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Tacrolimus, a widely used immunosuppressive drug for preventing graft rejection following organ transplantation, was reported to develop neurotoxic side effects ranging from mild to severe symptoms in the literature. Rats were randomly divided into three groups as control and 2-week and 3-week treatment groups and received a 2 mg/kg/day tacrolimus by oral gavage. Animals were sacrificed and sciatic nerves obtained from all groups were fixed and processed for light and electron microscopic investigations. The myelinated fiber diameter, axon diameter, G-ratio (axon diameter/myelinated fiber diameter), and myelin thickness were also determined. The data obtained in the control and tacrolimus-treated groups were compared. The control group sciatic nerve fascicles showed normal morphology with myelinated and unmyelinated fibers. Experimental groups exhibited axonal dilatation, irregularly thickened and vacuolated myelin sheaths with separation of myelin layers. The morphometric analysis showed that the myelinated fibers of the 2-week tacrolimus-treated group displayed a moderate increase in the myelin thickness and axon and fiber diameter in comparison with the control and 3-week tacrolimus-treated groups. The G-ratio was found to be in normal range in all groups and there were no statistically significant difference. The present study indicates that the treatment with tacrolimus may produce a mild degenerative change but prolonged drug administration for 3 weeks led to improvement in morphometric and morphologic data and the normal G-ratio values, suggesting that the regeneration capacity of the myelinated fibers maintains their normal function to transmit nerve impulses. WOS:000619073900001 2-s2.0-85101043101 PubMed: 33596749

The aim of this study was to investigate the ocular distribution of tacrolimus (FK506) and absorption into the systemic circulation after a single or repeated topical instillation of FK506 ophthalmic suspension in male New Zealand white rabbits.In the single instillation study (group 1), 29.1-34.8 microL of a 0.1, 0.3, and 1% suspension was administered to each of the 15 rabbits. In the repeated instillation study (group 2), 27.1-39.5 microL of a 0.3% suspension was administered to 27 rabbits q.i.d. (i.e., at 3-h intervals) for 14 days. In the intravenous (i.v.) dose study (group 3), 1 mg/kg of FK506 was administered to 3 rabbits. The amount of FK506 was measured by using a competitive enzyme immunoassay.The results for single and repeated instillation studies were similar. In the single instillation study, blood T(max) after an instillation of the 0.1, 0.3, and 1% suspensions (at 0.8, 1.0, and 1.0 hours) did not differ significantly among these doses. One (1) h after an instillation of the 1% suspension, ocular tissue concentrations, except the retina/choroid, vitreous body, and lens, were higher than the blood concentration (C(max): 2.7 ng/mL). In particular, concentrations in the conjunctiva, cornea, iris, and anterior sclera were much higher than the blood concentration (148, 900, 120, and 145 ng/g tissue). In the repeated instillation study, concentrations in the blood and ocular tissues (except the lens) reached a steady state by the 7th day. In the i.v. dose study, AUC(0-24h) and T(1/2) were 1643 ng h/mL and 18.5 h, respectively.The high-level distribution of FK506 was observed in the conjunctiva, which is desirable because the conjunctiva is the target tissue for pharmacologic effect (i.e., efficacy).

Immunosuppressive therapy with intravenous ciclosporin is an alternative treatment option to total colectomy for patients with ulcerative colitis (UC), while the benefits of oral administration of tacrolimus are not well defined and are based on reports of several uncontrolled studies.Patients with refractory active UC were randomly assigned to a high trough concentration (10-15 ng/ml) group (HT group) (n = 21), low trough concentration (5-10 ng/ml) group (LT group) (n = 22), or placebo group (n = 20). Patients received an initial oral dose of 0.025 [DOSAGE ERROR CORRECTED] mg/kg tacrolimus or placebo twice daily. Efficacy was evaluated in 60 patients based on a disease activity index (DAI) score. Fifty eight patients had additional treatment with tacrolimus and were evaluated for efficacy in a 10 week open label extension.An improvement in DAI score (or=4 points, all categories improved) was observed for 68.4% of cases in the HT group compared with 10.0% in the placebo group (p0.001). In the HT group, 20.0% of patients had clinical remission and 78.9% had mucosal healing. In the open label extension, 55.2% of all patients had an improved DAI score at week 10. Mean dose of prednisolone was reduced from 19.7 mg/day at study entry to 7.8 mg/day at week 10. The incidence of side effects in the HT group was significantly higher than that of the placebo group (p = 0.043). The most common event was mild finger tremor.Our findings demonstrate dose dependent efficacy and safety of oral tacrolimus for remission-induction therapy of refractory UC. The optimal target range appears to be 10-15 ng/ml in terms of efficacy with two week therapy.

Psoriasis is a chronic recurrent inflammatory dermatosis, which is characterized by epidermal proliferation and erythema scales. Its etiology and pathogenesis are still unknown and treatment is difficult. The concentration of tacrolimus for the treatment of psoriasis has not been reported at home and abroad. In this report, we detected the tacrolimus plasma concentration and hope to provide a certain reference value for the clinical treatment of psoriasis.

Resume Le tacrolimus est un puissant immunosuppresseur utilise dans le cadre de la transplantation d’organes. En raison de son index therapeutique etroit un suivi biologique s’impose. Le but de ce travail a ete d’evaluer les performances analytiques du kit de dosage Emit ® 2000 tacrolimus commercialise par Dade Behring et de le comparer au kit IMx ® Tacrolimus II Abbott. L’etude de la reproductibilite inter- et intraserie realisee sur des echantillons temoins ( n = 20) montre une precision intraserie de 8, 4,7 et 3,9 et interserie de 11,9, 9,1 et 5,6 % pour les trois niveaux de concentration etudies. La limite de detection a ete trouvee a 1,98 μg/l. L’etude de comparaison effectuee sur des specimens provenant de greffes hepatiques a montre une bonne correlation avec le kit IMx ® tacrolimus Abbott (Emit = 1,19 MEIA – 1,70). La methode EMIT est une bonne alternative a la methode MEIA couramment utilisee dans la surveillance des patients sous tacrolimus.

The neuroprotective effect of the immunosuppressant agent FK506 was evaluated in rats after brain ischemia induced for 15 min in the 4-vessel occlusion model. In the first experimental series, single doses of 1.0, 3.0 or 6.0 mg FK506/kg were given intravenously (iv) immediately after ischemia. In the second series, FK506 (1.0 mg/kg) was given iv at the beginning of reperfusion, followed by doses applied intraperitoneally (ip) 6, 24, 48, and 72 h post-ischemia. The same protocol was used in the third series except that all 5 doses were given iv. Damage to the hippocampal field CA1 was assessed 7 or 30 days post-ischemia on three different stereotaxic planes along the septotemporal axis of the hippocampus. Ischemia caused marked neurodegeneration on all planes (P

Summary. Introduction. Gingival overgrowth associated with immunosuppression following liver transplantation is a commonly recognized clinical problem. The aims of this study were to determine the incidence of gingival overgrowth in a group of children post liver transplantation and to compare gingival overgrowth in children receiving FK506 with those receiving cyclosporin. Methods. Seventy-nine children (aged 15–196 months) undergoing liver transplantation at Birmingham Children's Hospital between October 1998 and October 2000 were studied. Gingival overgrowth was assessed in a blinded fashion and scored in a previously validated manner. Gingival overgrowth scores of the patients on each immunosuppressant drug were then compared. Results. Fifty-two patients were treated with cyclosporin and 27 treated with tacrolimus. Eighteen children were also receiving nifedipine (also known to cause gingival overgrowth) and were considered separately. Of the 41 children receiving cyclosporin alone, 26 exhibited gingival overgrowth compared to zero of 20 patients receiving tacrolimus alone. Those children treated with immunosuppression plus nifedipine developed gingival overgrowth, however, this was much less marked in the tacrolimus group. Conclusion. Tacrolimus, unlike cyclosporin, is not associated with gingival overgrowth when used for immunosuppression following liver transplantation in children, and may be the drug of choice for children.

久留米大学病院皮膚科でアトピー性皮膚炎に対しタクロリムス軟膏(プロトピック®軟膏)を使用した症例で経過を評価しえた101症例について,効果と副作用を集計するとともに,特に皮疹軽快後の維持療法,中止後の経過について調査検討した。その結果,顔面に使用した例では全体でやや有効以上が93%で,副作用の認められた41%のうち局所刺激感が30%と最も多く,重篤な副作用は少なかったが,注意を要するものとしてカポジ水痘様発疹症が5例(5%)に出現した。症状消失後は,軽症例では皮疹再燃時に使用を再開するよう指導した上で外用中止した5例全例が経過良好であった。中等症ないし重症例では,症状が消失した後も外用中止すると2ないし3日後に再燃の見られた例が多く,2ないし3日に1回の外用に減量してほぼ皮疹のコントロール可能で,症状の増悪した時に適宜外用回数を戻す方式で対応できた。しかし,1日1回外用への減量から様子をみながら数週間ないし数ヵ月に一度外用間隔をみなおして徐々に減らしていく方法をとった群が,14例全例に再燃がなく維持ないしさらに減量可能であり,患者のコンプライアンスの低下しない選択肢であると思われた。

Objective To assess the efficacy and side effects of tacrolimus in the management of patients with high-risk corneal and limbal grafts. Design Noncomparative case series. Participants Seventeen patients (23 grafts) were treated with tacrolimus; 15 patients (20 host corneas) had two or more quadrants of stromal vascularization, 6 patients had stem cell deficiency, and 6 patients had glaucoma. Seven patients had received one previous graft, six patients had two previous grafts, and four patients had three previous grafts. Intervention Patients with high-risk corneal and limbal grafts were treated with systemic tacrolimus at a mean optimum dosage of 4.4 mg daily (range, 2–12 mg daily). Main outcome measures Graft survival, visual acuity. Results No patient has had irreversible graft rejection while receiving tacrolimus. The follow-up period ranges from 12 to 46 months, with a mean of 24 months. Three patients have had reversible graft rejection associated with low tacrolimus levels. Nine patients have stopped treatment; two had reversible rejection within 2 months of stopping, and five grafts remain clear. The other four patients stopped treatment because of graft failure, which was not considered to be rejection related. Eight patients remain on treatment, and all have clear grafts. Conclusions Tacrolimus (FK506) is effective in prevention of rejection in patients with high-risk corneal and limbal grafts.

The pharmacokinetics of tacrolimus (FK506) were studied in the male rat after a single dermal application of FK506 ointment over an application period of 24 hours. In the typical experiment, the amount of ointment applied was 100 mg per each rat, and application area was 10 cm2. The pharmacokinetic parameters estimated were maximal blood concentration (Cmax), time to reach Cmax (Tmax), and area under the blood concentration-time curve (AUC). 1. Blood concentrations of FK506 were determined after a single dermal application of FK506 ointment under the occlusive or non-occlusive dressing condition. After respective application of 0.5 and 0.1% FK506 ointment to the intact and damaged skin, Cmax and AUC values did not differ significantly between either dressing conditions. Blood concentrations of FK506 after a single dermal application of FK506 ointment to the damaged skin were much higher than those applied to the intact skin. The bioavailability of FK506 after application of 0.5% FK506 ointment to the intact skin was 5% and that to the damaged skin was 62%. 2. After a single dermal application of 0.03, 0.1 and 0.5% FK506 ointment to the intact skin, the Cmax and AUC values increased in proportion to the strength of the ointment. After a single dermal application of 0.3% FK506 ointment to 2.5, 5 and 10 cm2 of the intact skin, the Cmax and AUC values increased proportionally to the area of the skin. The Cmax and AUC values did not the differ significantly after single dermal application of 10, 30, 100 and 300 mg of 0.3% FK506 ointment to the intact skin.

Efficacy and safety of long term use of FK506 (2-4.5 mg/day) for a maximum of two years were evaluated in 12 patients with generalised myasthenia gravis (MG). At the end of the study, eight patients (67%) showed improvement in either MG score or Activities in Daily Living score, and prednisolone dosage could be reduced in seven patients (58%), with a mean reduction ratio of 37%. Long term use of FK506 for MG can be more effective than short term administration, with no serious side effects.

The current off-patent state of tacrolimus (FK506) has opened the hunting season for new generic pharmaceutical formulations of this immunosuppressant. This fact has boosted the scientific and industrial research on tacrolimus for the last 5 years in order to improve its production. The fast discovery of tacrolimus producer strains has generated a huge number of producers, which presents the biosynthetic cluster of FK506 as a high promiscuous genetic region. For the first time, the current state-of-the-art on the tacrolimus biosynthesis, production improvements and drug purification is reviewed. On one hand, all the genes involved in the tacrolimus biosynthesis, in addition to the traditional PKS/NRPS, as well as their regulation are analysed. On the other hand, tacrolimus direct and indirect precursors are reviewed as a straight manner to improve the final yield, which is a current trend in the field. Twenty years of industrial and scientific improvements on tacrolimus production are summarised, whereas future trends are also drafted.

This report is a retrospective analysis of 27 patients who received Tacrolimus because of intolerance or for refractoriness to Cyclosporin A (CyA) as prophylaxis against acute and chronic GvHD at a single institution. 9 patients were treated with Tacrolimus as acute GvHD developed despite optimal concentrations of CyA and 8 developed chronic GvHD despite continuation of CyA. 10 patients developed World Health Organisation Score (WHO) grade 2–3 toxicity to CyA. Overall 21 of 27 patients responded to Tacrolimus. Patients who underwent reduced conditioning responded as well as those patients who underwent conventional conditioning regimens. Tacrolimus is well tolerated and effective and might be an alternative primary agent for prevention of GvHD. Its role in reduced conditioning regimens needs to be further explored.

In adults, the outcome of nerve suture and nerve autograft remains generally unsatisfactory. FK506 (tacrolimus), an immunosuppressant drug used in transplantation, has been reported in animal studies to enhance nerve regeneration. In hand transplantation patients, nerve regeneration was unexpectedly good and rapid, and this observation has been attributed to FK506. The present Phase II experiment investigated the tolerance to FK506 after nerve suture or autograft, and the potential effects of the drug on axonal regeneration. Following strict criteria, five patients were included in this study. Within 7 days of nerve repair (median, ulnar and sciatic transections), patients received FK506 (aiming for blood concentrations between 5 and 8 ng/ml) for a total duration of 60 days. The patients were carefully followed with clinical and biological monitoring in order to detect side-effects. A clinical and electrophysiological assessment of the effect of FK506 on nerve regeneration was conducted. No undesirable side-effect was observed during or after FK506 treatment, but one non-compliant patient discontinued treatment. There was no evident improvement of sensory, motor or functional recovery at the end of the follow-up period (average duration 39.8 months), as compared to the expected clinical result without treatment. Although statistically non-significant, FK506 seemed to accelerate the progression of the Hoffmann–Tinel sign, but without impact on the final result.

A variety of renal lesions have been described in patients undergoing episodes of tacrolimus nephrotoxicity. Although helpful to the pathologist seeking morphologic clues to substantiate drug toxicity, none of these lesions is specific to the extent that it has not been reported in other conditions. This is not surprising because all organs in the human body possess only a limited repertoire of tissue reactions to deal with injurious stimuli. The diagnosis of tacrolimus nephrotoxicity is therefore best made with reference to the clinical context and after exclusion of other causes of graft dysfunction. The ultimate confirmation is a decline in serum creatinine levels following a reduction in tacrolimus dosage. Chronic tacrolimus nephrotoxicity can be nonreversible, however, and may be regarded as the “price to be paid” for maintaining continuous immunosuppression. Because the nephrotoxic and antirejection actions of tacrolimus might be mechanistically related, it may not be possible to avoid tacrolimus nephrotoxicity altogether. Fortunately, there is evidence that the effects can be minimized by the use of low-dose regimens. Observed and projected long-term graft survivals with tacrolimus now equal or exceed those obtainable with alternative immunosuppressive drugs (10).

The present study examined the effects of tacrolimus (FK506) on the development of osteonecrosis in rabbits. In Experiment A, rabbits were given FK506, and also given a single dose of steroid. Control rabbits were given the same dose of steroid only. In Experiment B, rabbits were given FK506 and a reduced dose of steroid. The results showed that addition of FK506 did not change the number of rabbits with osteonecrosis when an identical steroid dose was given. When the steroid dose was reduced, the osteonecrosis incidence significantly decreased (p < 0.01). These results suggest that the clinically reported decrease in the osteonecrosis incidence following the introduction of FK506 is most likely attributable to the lower doses of steroids.

Tacrolimus (FK506) was discovered as the result of a systematic screening program to look for an improved immunosuppressant. In the mid-1980s Goto and associates from the Exploratory Research Laboratories of Fujisawa Pharmaceutical Co. Ltd, Japan, discovered a macrolide compound that had potent immunosuppressive properties[1]–[3]. This compound, then named FK506, was extracted from the fermentation broth of the soil fungus Streptomyces tsukubaensis. Further preclinical studies on the immunosuppressive properties of this compound on organ transplantation were carved out intensively at Chiba University, Japan[4]–[9], Cambridge University, UK[10]–[12], and the University of Pittsburgh, USA[13]–[18]. The initial results of FK506 as an effective immunosuppressant in organ transplantation were presented at the first International Symposium on FK506 in June 1987, in Geteborg, Sweden, and were subsequently published in Transplantation Proceedings (Vol. 19, Suppl. 6, 1987).

Microangiopathic hemolytic anemia (MAHA) is a well recognized complication of cyclosporin A (CyA) immunosupressive therapy post bone marrow and solid organ transplant but has rarely been reported in association with FK506 (tacrolimus), we describe a unique patient in whom both CyA and FK506 appear to have caused microangiopathy following an allogeneic peripheral stem cell transplant.

We describe two male patients with ulcerative colitis and refractory pyoderma gangrenosum including periorbital phlegmona in one case. Both patients were successfully managed with low dose oral tacrolimus (0.1 mg/kg bodyweight per day). Serum trough levels were closely monitored and maintained between 4 and 6 ng/mL. A rapid response was noted in both cases. Complete non-scarring skin restitution without side effects was accomplished in both cases. Low dose oral tacrolimus provides a valuable alternative treatment option for IBD patients with refractory pyoderma gangrenosum.

Key Clinical Message Haematopoietic abnormalities associated with tacrolimus are relatively rare with reversible pure red cell aplasia being the most common. We report for the first time, to our best knowledge, tacrolimus therapy associated with bone marrow fibrosis, abnormal megakaryocytosis, and dyserythopoiesis in a 17-year-old male treated with tacrolimus for nephrotic syndrome.

We report the results of a phase III trial comparing tacrolimus (FK506) with cyclosporine for GVHD prophylaxis after allogeneic BMT. From February 1995 to July 1996, 136 patients were enrolled and followed up to September 1997. During the first 100 days post-transplant the incidence of grade II-IV acute GVHD (the primary end-point) was lower in the tacrolimus group (17.5%) compared with the cyclosporine group (48.0%, P < 0.0001). A significant difference was observed between the tacrolimus and cyclosporine groups when subset analyses were performed based on recipients from HLA-matched siblings (13.3% vs 41.3%, P = 0.015) or donors other than HLA-matched siblings (21.4% vs 53.8%, P= 0.0029). The incidence of chronic GVHD (47.3% and 47.8%) and Kaplan-Meier estimate of overall survival (62.9% and 65.2%) were similar between the tacrolimus and cyclosporine groups, respectively. The overall leukemia relapse rate was not significantly different between the tacrolimus and cyclosporine groups (19.6% and 11.4%, respectively). However, the relapse rate among recipients from HLA-matched siblings was significantly higher in the tacrolimus group (30.9%) compared with the cyclosporine group (3.6%, P = 0.013). These results suggest the merit of tacrolimus for the prophylaxis of acute GVHD, but a lack of merit for a graft-versus-leukemia effect among recipients from HLA-matched sibling donors.

The present study analyzes pretransplantation variables associated with long-term liver allograft survival in 278 children who underwent transplantation under primary tacrolimus (FK506) therapy at a single center between October 1989 and October 1996.The influence of 17 pretransplantation variables on long-term liver allograft outcome was analyzed. Donor variables included age, weight, gender, and cold ischemia time. Recipient variables included age, weight, gender, original liver disease, pretransplantation waiting time, previous abdominal surgery, United Network of Organ Sharing (UNOS) status, ABO blood group, bilirubin level, prothrombin time, ammonia level, creatinine level, and reduced-size/split liver grafts.Overall actuarial graft survival was 79.9% at 1 year, 79.1% at 2 years, and 78.3% at 3, 4, and 5 years. Retransplantation rate was 10.8%. Pretransplantation variables with a significant adverse effect on graft survival by univariate analysis were donor ageor = 1 year (P0.004), donor weightor = 10 kg (P0.003), UNOS status I and II (P0.007), ABO type O, B, and AB (P0.03), and reduced-size/split liver grafts (P0.02). Pretransplantation variables significant by multivariate analysis and therefore independent predictors of inferior graft outcome were donor weight '10 kg (relative risk [RR] 2.91, confidence interval [CI] 1.53-5.51); reduced-size/split liver grafts (RR 2.53, CI 1.30-5.64); and UNOS status I (RR 2.22, CI 1.11-4.43).Pediatric liver transplant recipients receiving primary tacrolimus therapy have long-term graft survival rates approaching 80%. UNOS status, donor weight, and the use of reduced-size/split liver grafts are the most important factors affecting survival.

Background: We clinically and pathologically analyzed renal allografts from 19 renal transplant patients treated with tacrolimus (FK506) for more than 1 year. Methods: Twenty-six renal allograft biopsy specimens from 19 renal transplant patients who underwent transplantations between 1991 and 1 993 were evaluated. Thirteen biopsies were performed from stable functioning renal allografts with informed consent (nonepisode biopsy) and the other 13 were from dysfunctional renal allografts with a clinical indication for biopsy (episode biopsy). Results: The main pathologic diagnoses (some overlap) were acute rejection (AR; n = 4), chronic rejection (CR;n = 5), AR + CR(n=4), recurrent IgA nephropathy (n = 5), normal findings (n = 2), minimal-type chronic FK506 nephropathy (n = 9), and mild-type FK506 nephropathy (n = 11). Of the nonepisode biopsies, 7 and 4 biopsies showed minimal-type and mild-type chronic FK506 nephropathy, respectively. Chronic FK506 nephropathy consisted of rough and foamy tubular vacuolization (5 biopsies), arteriolopathy (angio-degeneration of the arteriolar wall; 20 biopsies), focal segmental glomerulosclerosis (4 biopsies) and the striped form of interstitial fibrosis (11 biopsies). The serum creatinine levels of patients in the mild-type chronic FK506 nephropathy group, which included 7 episode biopsies, were statistically higher than those in the minimum-type chronic FK506-nephropathy group (P < 0.001). Conclusions: This study demonstrates that chronic FK506 nephropathy consists primarily of arteriolopathy manifesting as insudative hyalinosis of the arteriolar wall, and suggests that mild-type chronic FK506 nephropathy is a condition which may lead to deterioration of renal allograft function.

In the present chapter, we will review our studies of the potential role of tacrolimus in xenotransplantation based largely on experiments in which rats were recipients of vascularized organs from either hamsters or mice. Because these xenografts after transplantation elicit a strong humoral response and are rejected within a few days, these models were considered until the last few years to be moderately difficult [1–10], more so than the sheep-to-goat combination of Per-per and Najarian [11] or the wolf-to-dog model of Hammer et al. [12].

A Quality Assurance Program for the IMx assay for FK506 in whole blood samples was established to monitor the performance of the assay in clinical sites enrolled by Fujisawa USA, Inc. Forty investigative sites participating in the program were required to perform assay to establish intraassay variability, interassay variability, and performance on blinded samples. Only two of the sites were required to repeat part of the program. The intraassay and interassay results at the sites were in good agreement with the target values obtained at Fujisawa Research Laboratory. Most of the coefficients of variation (CV) were within +/- 15%, well within the acceptance range of +/- 30%. Only a few values were outside the acceptance window. For the blinded samples, the CVs were variable and depended on the concentration of FK506 in the sample. At lower blood FK506 concentrations (5-10 ng/ml), the mean CVs were often outside the acceptance window, and many individual values were not acceptable. At concentrations of 15-50 ng/ml, the CVs were generally acceptable. Thus individual sites can quickly learn to perform the FK506 IMx assay and achieve good within- and between-day results. The assay of lower blood concentrations of FK506 may show higher variability. Patients are usually monitored for clinical signs of rejection and toxicity in addition to blood FK506 concentrations.

A little over a decade has passed since the discovery of the potent immunosuppressant FK506 (tacrolimus). In April 1983, Fujisawa expanded the research arm of the company by setting up new research laboratories at Tsukuba science city, Japan’s comprehensive research complex for business and industry. Fujisawa then began a year of screening for new immunosuppressants at the Tsukuba laboratories, which introduced us to the field of immunosuppressive drugs.