makowka (31) have reported that CsA enhan-
`ces the regenerative response induced by partial hepatectomy
`(PH). Subsequently, FK 506 has been shown to stimulate
`hepatic regeneration in rats following a PH (23). The growth
`enhancement achieved with FK 506 is greater than that ob-
`tained with CsA. Importantly, the growth stimulatory activity
`obtained with both CsA and FK 506 is organ-specific in that
`it does not alter the proliferative response of the kidney fol-
`lowing a unilateral nephrectomy or that of the remnant intes-
`tine following a 40% intestinal resection (22). Experiments
`performed in nude rats have ruled out a direct effect of im-
`
`mune modulation via T cells in the control of the regenera-
`tive process in response to either CsA and FK 506 (24, 32-
`34). FK 506 and CsA bind to intracellular proteins, im-
`munophillins, to form complexes which modulate a wide
`variety of calcium dependent signal transduction pathways
`that affect T-lymphocytes (35-37). The interaction of these
`two agents with immunophillins also modulates the process
`of liver cell proliferation but not through an alteration in in-
`tracellular calcium levels. In contrast, Rapamycin, another
`macrolide antibiotic that binds to the same immunophillin as
`does FK 506, is anti-hepatotrophic and inhibits hepatic
`regeneration in rats subjected to a partial hepatectomy
`(38,39). These observations constitute the first physiologic
`evidence that the immunophillin network regulates growth
`control (33).
`
`PHARMACOKINETIC AND PHARMACODYNAMIC
`PROPERTIES
`Experimental Studies In most of the available studies con-
`cerning the pharmacokinesis of FK 506, an enzyme-linked
`immunosorbant assay (ELISA) has been used for the quan-
`titation of the drug (40). Tamura et al (40) showed that the
`FK 506 serum levels in dogs range between 0.1 and 0.4
`ng/ml following a dose of 0.1 mg/Kg per os. After ad-
`ministration, FK 506 is distributed in various organs includ-
`ing the lungs, spleen, heart and kidneys (41). The majority of
`the drug is metabolized by the liver and is excreted in bile,
`urine and feces within 48 hrs of administration (41). FK 506
`has been shown to down-regulate the activity of certain
`Cytochrome P-450 systems (41). In addition FK 506, like
`CsA, possesses both hepatotrophic and hepatoprotective
`properties (22,42). The coadministration of CsA and FK 506
`in vitro reduces the effective level of each required to
`produce immunosuppression and suggests a synergy might
`exist between the two drugs (43). Clinically however, en-
`hanced renal toxicity, rather than immunosuppressive syner-
`gy has been observed when both agents are used simul-
`taneously.
`
`Clinical Studies The toxic effects of FK 506 have limited the
`available studies addressing the important issue of dose and
`route of administration of the drug. In the first clinical trial of
`FK 506 for liver transplantation (44) the following protocol
`was utilized: 0.15 mg/Kg was administered intravenously
`within one hour after the liver graft was revascularized. This
`was followed by an infusion of FK 506 at the dose of 0.075
`mg/Kg/12hrs until the patient could eat at which time the
`patient was switched to oral drug at a dose of 0.15 mg/Kg/12
`hrs. Peak plasma levels are observed immediately after the
`intravenous administration and decline slowly for 24 hrs
`(41). Plasma through levels range about I ng/ml (41).
`Following oral administration of the drug, absorption is quite
`variable: peak plasma levels of 0.4-3.7 ng/ml occur after an
`oral dose of 0.15 mg/Kg (41). Similar to what occurs with
`
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`S FAGIUOLI et al : FK 506: a new immunosuppressive agent
`
`357
`
`CsA, impaired liver function alters the absorption and
`metabolism of FK 506 (45,46). Patients with hepatic dys-
`function experience higher FK 506-levels, have an increased
`FK 506 half life and reduced clearance than patients with
`good liver function (46). As a result, liver transplant
`recipients, whose grafts do not function well and/or fail, can
`experience very high plasma levels with associated
`neurotoxicity and renal failure following i.v. administration
`of the drug. Even with good hepatic function, it is necessary
`to carefully control the plasma levels of the drug, maintain-
`ing the level below 3 ng/ml to avoid toxicity. Failure to ob-
`serve these rules constitutes a serious risk for patient mor-
`bidity. Currently at the University of Pittsburgh smaller doses
`of FK 506 as compared to those used in the initial clinical tri-
`als are being used (0.075 or 0.10 mg/Kg/day; i.v. or p.o.
`respectively).
`
`CLINICAL APPLICATIONS
`Organ Transplantation Preliminary clinical studies have
`reported that FK 506 is highly effective in increasing survival
`in both solid organ and skin transplantation (47). These ob-
`servations confirm the published reports of enhanced graft
`survival in animal models of transplantation (15-20).
`Importantly and quite different from that achieved with CsA,
`FK 506 is capable of reversing acute as well as chronic rejec-
`tion in liver, kidney and heart transplantation (15-20, 48).
`Equally important is the fact that FK 506 based immunosup-
`pression requires less steroids than does conventional im-
`munotherapy with CsA (47).
`Clinically, FK 506 was introduced in February 1989 at the
`University of Pittsburgh. Initially it was used to treat liver
`recipients who were facing intractable rejection or excessive
`drug toxicity under conventional CsA-based immunosuppres-
`sion. This "rescue" therapy with FK 506 was shown to be ef-
`fective in reversing rejection in 7 out of 10 patients, who
`were unresponsive to the highest permissible immunotherapy
`under CsA combined with steroids and OKT3 (47).
`Following this experience, FK506 was used as a primary im-
`munosuppressive agent, initially for liver transplantation and
`subsequently for renal, heart, lung, small bowel and
`pancreatic islet cell transplantation (49-55).
`
`Liver transplantation Recipient survival rates were im-
`proved significantly over that of 325 historical controls in the
`first 125 patients receiving FK 506 for both primary hepatic
`transplantation and retransplantation (91.2% vs 78.2% and
`88.8% vs 75.4% at 6 months and one year, respectively)
`(both p<O.O I). For graft survival, the rates at 6 months and 1
`year were 84.8% vs 72.6% and 80.8% vs 68.5% respectively
`(both p<O.Ol) (49).
`In order to assess the true rates of patient and graft survival
`and rejection as well as to define the incidence of adverse
`side effects of FK 506, a prospective randomized trial was
`performed in Pittsburgh (49, 53) to compare FK 506 and CsA
`
`in a head to head competition using only ideal transplant
`recipients. This study included III patients, 57 on FK 506
`and 54 on CsA and demonstrated a 1 year survival rate of
`95% for the FK 506 group vs 85% for the CsA treated group.
`Corresponding graft survival rates were 93% and 77%,
`respectively. After a median follow-up of 256 days (range
`41-405), 44% of the patients in the FK 506 group were still
`free of a rejection episode, compared to only 23% of the CsA
`treated group (p<O.OI). The use of OKT3 as adjuvant im-
`munosuppressive agent was required in 43% of the CsA
`patients but only 22% of the FK 506 treated patients
`(p<O.O I). Moreover, FK 506-treated patients required a
`statistically significant lower amount of steroid and, as a
`result, had a lower incidence of untoward side effects such as
`hypertension, hyperkalemia and hirsutism than did the group
`treated with conventional CsA-based immunosuppressive
`therapy. The incidence of hypertension was statistically
`higher in the CsA treated patients (33%) as compared to the
`FK 506 (27%) (p<0.05). No significant difference between
`the two groups was observed for renal dysfunction, infectious
`complications and frequency of new onset carbohydrate in-
`tolerance (49, 53).
`
`Kidney transplantation The first kidney transplant using FK
`506 was performed at the University of Pittsburgh in March
`1989. Since then 411 kidneys have been transplanted in
`Pittsburgh through January 1991. Of these, 202 received FK
`506 as their primary immunosuppressive therapy. No sub-
`stantial difference between FK 506 and CsA treated patients
`for the one year actuarial patient and graft survivals (91 % vs
`94% and 75% vs 81 % respectively) was observed. The in-
`cidence of graft rejection episodes (57% vs 54%) and of
`CMV infection (14.6% vs 13.8%) were similar between the
`two groups; twenty one percent and 38% of the recipients
`respectively required OKT3.
`The principal difference between the two groups was in the
`rate of use of prednisone, 38% of the FK 506 recipients were
`not requiring prednisone as compared to none of the CsA
`group. The use of anti-hypertensive medications was similar-
`ly reduced in the FK 506 group with 52% requiring no anti-
`hypertensive drugs as compared to 29% of-the CsA group.
`Another advantage for the FK 506 treated group was the
`reduced mean serum cholesterol level (193±44 mg/dl) in the
`FK 506 group as compared to the CsA group (231±64 mg/dl)
`(3, 55).
`
`Heart tramplal/ration FK 506 as the primary immunosup-
`pressive therapy has been used in 42 adult and 13 children
`receiving heart transplants at the University of Pittsburgh
`since October 1989. Overall patient survival has been 93%
`after a mean follow-up of 400 days. Actuarial freedom from
`rejection has been 65%. Compared to historical controls
`treated with CsA, patients treated with FK 506 experience a
`lower incidence of infection, require less steroid and have a
`
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`

`S FAGIUOLI et af : FK 506: a new immunosuppressive agent
`
`357
`
`CsA, impaired liver function alters the absorption and
`metabolism of FK 506 (45,46). Patients with hepatic dys-
`function experience higher FK 506-levels, have an increased
`FK 506 half life and reduced clearance than patients with
`good liver function (46). As a result, liver transplant
`recipients, whose grafts do not function well and/or fail, can
`experience very high plasma levels with associated
`neurotoxicity and renal failure following i.v. administration
`of the drug. Even with good hepatic function, it is necessary
`to carefully control the plasma levels of the drug, maintain-
`ing the level below 3 ng/ml to avoid toxicity. Failure to ob-
`serve these rules constitutes a serious risk for patient mor-
`bidity. Currently at the University of Pittsburgh smaller doses
`of FK 506 as compared to those used in the initial clinical tri-
`als are being used (0.075 or 0.10 mg/Kg/day; Lv. or p.o.
`respectively).
`
`CLINICAL APPLICATIONS
`Organ Transplantation Preliminary clinical studies have
`reported that FK 506 is highly effective in increasing survival
`in both solid organ and skin transplantation (47). These ob-
`servations confirm the published reports of enhanced graft
`survival in animal models of transplantation (15-20).
`Importantly and quite different hom that achieved with CsA,
`FK 506 is capable of reversing acute as well as chronic rejec-
`tion in liver, kidney and heart transplantation (15-20, 48).
`Equally important is the fact that FK 506 based immunosup-
`pression requires less steroids than does conventional im-
`munotherapy with CsA (47).
`Clinically, FK 506 was introduced in February 1989 at the
`University of Pittsburgh. Initially it was used to treat liver
`recipients who were facing intractable rejection or excessive
`drug toxicity under conventional CsA-based immunosuppres-
`sion. This "rescue" therapy with FK 506 was shown to be ef-
`fective in reversing rejection in 7 out of 10 patients, who
`were unresponsive to the highest permissible immunotherapy
`under CsA combined with steroids and OKT3 (47).
`Following this experience, FK506 was used as a primary im-
`munosuppressive agent, initially for liver transplantation and
`subsequently for renal, heart, lung, small bowel and
`pancreatic islet cell transplantation (49-55).
`
`Liver transplantation Recipient survival rates were im-
`proved significantly over that of 325 historical controls in the
`first 125 patients receiving FK 506 for both primary hepatic
`transplantation and retransplantation (91.2% vs 78.2% and
`88.8% vs 75.4% at 6 months and one year, respectively)
`(both p<O.Ol). For graft survival, the rates at 6 months and 1
`year were 84.8% vs 72.6% and 80.8% vs 68.5% respectively
`(both p<O.Ol) (49).
`In order to assess the true rates of patient and graft survival
`and rejection as well as to define the incidence of adverse
`side effects of FK 506, a prospective randomized trial was
`performed in Pittsburgh (49, 53) to compare FK 506 and CsA
`
`in a head to head competition using only ideal transplant
`recipients. This study included III patients, 57 on FK 506
`and 54 on CsA and demonstrated a 1 year survival rate of
`95% for the FK 506 group vs 85% for the CsA treated group.
`Corresponding graft survival rates were 93% and 77%,
`respectively. After a median follow-up of 256 days (range
`41-405),44% of the patients in the FK 506 group were still
`free of a rejection episode, compared to only 23% of the CsA
`treated group (p<O.OI). The use of OKT3 as adjuvant im-
`munosuppressive agent was required in 43% of the CsA
`patients but only 22% of the FK 506 treated patients
`(p<O.O 1). Moreover, FK 506-treated patients required a
`statistically significant lower amount of steroid and, as a
`result, had a lower incidence of untoward side effects such as
`hypertension, hyperkalemia and hirsutism than did the group
`treated with conventional CsA-based immunosuppressive
`therapy. The incidence of hypertension was statistically
`higher in the CsA treated patients (33%) as compared to the
`FK 506 (27%) (p<0.05). No significant difference between
`the two groups was observed for renal dysfunction, infectious
`complications and frequency of new onset carbohydrate in-
`tolerance (49, 53).
`
`Kidney transplantatioll The first kidney transplant using FK
`506 was performed at the University of Pittsburgh in March
`1989. Since then 411 kidneys have been transplanted in
`Pittsburgh through January 1991. Of these, 202 received FK
`506 as their primary immunosuppressive therapy. No sub-
`stantial difference between FK 506 and CsA treated patients
`for the one year actuarial patient and graft survivals (91 % vs
`94% and 75% vs 81 % respectively) was observed. The in-
`cidence of graft rejection episodes (57% vs 54%) and of
`CMV infection (14.6% vs 13.8%) were similar between the
`two groups; twenty one percent and 38% of the recipients
`respectively required OKT3.
`The principal difference between the two groups was in the
`rate of use of prednisone, 38% of the FK 506 recipients were
`not requiring prednisone as compared to none of the CsA
`group. The use of anti-hypertensive medications was similar-
`ly reduced in the FK 506 group with 52% requiring no anti-
`hypertensive drugs as compared to 29% of-the CsA group.
`Another advantage for the FK 506 treated group was the
`reduced mean serum cholesterol level (193±44 mg/dl) in the
`FK 506 group as compared to the CsA group (231±64 mg/dl)
`(3,55).
`
`Heart tram1Jlantatz'on FK 506 as the primary immunosup-
`pressive therapy has been used in 42 adult and 13 children
`receiving heart transplants at the University of Pittsburgh
`since October 1989. Overall patient survival has been 93%
`after a mean follow-up of 400 days. Actuarial freedom from
`rejection has been 65%. Compared to historical controls
`treated with CsA, patients treated with FK 506 experience a
`lower incidence of infection, require less steroid and have a
`
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`358
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`S FAGIUOLI et al : FK 506: a new immunosuppressive agent
`
`diminished incidence of hypertension (15% vs 70%) (all
`p<O.OOI) (54).
`
`Small bowel transplantation Since the first small bowel
`transplantation was performed by Lillehei in the early 1960's,
`it has been evident from a purely technical point of view that
`intestinal transplantation is a practical possibility. In contrast
`with the kidney and liver transplantation, however, no im-
`munosuppressive agent has been shown to be truly effective
`in preventing rejection within days of the transplant
`procedure. Additionally, intestinal transplantation presents a
`very high risk for graft-versus-host disease (GVHD).
`Recently FK 506 has been shown to be an effective im-
`munosuppressive agent in a rat model of intestinal
`transplantation (IS). These experimental studies have been
`confirmed in human intestinal transplantation (56).
`The preliminary results at the University of Pittsburgh are en-
`couraging and have shown FK 506 to be a useful agent in
`this type of transplant. Moreover, no GVHD has been ob-
`served following intestinal transplantation with FK 506 (56).
`
`altering renal cortical hemodinamics. It also has some ad-
`verse tubular effects. Hyperkalemia is a frequent complica-
`tion of FK 506 therapy and is due either to an effect on
`mineralcorticoid secretion either at the level of the adrenal Or
`juxtaglomerular apparatus or an alteration in mineralcorticoid
`activity at the level of the renal tubules. With high levels of
`FK 506, renal failure can occur necessitating hemodialysis.
`The reported incidence of hemodialysis in liver transplant
`recipients is 4% and appear to be a unique problem for these
`patients, as it is not seen in either heart or heart/lung
`recipients (53, 61).
`
`Glucose metabolism New onset diabetes mellitus requiring
`insulin occurs at a rate of about IS% with the use of FK 506.
`This rate is similar to that experienced with CsA.
`Glucose intolerance in response to FK 506 administration ap-
`pears to be due to changes in the peripheral sensitivity to in-
`sulin as well as a reduced insulin secretion rate by B cell in
`pancreatic islets in response to a hyperglycemic stimulus (53,
`62,63).
`
`Immune-related disease and FK 506 The rationale for the use
`of FK 506 in the clinical management of autoimmune diseases
`is the observation that: 1) many of these diseases are T-cell
`mediated and FK 506 is a powerful T-cell inhibitor and 2) most
`if not all T-cell mediated putative autoimmune disorders have
`been shown to be responsive to CsA therapy, but concern about
`CsA toxicity, have limited its use. Preliminary results with FK
`506 have shown a beneficial effect in 10 patients treated for
`severe, recalcitrant chronic plaque forming psoriasis (two of
`whom also had psoriatic arthritis) (57); in 3 patients with severe
`pyoderma gangrenosum associated with inflammatory bowel
`disease (IBD) (5S) and in 7 patients with the nephrotic
`syndrome caused by steroid-resistent focal sclerosing
`glomerulonephritis where FK 506 markedly reduced the
`proteinuria without altering overall renal function (59).
`As a result of the success of these preliminary studies, several
`randomized clinical trials (new onset type I diabetes, scleroder-
`ma, autoimmune glomerulonephritis, systemic lupus
`erythematous, polymyositis-dermatomyosius, reumatoid
`arthritis, psoriasis, pyoderma gangrenosum, Crohn colitis, ul-
`cerative colitis, primary biliary cirrhosis, primary sclerosing
`cholangitis, autoimmune chronic acute hepatitis and uveitis) are
`presently underway at the University of Pittsburgh with this
`agent (60).
`
`UNTOWARD EFFECTS OF FK 506
`As with all conventional immunosuppressive therapies, the
`major untoward effects of FK 506 can be segregated into 4
`principal groups: renal dysfunction, diabetogenic effects,
`neurotoxicity and infections.
`
`Renal dysfunction Although FK 506 is not a typical
`nephrotoxin, it does reduce glomerular filtration, probably by
`
`eNS dy~function CNS dysfunction following FK 506 treat-
`ment is rare. When it occurs, however, it can be severe (53,
`64). A reversible expressive aphasia, new onset seizures and
`paranoid psychosis have all been reported in liver recipients
`taking FK 506. This unique susceptibility of liver recipients
`to neurotoxicity following FK 506 administration may
`depend in part to an underlying metabolic dysfunction that is
`due to the presence of preexisting hepatic encephalopathy
`and/or a disruption of the blood brain barrier associated with
`hepatic encephalopathy that persists during the peri operative
`period. Minor neurotoxic complications of FK 506 include:
`insomnia, tremors, headache, hyperesthesia, blurred vision,
`tinnitus, dizziness and nightmares (53, 64).
`
`Infections The incidence of bacterial infections during FK
`506 immunosuppression is low (65). Viral infections, such as
`cytomegalovirus, occur in 20% of transplant patients (53, 65,
`66). Fortunately, the CMV infections seen in transplant
`recipients using FK 506 are typically mild and respond rapid-
`ly to gancyclovir administration. To date no CMV infection
`has been reported in a patients treated with FK 506 for a non-
`transplant indication (53, 65, 66).
`Despite its increased immunosuppressive activity, FK 506
`has not been shown to have an increased risk of lympho-
`proliferative disorders (LPD) associated with its chronic use
`as a primary immunosuppressive agent. Moreover, when
`compared to CsA, the rate of LPD with FK 506 is 1/3 less
`than that seen in organ graft recipients treated with CsA (53,
`67). Hypertension is not a serious problem with FK 506
`therapy, a fact that distinguishes it from CsA (53). Gingival
`hyperplasia and excessive hair growth are also not seen with
`FK 506 administration (6S). Importantly, hyperuricacidemia
`and hypercholesterolemia are not seen with FK 506 ad-
`
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`S FAGIUOLI et al : FK 506: a new immullosuppressive agent
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`359
`
`ministration (53). The status of hepatic function is the most
`important factor affecting FK 506 levels and dosing require-
`ments. A sudden increase in the FK 506 level, often with ex-
`tremely high serum levels being achieved, can occur in
`patients with clinically significant hepatic dysfunction. As a
`result, frequent dose monitoring with blood levels of the drug
`is essential in patients with liver disease. The elevated blood
`levels of FK 506 seen in such cases can easily lead to severe
`impairments of renal function and precipitate neurotoxicity
`leading to coma and/or seizures if not monitored closely.
`
`CONCLUSIONS
`Preliminary clinical and experimental studies indicate that
`FK 506 is a powerful new immunosuppressive agent that
`should be a a promising addition to the current immunosup-
`pressive armamentarium clinically available for organ
`transplantation. The superior potency of FK 506 as compared
`to CsA will make it one of the more extensively studied
`drugs to be developed over the next several years. The
`preliminary clinical experience at the University of
`Pittsburgh with FK 506 which has resulted in improved
`patient and graft survival rates as well as in a reduction in the
`number of rejection episodes is exciting but needs to be cor-
`roborated by the results of other centers. A major advantage
`of FK 506 use is that it allows for a significant reduction in
`the co-use of steroids and as a consequence, hypertension
`and anti-hypertensive drugs which lead to a resultant im-
`proved quality of life for the organ recipient. Nephrotoxicity,
`neurotoxicity and interference with carbohydrate metabolism
`represent the major untoward effects of FK 506 use. Close
`control of FK 506 levels is recommended to reduce the in-
`cidence of these adverse effects.
`Two prospective, randomized, multicentric liver transplant
`studies have begun in Europe and the USA to compare the
`use of FK 506 with that of conventional cyclosporine based
`immunosuppressive therapy. Additional clinical trials are
`also underway at the University of Pittsburgh to determine
`the toxicity and the potential benefits of FK 506 in other
`clinical conditions, particularly autoimmune diseases.
`Finally a great deal of interest in the use of FK 506 in the
`transplantation of so-called "forbidden organs" (intestine and
`multivisceral transplantation, pancreatic islet graft
`transplantation) appears to be developing at centers where
`the drug is available.
`
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