tacrolimus and Drug-Related-Side-Effects-and-Adverse-Reactions

Tacrolimus is a powerful macrolide calcineurin inhibitor that has low adverse effects which lead to a rapid response in the control of signs and symptoms in comparison to that of corticosteroids in Oral Lichen Planus(OLP). There have been increasing number of studies establishing the use of topical tacrolimus in oral lichen planus. Still, there is a need to find evidence of the successful use of tacrolimus in comparison to other drugs used in the treatment of OLP, by means of a systematic review and meta-analysis, so that an informed and accurate approach can be utilized.. A comprehensive literature review was performed, including PubMed, the Cochrane Library, published up to and including December 2021. There were no restrictions on date of publication. Articles available in English language were included. Using the Cochrane Collaboration tool, we assessed the risk of bias for randomized controlled trials. A meta-analysis was performed on the relevant studies.. A total of 11 RCTs evaluating the effects of tacrolimus were included in this study after application of inclusion and exclusion criteria. Seven studies revealed a low bias risk, three presented a moderate risk and one had a high risk of bias. The results revealed no significant difference in clinical resolution and adverse effects between tacrolimus and corticosteroids. The pooled data from our meta-analysis shows that there is not sufficient evidence to prove that Tacrolimus is better in efficacy than other topical corticosteroids.. According to the current systematic study and meta-analysis, there is not sufficient evidence to prove that Tacrolimus is better in efficacy than other drugs. Uniform trials are required with larger sample sizes and standardized methodology are required for a better analysis.

Topics: Calcineurin Inhibitors; Drug-Related Side Effects and Adverse Reactions; Humans; Lichen Planus, Oral; Macrolides; Retinoids; Tacrolimus

Idiopathic membranous nephropathy (IMN) is a common cause of nephrotic syndrome in adults and one of the leading causes of end-stage renal disease (ESRD). During recent years, the incidence of IMN has been increasing. The main treatment option for IMN is the use of immunosuppressive (IS) drugs combined with glucocorticoids (GC). However, the infection risk with different IS drug treatments has not been systematically compared. Therefore, a network meta-analysis was performed to compare the risk of infection of different IS drug treatments for IMN.. Randomized controlled trials (RCTs) that assessed the risk of infection in patients with IMN treated with different IS drugs combined with GC were included in the network meta-analysis. Risk ratios for dichotomous data with 95% confidence intervals (CI) were calculated and the data were pooled with a random-effects model. The surface under the cumulative ranking area (SUCRA) was calculated to rank the risk of infection with different interventions.. A total of 38 RCTs with 2066 participants were included for comparison of nine interventions. Tacrolimus combined with GC (TAC + GC) was associated with a significantly lower risk of infection than that with intravenous cyclophosphamide (IVCTX) + GC with a risk ratio (95% CI) of 0.52 (0.34-0.79). IVCTX + GC was associated with a significantly higher risk of infection than that with TAC + GC, cyclosporin (CSA) + GC, and oral cyclophosphamide (POCTX) + GC. A sensitivity analysis, excluding studies with a very long follow-up period, revealed minimal differences in the estimates. The SUCRA showed that CSA + GC had the lowest risk of infection (SUCRA 86.0%), and the second best treatment was POCTX + GC (SUCRA 78.6%). Conversely, IVCTX + GC (SUCRA 16.2%) had a higher risk of infection than that with the other IS drugs.. CSA + GC and POCTX+ GC were associated with a lower risk of infection than that with other IS drugs combined with GC for IMN. Combined with comparative efficacy data, these results can help patients make informed decisions about treatment options for IMN. PROSPERO registration: CRD42018104849.

Topics: China; Cyclophosphamide; Cyclosporine; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Glomerulonephritis, Membranous; Glucocorticoids; Humans; Immunosuppressive Agents; Infections; Kidney Failure, Chronic; Randomized Controlled Trials as Topic; Risk; Tacrolimus

Since its introduction to the antirejection armamentarium in 1994, tacrolimus has become the workhorse of transplant professionals for avoidance of solid organ transplant rejection. Not only does tacrolimus have potent immunosuppressive qualities that prevent rejection, but dosing is straight forward and it is generally well tolerated. However, in the long term, conditions such as calcineurin inhibitor nephrotoxicity can become a problem. A discussion of the compound, the pharmacokinetics, history, and current approved uses for tacrolimus is described. Indeed, tacrolimus is the most important drug for preventing transplant rejection. However, the increased appreciation for significant side effects, particularly in the long term, has led to building interest in new agents with different mechanisms of action and different metabolism.

Topics: Animals; Calcineurin Inhibitors; Drug-Related Side Effects and Adverse Reactions; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Diseases; Organ Transplantation; Tacrolimus

The prevalence of acute renal allograft rejection has decreased substantially in past decades due to new and more specific immunosuppressive compounds but improvements in long-term graft function have not been achieved. There is a large need for new immunosuppressive agents that lack toxicity of current agents such as calcineurin inhibitors but show high synergistic efficiency in preventing rejection processes.. This review summarizes data concerning the pharmacokinetics, pharmacodynamics and clinical efficacy of the new PKC inhibitor sotrastaurin with a focus on renal transplantation. The article contains information that has been presented at international transplant meetings and congresses and that has been published between 2006 and 2010. Additionally, current ongoing trials are described in detail.. Immunosuppressive regimens after kidney transplantation consist of a combination of several agents in order to minimize drug toxicity. Therefore, the reader is presented with the most up-to-date/current developments in sotrastaurin applications in Phase I and II trials with emphasis on data maintained from studies that combined sotrastaurin with established agents such as mycophenolic acid and tacrolimus.. Several trials are ongoing and planned to determine the optimal immunosuppressive regimen to benefit from sotrastaurin's distinct mechanism of action.

Topics: Calcineurin Inhibitors; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Cyclosporine; Drug Evaluation; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Protein Kinase C; Protein Kinase Inhibitors; Pyrroles; Quinazolines; Sirolimus; Tacrolimus; Treatment Outcome

The calcineurin inhibitors ciclosporin and tacrolimus are used to prevent acute rejection of solid organs after transplantation. Their use can lead to chronic renal damage characterized by progressive and irreversible deterioration of renal function associated with interstitial fibrosis, tubular atrophy, arteriolar hyalinosis and glomerulosclerosis. Many approaches to better understand the mechanisms of this toxicity are in use. The aim of these approaches is to find biomarkers of early kidney injury and potential therapeutic targets. Despite these efforts, the biological processes leading to calcineurin inhibitor nephrotoxicity remain poorly understood. Furthermore, the diagnosis of chronic renal damage remains inaccurate without definitive diagnostic tools, no effective prevention exists and a therapy to treat the damage has yet to be developed. In this article, theories of pharmacodynamics, pharmacokinetics, therapeutic drug monitoring and pharmacogenetics are synthesized in ways that may improve the understanding of mechanisms leading to calcineurin inhibitor toxicity. The importance of global approaches such as toxicogenomics is emphasized to characterize early cellular responses implicated in calcineurin inhibitor nephrotoxicity.

Topics: Animals; Calcineurin; Calcineurin Inhibitors; Cyclosporine; Drug-Related Side Effects and Adverse Reactions; Enzyme Inhibitors; Humans; Kidney Diseases; Tacrolimus

Topical pimecrolimus 1% cream (Elidel) [hereafter referred to as topical pimecrolimus] is a nonsteroidal alternative in the treatment of pediatric atopic dermatitis. In vehicle-controlled, short-term, continuous-use trials in pediatric patients with mild to moderate atopic dermatitis, topical pimecrolimus was effective in treating disease symptoms. Topical pimecrolimus was effective in preventing disease flares and reducing the need for topical corticosteroids in longer term, intermittent-use trials. In addition, topical pimecrolimus was associated with improvements in the health-related quality of life (HR-QOL) of pediatric patients with atopic dermatitis and their parents. In vehicle-controlled trials, topical pimecrolimus was generally as well tolerated as vehicle. Topical pimecrolimus showed similar efficacy to topical tacrolimus 0.03% ointment (hereafter topical tacrolimus) in a short-term, continuous-use trial and the two agents had a generally similar tolerability profile. Although comparative data between topical pimecrolimus and topical corticosteroids are lacking in pediatric patients, and the long-term tolerability (beyond 1-2 years) of topical pimecrolimus is yet to be established, topical pimecrolimus is a useful agent in the management of pediatric patients with mild to moderate atopic dermatitis who do not achieve satisfactory treatment with other topical pharmacologic treatments, including topical corticosteroids.

Topics: Administration, Topical; Animals; Child; Dermatitis, Atopic; Drug-Related Side Effects and Adverse Reactions; Humans; Quality of Life; Tacrolimus

Tacrolimus ointment is a nonsteroid treatment for atopic dermatitis which is both effective and has a minimal side-effect profile. However, some clinicians may be reluctant to use tacrolimus ointment due to the "unknown risks", meaning those that have not been uncovered in human studies conducted thus far. Therefore, the available animal data regarding the "unknown risks" of topical tacrolimus therapy are reviewed, and a discussion of the interpretation of this available but limited data is presented.. Some of the fear on the part of clinicians regarding the use of topical tacrolimus may come from the results of animal studies which showed an increase in lymphoma and UV-induced skin cancer after treatment with topical tacrolimus in animal models of carcinogenesis. However, rigorous assessment of these studies suggest that it is somewhat likely that these represent a species-specific response to tacrolimus in an animal already predisposed to tumor formation, and therefore may not be relevant in assessing the possibility of an increased human health risk.. Animal and human studies suggest that topical tacrolimus is a safe alternative to topical steroids, with the major known adverse effect being a transient burning sensation, compared with the known adverse effects of topical steroids, including long-lasting ones. Therefore, in the opinion of the authors, currently available data, including animal studies, does not suggest that "unknown risks" of topical tacrolimus need be any more concerning than the known side-effects of the topical steroids.

Topics: Administration, Topical; Animals; Dermatitis, Atopic; Drug-Related Side Effects and Adverse Reactions; Humans; Immunosuppressive Agents; Lymphoma; Skin Absorption; Skin Neoplasms; Tacrolimus; Ultraviolet Rays

Topical calcineurin inhibitors (pimecrolimus, Elidel, East Hanover, NJ; and tacrolimus, Protopic, Tokyo, Japan) have been approved for the use in atopic dermatitis since the year 2000. These compounds represent a relatively safe class of topical anti-inflammatory, nonsteroidal therapy. However, in January of 2006, the US Food and Drug Administration issued a black box warning on these compounds about possible concerns of increased long-term malignancy risk due to systemic immunosuppression. To date, studies from clinical trials, systemic absorption, and post-marketing surveillance show no evidence for this systemic immunosuppression or increased risk for any malignancy.

Topics: Calcineurin Inhibitors; Dermatitis, Atopic; Dermatologic Agents; Drug-Related Side Effects and Adverse Reactions; Immunosuppression Therapy; Immunosuppressive Agents; Neoplasms; Tacrolimus; Time Factors; United States; United States Food and Drug Administration

The pharmacokinetics of once-daily extended-release tacrolimus tablets (LCPT) in de novo liver transplantation have not been previously reported. In this phase II, randomized, open-label study, de novo liver transplant recipients were randomized to LCPT 0.07-0.13 mg/kg/day (taken once daily; n = 29) or twice-daily immediate-release tacrolimus capsules (IR-Tac) at 0.10-0.15 mg/kg/day (divided twice daily; n = 29). Subsequent doses of both drugs were adjusted to maintain tacrolimus trough concentrations of 5 to 20 ng/mL through day 90, and 5-15 ng/mL thereafter. Twenty-four-hour pharmacokinetic profiles were obtained on days 1, 7, and 14, with trough concentration and efficacy/safety monitoring through year 1. Similar proportions of patients in both groups achieved therapeutic trough concentrations on days 7 and 14 (day 7: LCPT = 78%, IR-Tac = 75%; day 14: LCPT = 86%, IR-Tac = 91%) as well as similar systemic and peak exposure. There was a robust correlation between drug concentration at time 0 and area under the concentration-time curve for both LCPT and IR-Tac (respectively, day 7: r = 0.86 and 0.79; day 14: r = 0.93 and 0.86; P < .0001 for all). Dose adjustments during days 1 to 14 were frequent. Thirty-five patients completed the extended-use period. No significant differences in adverse events were seen between groups. Incidence of biopsy-proven acute rejection (LCPT = 6 and IR-Tac = 4) was similar on day 360. Between formulations, overall exposure was similar at 1 week after transplant with the characteristic delayed-release pharmacokinetic profile of LCPT demonstrated in this novel population. These data support further investigation of the safety and efficacy of LCPT in de novo liver transplantation.

Topics: Area Under Curve; Biological Availability; Capsules; Delayed-Action Preparations; Drug Administration Schedule; Drug-Related Side Effects and Adverse Reactions; Female; Graft Rejection; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Metabolic Clearance Rate; Middle Aged; Tablets; Tacrolimus

Compliance with immunosuppressive regimens may affect clinical outcomes in renal transplant recipients. The aim of this study was to assess the safety and efficacy of standard-dose tacrolimus modified-release (TAC-MR) once daily versus tacrolimus (TAC) twice daily in stable renal transplant recipients.. Ninety-nine stable renal transplant recipients were randomized to receive standard-dose tacrolimus twice daily or standard-dose modified-release tacrolimus once daily on a 1:1 (mg:mg) basis. The primary end point was the incidence of adverse events (AEs) in both groups. Secondary end points included biopsy-proven acute rejection, graft survival, patient survival, clinical indicators, and change in score of questionnaire.. The incidence of AEs was not different between the TAC and TAC-MR groups (56.0% vs 53.1%, P > .05). There were no significant differences in mean calculated glomerular filtration rate, blood pressure, glycosylated hemoglobulin (HbA1c), blood concentration of tacrolimus, and drug compliance. The scores of all items in the 36-item short form health survey (SF-36) were not different between groups, except for vitality. With respect to the subject questionnaire, there was no difference in question scores between the two treatment groups.. A regimen of TAC-MR once daily can be considered as an effective and safe alternative formulation of tacrolimus in stable renal transplant patients.

Topics: Adult; Blood Pressure; Delayed-Action Preparations; Drug Administration Schedule; Drug-Related Side Effects and Adverse Reactions; Female; Glomerular Filtration Rate; Glycated Hemoglobin; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Pilot Projects; Research Design; Surveys and Questionnaires; Tacrolimus

Acute graft-versus-host disease (aGVHD) is a major cause of morbidity and mortality after matched unrelated, related, or mismatched related donor hematopoietic stem-cell transplantation (HSCT). Improved GVHD prevention methods are needed. Pentostatin, an adenosine deaminase inhibitor, leads to lymphocyte depletion with low risk of myelosuppression. We hypothesized that addition of pentostatin to GVHD prophylaxis with tacrolimus and mini-methotrexate may improve outcomes, and we conducted a Bayesian adaptively randomized, controlled, dose-finding study, taking into account toxicity and efficacy.. Success was defined as the patient being alive, engrafted, in remission, without GVHD 100 days post-HSCT and no grade ≥ 3 GVHD at any time. Patients were randomly assigned to pentostatin doses of 0, 0.5, 1.0, 1.5, and 2.0 mg/m(2) with drug administered on HSCT days 8, 15, 22, and 30. Eligible patients were recipients of mismatched related (n = 10) or unrelated (n = 137) donor HSCT.. Median age was 47 years. Thirty-seven, 10, 29, 61, and 10 patients were assigned to the control and four treatment groups, respectively, with comparable baseline characteristics. Pentostatin doses of 1.0 and 1.5 mg/m(2) had the highest success rates (69.0% and 70.5%) versus control (54.1%). The posterior probabilities that the success rates were greater with 1.5 mg/m(2) or 1.0 mg/m(2) versus control are 0.944 and 0.821, respectively. Hepatic aGVHD rates were 0%, 17.2%, and 11.1%, respectively, for 1.5 mg/m(2), 1.0 mg/m(2), and control groups. No grades 3 to 4 aGVHD occurred in 11 HLA-mismatched recipients in the 1.5 mg/m(2) group.. Pentostatin increased the likelihood of success as defined here, and should be further investigated in larger randomized, confirmatory studies.

Topics: Adenosine Deaminase Inhibitors; Adolescent; Adult; Aged; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Intention to Treat Analysis; Male; Methotrexate; Middle Aged; Pentostatin; Survival Analysis; Tacrolimus; Transplantation Conditioning

Pimecrolimus cream 1% has been shown to effectively control atopic eczema (AE) when applied twice daily from the first signs or symptoms of AE until clearance. Moreover, pimecrolimus cream 1% has a favourable safety profile, lacking topical corticosteroid-related side-effects such as skin atrophy, making it particularly useful to treat delicate body regions (e.g. the face).. The objective of this naturalistic study was to monitor the safety, tolerability and efficacy of pimecrolimus when used in the long-term management of AE in a real-life setting.. A multicentre, open-label study was conducted in 2034 patients aged >or= 3 months with mild to moderate AE for up to 12 months' duration. Patients applied pimecrolimus cream twice daily, initiating treatment at first signs or symptoms of AE, continuing until clearance.. Patients (n= 1847; 91%) completed 3 months of the study. Treatment success (clear or almost clear AE) after 3 months of treatment was observed on the whole body in 59% of patients and on the face in 81% of patients. Disease improvement of whole body and face was seen in 77% and 63% of patients, respectively. Pruritus was absent or mild in 79% of patients. Pimecrolimus cream was well tolerated throughout the study.. In a daily practice setting, pimecrolimus cream 1% effectively and safely controls AE.

Topics: Adolescent; Child; Child, Preschool; Dermatitis, Atopic; Dermatologic Agents; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Infant; Male; Ointments; Pruritus; Tacrolimus; Treatment Outcome

Mycophenolic acid (MPA) pharmacokinetics using the mycophenolate mofetil (MMF) formulation are known to differ between patients receiving tacrolimus or cyclosporine, but only limited data exist concerning concomitant use of tacrolimus and enteric-coated mycophenolate sodium (EC-MPS).. In this six-month, multicenter, open-label, single-arm trial, 63 maintenance renal transplant patients receiving tacrolimus were converted from mycophenolate mofetil (MMF) to EC-MPS.. MPA concentration-time profiles in 21 patients showed that MPA exposure was similar with MMF or EC-MPS (mean area under the curve 39.9+/-11.6 microg x h/mL versus 43.7+/-17.4 microg x h/mL at day 14 post-conversion). Median time to peak concentration was 0.5 hr with MMF and 1.5 hr with EC-MPS. Inosine monophosphate dehydrogenase (IMPDH) activity was almost identical: area under the enzyme activity time curve (AEC) was 124.2+/-32.0 nmol x h/mg prot/h with MMF and 130.3+/-36.6 nmol x h/mg prot/h with EC-MPS at 14 days post-conversion; average daytime IMPDH activity was 10.3+/-2.7 nmol/h/mg protein and 10.9+/-2.7 nmol/h/mg protein, respectively. Maximal daytime inhibition of IMPDH activity was 67% with MMF and 62% with EC-MPS at day 14. One patient (1.6%) experienced mild biopsy-proven acute rejection. No graft losses or deaths occurred. Renal function remained stable (mean calculated creatinine clearance 70.6+/-26.8 mL/min with MMF and 68.8+/-25.4 mL/min six months post-conversion). Adverse events or infections with a suspected relation to EC-MPS occurred in 12 patients (19%). Four patients discontinued EC-MPS due to adverse events or infections.. MMF and EC-MPS are associated with similar MPA exposure and equivalent pharmacodynamic effect. Conversion of tacrolimus-treated maintenance renal transplant patients from MMF to EC-MPS is safe and well-tolerated and does not compromise therapeutic efficacy.

Topics: Adolescent; Adult; Aged; Drug Tolerance; Drug-Related Side Effects and Adverse Reactions; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Tacrolimus; Treatment Outcome

To compare the long-term effect and safety of tacrolimus (FK506) and cyclosporine (CsA) in kidney transplant (KT) recipients carrying hepatitis B Virus(HBV).. A total of 109 patients with HBV were randomized into FK506 group (52 cases) and CsA group (57 cases) after KT, and a 2-year-long follow-up of the patients was conducted to record the patient and graft survival, incidence of acute graft rejection and postoperative liver function.. The 2-year patient/graft survival was 86.0%/73.7% and 94.2%/90.3% in CsA and FK506 groups, respectively (P<0.05), with incidence of acute rejection of 10.5% and 9.6% (P>0.05), and rate of abnormal liver function of 26.3% and 15.4% (P<0.05), respectively. Eight patients (14.4%) in CsA group required a drug conversion but none in FK506 group. The drug conversion resulted in significant reduction of ALT/AST level from 255.13+/-31.38/201.88+/-21.25 U/L to 31.25+/-11.50/25.13+/-9.68 U/L (P<0.01).. For HBV-carrying renal transplant recipients, FK506 as the primary choice of immunosuppressant can be more effective and safer than CsA.

Topics: Adolescent; Adult; Carrier State; Cyclosporine; Drug-Related Side Effects and Adverse Reactions; Female; Graft Rejection; Hepatitis B Surface Antigens; Hepatitis B virus; Humans; Kidney Transplantation; Liver; Male; Middle Aged; Tacrolimus; Young Adult

The aim of our study was to evaluate the clinical efficacy and safety profile of a novel compound, Tacrolimus powder in Orabase 0.1% in patients with LP and LL.. Seven patients with LP and 3 with LL were asked to participate. All patients received a 1 week treatment of Fluconazole, prior to entering the study, and on follow up visit were provided with a 15 g container of the study medication. Patients were asked to treat the most symptomatic site, three times a day for two weeks.. Disease control (signs) was achieved in most patients by the end of two weeks (from 1.58 to 0.55); all patients experienced a high degree of discomfort (pain) at baseline, which dropped quickly by the end of the second week of treatment (from 1.95 to 0.45); none developed yeast during the course of treatment. Recurrent headaches were reported by one patient with erosive LP, and transient burning by a patient with reticular LP.. Tacrolimus powder in Orabase 0.1% appears to have a relatively safe profile, and represents a likely alternative to topical steroids in the treatment of LP and LL, especially in those at risk for oral candidiasis.

Topics: Administration, Topical; Adult; Aged; Anti-Inflammatory Agents; Carboxymethylcellulose Sodium; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Immunosuppressive Agents; Lichen Planus, Oral; Male; Middle Aged; Pain Measurement; Pharmaceutical Vehicles; Pilot Projects; Steroids; Tacrolimus; Treatment Outcome

Tacrolimus is an immunosuppressant widely used in transplantations requiring mandatory concentration-controlled dosing to prevent acute rejection or adverse effects, including new-onset diabetes mellitus (NODM). However, no relationship between NODM and tacrolimus exposure has been established. This study aimed to evaluate the relationship between cumulative tacrolimus exposure and NODM occurrence.. A total of 452 kidney transplant patients were included in this study. Sixteen patients developed NODM during the first 3 months after transplant. We considered all tacrolimus concentration (C0) values collected until the diagnosis of NODM in these patients and until 3 months after transplant in the others. New tacrolimus cumulative exposure metrics were derived from the time profile of the tacrolimus morning predose concentration, C0: the percentage of C0 values > cutoff, the average of C0 values above the cutoff, and the percentage of the area under C0 versus time curve, AUCC0, above the cutoff. The cutoff chosen was 15 ng/mL, corresponding to the higher end of the therapeutic range for the early post-transplant period. The influence of these metrics on NODM and other clinical and biological characteristics was investigated using the Cox models.. The percentage of C0 > 15 mcg/L was statistically different between patients with and without NODM (P = 0.01). Only these tacrolimus C0-derived metrics were significantly associated with an increased risk of NODM [HR: 1.73 (1.43-2.10, P < 0.001)].. This study shows that tacrolimus concentrations >15 mcg/L affect the incidence of NODM.

Topics: Diabetes Mellitus; Drug-Related Side Effects and Adverse Reactions; Humans; Immunosuppressive Agents; Kidney Transplantation; Tacrolimus

The current regulatory criterion for bioequivalence of narrow therapeutic index (NTI) drugs in the European Union requires that the 90% confidence interval for the ratio of the population geometric means of the test product compared with the reference for area under the plasma concentration-time curve (AUC), and in certain cases maximum plasma drug concentration (C

Topics: Biological Variation, Individual; Colchicine; Computer Simulation; Cyclosporine; Dose-Response Relationship, Drug; Drug Approval; Drug Compounding; Drug-Related Side Effects and Adverse Reactions; Europe; European Union; Everolimus; Humans; Models, Biological; Research Design; Sample Size; Tacrolimus; Therapeutic Equivalency; Therapeutic Index, Drug; Thyroxine; Treatment Failure

We identified two reports of drug levels increased and acute kidney injury caused by the drug-drug interaction between azithromycin (AZM) and tacrolimus (TAC). However, it is unclear whether the combination of these two drugs causes additive or synergistic adverse drug reactions. Therefore, we evaluated the disproportionality in reporting drug level increased and acute kidney injury for these two drugs are used alone and in combination with each other.. Data from the US Food and Drug Administration's Adverse Event Reporting System from 1974 to Q3/2021 were used. Reports based on exposure to macrolide antibiotic alone, TAC alone, and each macrolide antibiotic + TAC were extracted. Proportional reporting ratios (PRRs) and 95% confidence intervals (CIs) were calculated, and a lower limit of the 95% CI (Lower95CI) value of 2.0 or higher was interpreted as a signal of safety.. Lower95CIs for macrolide antibiotic alone and TAC showed no potential signals of safety, including drug level increase, acute kidney injury, and control event. The PRRs and 95% CI for drug levels increased were 3.27 (2.69-3.97) for AZM + TAC, and 10.81 (9.59-12.17) for clarithromycin (CAM) + TAC. For CAM + TAC, the PRR and 95% CI were 8.42 (7.51-9.44) in acute kidney injury. However, AZM + TAC was not associated with a signal of safety in acute kidney injury.. This suggests that AZM + TAC has a low risk of causing acute kidney injury but may cause increased drug levels.

Topics: Acute Kidney Injury; Anti-Bacterial Agents; Azithromycin; Clarithromycin; Drug-Related Side Effects and Adverse Reactions; Humans; Tacrolimus

Localized flushing after alcohol ingestion is a reported adverse effect of 2 topical calcineurin inhibitors, tacrolimus and pimecrolimus, which are approved to treat atopic dermatitis and used off label for other dermatologic conditions. We propose techniques for alleviating this phenomenon.

Topics: Administration, Topical; Calcineurin Inhibitors; Dermatitis, Atopic; Drug-Related Side Effects and Adverse Reactions; Humans; Tacrolimus

Mycophenolate (mycophenolate mofetil [MMF]; mycophenolate sodium [MPS]) and tacrolimus (FK-506) are commonly and concomitantly used to prevent rejection in organ transplant. Mycophenolate-induced hepatotoxicity causing the reduced FK-506 metabolism with nephrotoxicity may be less appreciated, leading to inappropriate management. We describe a new living donor kidney recipient receiving pretransplant and post-transplant immunosuppressants including oral mycophenolate (MMF 1 g daily) and tacrolimus (FK-506 4-8 mg daily) who developed progressive liver dysfunction (up to 10-fold increase) despite the reduced FK-506 dosage (6 mg daily). A thorough investigation including infection, inflammation, and autoimmune hepatitis were unremarkable. With a withdrawal of MMF, his liver function improved, but persistently higher trough serum FK-506 level (12-15 ng/mL) and increased serum creatinine were notable. Moreover, the reintroduction of MPS with the reduced FK-506 dosage (4 mg daily) worsened liver function along with FK-506 nephrotoxicity (serum creatinine from 1.4-2.4 mg/dL). The replacement of MPS with mammalian target of rapamycin inhibitor not only resolved liver injury but also normalized serum FK-506 level and kidney function. Mycophenolate should be kept in mind as a cause of drug-induced hepatotoxicity that can reduce tacrolimus metabolism, leading to FK-506 nephrotoxicity and acute kidney injury in organ transplant.

Topics: Chemical and Drug Induced Liver Injury; Creatinine; Drug-Related Side Effects and Adverse Reactions; Enzyme Inhibitors; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Renal Insufficiency; Tacrolimus

The interaction between azole antifungal therapy and immunosuppressant tacrolimus (TAC) is a barrier to use.. This study quantified the drug interaction between low-dose fluconazole (LDF) and TAC to determine the appropriate TAC dose adjustment when used concurrently in renal transplant recipients.. We conducted a single-center retrospective chart review of renal transplant patients. We evaluated 94 patients and included 81. Low-dose fluconazole received a greater TAC TDD prior to post-operative day (POD) 10 (10.5 ± 4.7 mg vs. 7.1 ± 4.5 mg,. A 20% reduction in TAC TDD is warranted in renal transplant patients when used concomitantly with LDF to achieve therapeutic levels.

Topics: Antifungal Agents; Azoles; Drug-Related Side Effects and Adverse Reactions; Fluconazole; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Nystatin; Retrospective Studies; Tacrolimus

Tacrolimus (Tac) is an effective remission inducer of refractory ulcerative colitis (UC). Gene polymorphisms result in interindividual variability in Tac pharmacokinetics. In this study, we aimed to examine the relationships between gene polymorphisms and the metabolism, pharmacokinetics, and therapeutic effects of Tac in patients with UC. Forty-five patients with moderate-to-severe refractory UC treated with Tac were retrospectively enrolled. Genotyping for cytochrome P450 (CYP) 3A4*1G, CYP3A5*3, CYP2C19*2, CYP2C19*3, nuclear receptor subfamily 1 group I member 2 (NR1I2)-25385C>T, ATP-binding cassette subfamily C member 2 (ABCC2)-24C>T, ABCC2 1249G>A, and ABCC2 3972C>T was performed. Concentration/dose (C/D) ratio, clinical therapeutic effects, and adverse events were evaluated. The C/D ratio of Tac in UC patients with the CYP3A4*1G allele was statistically lower than in those with the CYP3A4*1/*1 allele (P = 0.005) and significantly lower in patients with CYP3A5*3/*3 than in those with CYP3A5*1 (P < 0.001). Among patients with the CYP3A4*1G allele, the C/D ratio was significantly lower in patients with CYP3A5*1 than in those with CYP3A5*3/*3 (P = 0.001). Patients with the NR1I2-25385C/C genotype presented significantly more overall adverse events than those with the C/T or T/T genotype (P = 0.03). Although CYP3A4*1G and CYP3A5*3 polymorphisms were related to Tac pharmacokinetics, CYP3A5 presented a stronger effect than CYP3A4. The NR1I2-25385C/C genotype was related to the overall adverse events. The evaluation of these polymorphisms could be useful in the treatment of UC with Tac.

Topics: Adult; Colitis, Ulcerative; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP3A; Drug-Related Side Effects and Adverse Reactions; Female; Genotype; Humans; Inactivation, Metabolic; Male; Middle Aged; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins; Polymorphism, Single Nucleotide; Tacrolimus

The calcineurin inhibitor tacrolimus has been widely used to prevent allograft rejection after transplantation. The purpose of this study was to clarify the adverse events associated with tacrolimus in solid organ transplantation using a spontaneous reporting system database.. We performed a retrospective pharmacovigilance disproportionality analysis using the Japanese Adverse Drug Event Report (JADER) database. Adverse event reports submitted to the Pharmaceuticals and Medical Devices Agency were analyzed, and the reporting odds ratio (ROR) and 95% confidence interval (CI) for each adverse event were calculated.. The database comprised 26,620 reports associated with tacrolimus, of which 2,014, 1,988, and 725 reports involved heart, kidney, and liver transplantation, respectively. Infectious disorder was commonly detected in these transplant patients. There was a significant association between tacrolimus use and colon cancer in patients undergoing heart transplantation (ROR: 3.33, 95% CI: 2.18 - 5.08), but not kidney or liver transplantation. Tacrolimus use in those undergoing kidney transplantation is strongly associated with bronchitis (ROR, 8.95; 95% CI, 6.34 - 12.6). A signal for seizure was detected in liver transplant patients with tacrolimus (ROR, 4.12; 95% CI, 1.77 - 9.59).. It was suggested that there is a diversity in the strength of the association between tacrolimus and adverse events in patients receiving heart, kidney, and liver transplantation. Our results may provide useful information for treatment with tacrolimus, although further research with more data is needed to clarify this.

Topics: Adverse Drug Reaction Reporting Systems; Databases, Factual; Drug-Related Side Effects and Adverse Reactions; Humans; Kidney Transplantation; Pharmacovigilance; Retrospective Studies; Tacrolimus

Mycophenolate Mofetil (MMF) is an immunosuppressive drug usually used in kidney transplants to prevent rejection. It has various adverse effects such as leucopenia, anemia, diarrhea but Mouth ulcers are rarely reported.. We present a case report of MMF-induced mouth ulcers in an African patient.. A 41-year-old African-male patient has painful oral ulcers which developed 5 months after kidney transplantation. The immunosuppressive maintenance regimen comprised Steroids, Tacrolimus and MMF.. These ulcers were firstly related to a fungic or viral infection so the patient was prescribed Fluconazole and Aciclovir without any improvement. Then, Tacrolimus blood level was checked and it was in a therapeutic range. Finally, we decide to stop MMF and the ulcers healed quickly.. Oral ulcers are frequently seen complications in immunosuppressant patient but are rarely described with MMF. These ulcers can become large and very painful and degrade patient's life quality. So when infections causes are excluded, we have to keep in mind that these ulcers can be a drug adverse effect.

Topics: Adult; Drug-Related Side Effects and Adverse Reactions; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Mycophenolic Acid; Oral Ulcer; Steroids; Tacrolimus; Transplant Recipients

Little is known about the efficacy and safety of induction therapy with calcineurin inhibitors in combination with vedolizumab for patients with Crohn's disease (CD) or ulcerative colitis (UC). We analyzed the outcomes of patients receiving vedolizumab along with calcineurin inhibitors.. We collected data on patients with CD (n = 9) or UC (n = 11) who began treatment with vedolizumab from May 20, 2014, through March 30, 2015, and received calcineurin inhibitors (tacrolimus or cyclosporin) during the first 12 months of vedolizumab therapy. Clinical activity scores and inflammatory markers were measured at baseline and at weeks 14, 30, and 52 of vedolizumab treatment. Clinical remission was defined as a Harvey-Bradshaw index score ≤4 or short clinical colitis activity index score ≤2; steroid-free clinical remission was defined as clinical remission without corticosteroids.. By week 14 of treatment, 44% of the patients with CD and 55% of the patients with UC achieved steroid-free clinical remission; after 52 weeks of treatment, 33% of the patients with CD and 45% of the patients with UC were in steroid-free clinical remission. Seven patients received salvage therapy with a calcineurin inhibitor after primary nonresponse to vedolizumab-1 of the 2 patients with UC and 2 of 5 patients with CD stopped taking the calcineurin inhibitors and achieved steroid-free remission at week 52. In total, 16 patients (59%) received 52 weeks of treatment with vedolizumab. Three serious adverse events were associated with calcineurin inhibitors.. Combination therapy of vedolizumab with either cyclosporin or tacrolimus is effective and safe at inducing and maintaining clinical remission in patients with CD and UC with up to 52 weeks of follow-up evaluation. Larger studies of the ability of calcineurin inhibitors to induce remission in patients on vedolizumab are warranted.

Topics: Adolescent; Adult; Antibodies, Monoclonal, Humanized; Calcineurin Inhibitors; Cyclosporine; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Gastrointestinal Agents; Humans; Inflammatory Bowel Diseases; Male; Prospective Studies; Tacrolimus; Treatment Outcome; Young Adult

Tacrolimus has been associated with notable extrarenal adverse effects (AEs), which are unpredictable and impact patient morbidity. The association between model-predicted tacrolimus exposure metrics and standardized extrarenal AEs in stable renal transplant recipients was investigated and a limited sampling strategy (LSS) was developed to predict steady-state tacrolimus area under the curve over a 12-h dosing period (AUC. All recipients receiving tacrolimus and mycophenolic acid ≥6 months completed a 12-h cross-sectional observational pharmacokinetic-pharmacodynamic study. Patients were evaluated for the presence of individual and composite gastrointestinal, neurological, and aesthetic AEs during the study visit. The associations between AEs and tacrolimus exposure metrics generated from a published population pharmacokinetic model were investigated using a logistic regression analysis in NONMEM 7.3. An LSS was determined using a Bayesian estimation method with the same patients.. Dose-normalized tacrolimus AUC. Several AEs (i.e. diarrhoea, dyspepsia, insomnia and neurological AE ratio) were associated with tacrolimus dose normalized AUC

Topics: Administration, Oral; Adult; Aged; Area Under Curve; Cross-Sectional Studies; Dose-Response Relationship, Drug; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Male; Middle Aged; Models, Biological; Mycophenolic Acid; Tacrolimus; Transplant Recipients; Young Adult

Treatment of tacrolimus toxicity includes holding tacrolimus and supportive care. The objective is to describe considerations for pharmacologic induction of tacrolimus metabolism.. A 52-year-old male with a failed renal transplant on chronic haemodialysis developed tacrolimus toxicity due to a drug-drug interaction with darunavir/ritonavir. Tacrolimus concentrations were >60 ng/mL for 10 days despite holding tacrolimus and darunavir/ritonavir. Development of encephalopathy prompted initiation of phenytoin to induce tacrolimus metabolism. Tacrolimus concentration was <2 ng/mL within 4 days and mental status normalized.. Phenytoin metabolic induction is a therapeutic option for prolonged tacrolimus toxicity.

Topics: Darunavir; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Humans; Immunosuppressive Agents; Male; Middle Aged; Phenytoin; Renal Dialysis; Ritonavir; Tacrolimus

Alcohol-related liver disease (ALD) is one of the main indications for liver transplantation (LT). For 20 years, tacrolimus (Tac) is the cornerstone immunosuppressive drug used after LT and is very efficient for the prevention of rejection. Nevertheless, the major drawback of long-term use of Tac is the risk for developing dose-dependent adverse effects.. The aim of the present study was to assess the impact of Tac exposure (trough concentrations and concentration/dose (C/D) ratio) during the first year after LT, on short- and long-term complications after LT for ALD.. All patients who underwent a LT for ALD at Lyon Edouard Herriot Hospital from October 1990 to September 2010, and who were treated with Tac for at least one year after LT, were analyzed.. The study population consisted in 251 patients, mean age 53.4 ± 7.3 years, and followed during 11.6 ± 4.8 years. Post-LT complications included severe infectious events (44.6%), malignancies (41.4%), arterial hypertension (49.4%) dyslipidemia (44.2%), diabetes (18.7%) and cardiovascular events (15.5%). De novo hypertension, cardiovascular event, CMV infection, non-melanoma skin cancers and HCC recurrence after transplantation were significantly associated with higher Tac trough blood concentration. In addition, Tac fast-metabolizers (defined as C/D < 1.8) had significantly more impaired renal function at 1, 5, and 10 years and more cardiovascular events, PTLD, diabetes and hypertension than slow-metabolizers.. Our results strongly support that, in addition to blood trough concentrations, Tac metabolism, as estimated by the simple C/D ratio, could be an efficient parameter in daily practice to identify LT patients at risk to develop long term general complications of Tac.

Topics: Cytomegalovirus Infections; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; France; Humans; Hypertension; Immunosuppressive Agents; Liver Diseases, Alcoholic; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Risk; Skin Neoplasms; Tacrolimus; Time Factors

One factor that significantly contributes to renal allograft loss is chronic calcineurin inhibitor (CNI) nephrotoxicity (CIN). Among other factors, the complement (C-) system has been proposed to be involved CIN development. Hence, we investigated the impact of CNIs on intracellular signalling and the effects on the C-system in human renal tubule cells. In a qPCR array, CNI treatment upregulated C-factors and downregulated SOCS-3 and the complement inhibitors CD46 and CD55. Additionally, ERK1/-2 was required for these regulations. Following knock-down and overexpression of SOCS-3, we found that SOCS-3 inhibits ERK1/-2 signalling. Finally, we assessed terminal complement complex formation, cell viability and apoptosis. Terminal complement complex formation was induced by CNIs. Cell viability was significantly decreased, whereas apoptosis was increased. Both effects were reversed under complement component-depleted conditions. In vivo, increased ERK1/-2 phosphorylation and SOCS-3 downregulation were observed at the time of transplantation in renal allograft patients who developed a progressive decline of renal function in the follow-up compared to stable patients. The progressive cohort also had lower total C3 levels, suggesting higher complement activity at baseline. In conclusion, our data suggest that SOCS-3 inhibits CNI-induced ERK1/-2 signalling, thereby blunting the negative control of C-system activation.

Topics: Aged; Aged, 80 and over; Apoptosis; Calcineurin Inhibitors; CD55 Antigens; Cell Line; Cell Survival; Complement Membrane Attack Complex; Complement System Proteins; Cyclosporine; Drug-Related Side Effects and Adverse Reactions; Female; Gene Expression Regulation; Graft Rejection; Humans; Kidney Diseases; Kidney Transplantation; Kidney Tubules; Male; MAP Kinase Signaling System; Membrane Cofactor Protein; Middle Aged; Phosphorylation; RNA, Small Interfering; Suppressor of Cytokine Signaling 3 Protein; Tacrolimus

Inpatient tacrolimus therapeutic drug monitoring (TDM) lacks standardized guidelines. In this study, the authors analyzed variability in the preanalytical phase of the inpatient tacrolimus TDM process at their institution.. Patients receiving tacrolimus (twice-daily formulation) and tacrolimus laboratory analysis were included in the study. Times of tacrolimus administration and laboratory study collection were extracted, and time distribution plots for each step in the inpatient TDM process were generated.. Trough levels were drawn appropriately in 25.9% of the cases. Timing between doses was consistent, with 91.9% of the following dose administrations occurring 12 ± 2 hours after the previous dose. Only 38.1% of the drug administrations occurred within 1 hour of laboratory study collection. Tacrolimus-related patient safety events were reported at a rate of 1.9 events per month while incorrect timing of TDM sample collection occurred approximately 200 times per month. Root cause analysis identified a TDM process marked by a lack of communication and coordination of drug administration and TDM sample collection. Extrapolating findings nationwide, we estimate $22 million in laboratory costs wasted annually.. Based on this large single-center study, the authors concluded that the inpatient TDM process is prone to timing errors, thus is financially wasteful, and at its worst harmful to patients due to clinical decisions being made on the basis of unreliable data. Further work is needed on systems solutions to better align the laboratory study collection and drug administration processes.

Topics: Blood Specimen Collection; Drug Administration Schedule; Drug Costs; Drug Monitoring; Drug-Related Side Effects and Adverse Reactions; Humans; Immunosuppressive Agents; Inpatients; Michigan; Retrospective Studies; Tacrolimus; Time Factors; Transplants

The aim of the study was to investigate the relationship between tacrolimus (TAC) immunosuppressive treatment and serum concentrations of immunoglobulin heavy/light chain pairs (sHLC) and free light chains (sFLC) in patients after heart transplantation (HTX) and to use these biomarkers to predict the risk of infection in these patients. A total of 88 patients with an immunosuppressive regimen involving tacrolimus who underwent HTX were analyzed over 24 months of follow-up. sFLC and sHLC levels were determined before and at three time points after HTX. TAC concentrations were determined at several time points after HTX, and mean TAC concentrations and areas under the curve (AUCs) of TAC concentration were calculated. Relevant clinical data were obtained from patients' medical records. A larger AUC of TAC was associated with decreases in the concentrations of IgG total (p < 0.05); similarly, cumulative AUC of TAC during 18 post-transplant months correlated inversely with sHLC IgG kappa (r = -0.228, p < 0.05) and IgG total (r = -0.352, p < 0.05). Concentrations of sFLC kappa, sFLC lambda, sHLC IgG kappa, and sHLC IgG total were significantly lower in infected patients (in the 9th month after HTX, all p < 0.05). Combined criteria for increased AUC (greater than the median of 12.9 mg·d/l) and decreased sFLC kappa (less than the median of 12.5 mg/l) correlated with the presence of infection (p < 0.03) in the 9th month after HTX. Ratio of concentration of TAC to sFLC kappa or lambda was significantly higher in infected patients (both p < 0.05). Intensive treatment with tacrolimus after HTX is possibly reflected by decreases in sFLC and sHLC (mainly sHLC IgG). Patients with decreased concentrations of these biomarkers are at increased risk for infection, primarily in the 9th month after HTX, when the concentrations of tacrolimus were the highest.

Topics: Adult; Aged; Biomarkers; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; Graft Rejection; Heart Transplantation; Humans; Immunoglobulin Heavy Chains; Immunoglobulin Light Chains; Immunosuppressive Agents; Infections; Male; Middle Aged; Predictive Value of Tests; Prognosis; Risk; Tacrolimus; Young Adult

Predniso(lo)ne, alone or in combination with azathioprine, is the standard-of-care (SOC) therapy for autoimmune hepatitis (AIH). However, the SOC therapy is poorly tolerated or does not control disease activity in up to 20% of patients. We assessed the efficacy of mycophenolate mofetil (MMF) and tacrolimus as second-line therapy for patients with AIH.. We performed a retrospective study of data (from 19 centers in Europe, the United States, Canada, and China) from 201 patients with AIH who received second-line therapy (121 received MMF and 80 received tacrolimus), for a median of 62 months (range, 6-190 mo). Patients were categorized according to their response to SOC. Patients in group 1 (n = 108) had a complete response to the SOC, but were switched to second-line therapy as a result of side effects of predniso(lo)ne or azathioprine, whereas patients in group 2 (n = 93) had not responded to SOC.. There was no significant difference in the proportion of patients with a complete response to MMF (69.4%) vs tacrolimus (72.5%) (P = .639). In group 1, MMF and tacrolimus maintained a biochemical remission in 91.9% and 94.1% of patients, respectively (P = .682). Significantly more group 2 patients given tacrolimus compared with MMF had a complete response (56.5% vs 34%, respectively; P = .029) There were similar proportions of liver-related deaths or liver transplantation among patients given MMF (13.2%) vs tacrolimus (10.3%) (log-rank, P = .472). Ten patients receiving MMF (8.3%) and 10 patients receiving tacrolimus (12.5%) developed side effects that required therapy withdrawal.. Long-term therapy with MMF or tacrolimus generally was well tolerated by patients with AIH. The agents were equally effective in previous complete responders who did not tolerate SOC therapy. Tacrolimus led to a complete response in a greater proportion of previous nonresponder patients compared with MMF.

Topics: Adolescent; Adult; Aged; Canada; Child; China; Drug-Related Side Effects and Adverse Reactions; Europe; Female; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies; Tacrolimus; Treatment Outcome; United States; Young Adult

Drug-induced transplant-associated thrombotic microangiopathy (DTA-TMA) is a rare but serious complication that can occur after hematopoietic cell transplantation (HCT) or solid organ transplantation (SOT) without guidelines for optimal management of this condition.. Given the ambiguity surrounding the treatment for DTA-TMA, we conducted a retrospective review to evaluate the impact of different treatment strategies in DTA-TMA patients. Our primary endpoint was to determine the overall response rate (ORR) for DTA-TMA based on the type of treatment modality chosen while secondary endpoints included the time to response, relapse rates, and overall survival for DTA-TMA cases.. There were a total of 14 DTA-TMA patients of whom nine were post-HCT and five were post-SOT. Most of the DTA-TMA cases were due to tacrolimus (n = 11) with a minority related to sirolimus (n = 3). A total of nine of 14 patients demonstrated response and five had no response to therapy. The ORR among the DTA-TMA patients after HCT and SOT who received plasma exchange (PLEX) were 25 and 100%, respectively. The ORRs among the patients (includes HCT and SOT) who received rituximab (n = 3) and eculizumab (n = 5) were 67 and 60%, respectively. There were two relapses noted in our study and both were in the HCT group.. While discontinuation of the offending agent may be sufficient for treatment of DTA-TMA after HCT, PLEX may be a reasonable option for DTA-TMA after SOT. Although the results are encouraging with rituximab and eculizumab in the treatment of DTA-TMA, larger prospective studies are needed to validate our findings.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Drug-Related Side Effects and Adverse Reactions; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Middle Aged; Organ Transplantation; Plasma Exchange; Retrospective Studies; Rituximab; Sirolimus; Tacrolimus; Thrombotic Microangiopathies; Treatment Outcome; Young Adult

The KDIGO Clinical Practice Guidelines for Glomerulonephritis recommended tacrolimus as an alternative regimen for the initial therapy for Idiopathic membranous nephropathy (IMN), however, large observational studies evaluating tacrolimus treatment in IMN remains rare.. A total of 408 consecutive IMN patients with nephrotic syndrome who were treated with tacrolimus in Jinling Hospital were included. The effectiveness and safety of tacrolimus treatment in IMN were analyzed in this study.. The cumulative partial or complete remission after tacrolimus therapy were 50%, 63% and 67% at 6, 12 and 24 months, respectively, and the cumulative complete remission rates were 4%, 13% and 23%, respectively. Multivariate logistic analysis showed that higher tacrolimus exposure during induction treatment, female gender, higher eGFR and no history of previous immunosuppressive therapy were independently associated with higher probability of remission. A relapse occurred in 101 of the 271 (37.3%) patients with partial or complete remission, and 18 of the 95 (18.9%) patients with complete remission. Tapering duration of tacrolimus and complete remission versus partial remission status were independent factors associated with risk of relapse. A decline in eGFR was the most frequent adverse event during tacrolimus treatment. During tacrolimus treatment, a ≥40% decrease in eGFR was observed in 43 (10.5%) patients.. Low dose tacrolimus is effective for IMN, with a total remission rate of 66% whereas with a rather high rate of relapse. However, the safety of tacrolimus treatment needs to be further validated in large randomized clinical trials.

Topics: Adult; China; Cohort Studies; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Female; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Longitudinal Studies; Male; Prevalence; Recurrence; Risk Factors; Sex Distribution; Tacrolimus; Treatment Outcome

Drug adherence is one of the most important factors determining graft and patient survivals after liver transplantation. A systematic pharmaceutical educational approach has been implemented to improve adherence in immunosuppressive drugs therapy at Siriraj Hospital.. This study was a single-center cross-sectional study of liver transplant patients who received pharmaceutical care from transplant pharmacists. The clinical pharmacy services, including medication review to emphasize patients' knowledge and awareness of immunosuppressive and general drug therapies with the use of various tools, were used to educate the patients. Drug-related problems (DRPs) and pre- and post-transplantation educational tests (divided into 3 parts: immunosuppressants [12 points], drug monitoring [6 points], and general drugs [2 points]) were analyzed.. From October 2012 to September 2014, a total of 50 liver transplant recipients (86 visits) were enrolled. After the systematic pharmaceutical educational program, the average total score of post-transplantation educational test improved from 3.48 to 13.30 (P < .001). Likewise, the mean scores of all 3 parts significantly increased (part I: 2.28 vs 8.18 [P < .001]; part II: 0.75 vs 3.63 (P < .001); and part III: 0.46 vs 1.50 [P < .001]). The incidences of major DRPs, nonadherence, and adverse drug reactions were 8%, 4%, and 2%, respectively.. A systematic pharmaceutical educational approach can significantly improve patients' knowledge and awareness concerning immunosuppressive drug usage.

Topics: Adult; Carcinoma, Hepatocellular; Cross-Sectional Studies; Drug Monitoring; Drug-Related Side Effects and Adverse Reactions; End Stage Liver Disease; Female; Graft Rejection; Hepatitis B, Chronic; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Incidence; Liver Neoplasms; Liver Transplantation; Male; Medication Adherence; Middle Aged; Mycophenolic Acid; Patient Education as Topic; Pharmaceutical Services; Risk Factors; Tacrolimus

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Body Mass Index; Drug-Related Side Effects and Adverse Reactions; Genotype; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Polymorphism, Single Nucleotide; Pregnane X Receptor; Receptors, Steroid; Risk Factors; Sequence Deletion; Tacrolimus

Two variants in the gene encoding the cytochrome P450 2C9 enzyme (CYP2C9) are considered the most significant genetic risk factors associated with bleeding after warfarin prescription. A variant in the vitamin K epoxide reductase (VKORC1) has been also associated by several studies with warfarin response. Another variant in the P450 3A5 enzyme (CYP3A5) gene is known to affect the metabolism of many drugs, including tacrolimus.. We conducted a population genetic study in 148 unrelated healthy Greek-Cypriot volunteers (through PCR-RFLP assays), in order to determine the frequencies of the above pharmacogenetics variants and to compare allele frequencies with those in other major ethnic groups. The allele frequencies of CYP2C9*2, CYP2C9*3 and CYP3A5*3 were found to be 0.162, 0.112 and 0.943 respectively, whereas VKORC1 - 1639A was 0.534. The latter frequency differs significantly when compared with Caucasians, Asians and Africans (p < 0.001) and is still significant when compared with the geographically and culturally closely related to Greek-Cypriots, Hellenes of Greece (p = 0.01). Interestingly ~18% of our population are carriers of four or three risk alleles regarding warfarin sensitivity, therefore they have a high predisposition for bleeding after taking high or even normal warfarin doses.. Our data show no significant difference in the frequency of CYP2C9 and CYP3A5 allelic variants when compared to the Caucasian population, but differ significantly when compared with Africans and Asians (p < 0.001). Also, the frequency of variant VKORC1 - 1639A differs between Greek-Cypriots and every other population we compared. Finally, about 1/5 Greek-Cypriots carry three or four risk alleles and ~50% of them carry at least two independent risk alleles regarding warfarin sensitivity, a potentially high risk for over-anticoagulation.

Topics: Adult; Aryl Hydrocarbon Hydroxylases; Cyprus; Cytochrome P-450 CYP2C9; Cytochrome P-450 CYP3A; Drug-Related Side Effects and Adverse Reactions; Gene Frequency; Genetic Predisposition to Disease; Genotype; Greece; Humans; Male; Polymerase Chain Reaction; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length; Risk Factors; Tacrolimus; Vitamin K Epoxide Reductases; Warfarin; Young Adult

The bile salt export pump (BSEP) is expressed at the canalicular domain of hepatocytes, where it serves as the primary route of elimination for monovalent bile acids (BAs) into the bile canaliculi. The most compelling evidence linking dysfunction in BA transport with liver injury in humans is found with carriers of mutations that render BSEP nonfunctional. Based on mounting evidence, there appears to be a strong association between drug-induced BSEP interference and liver injury in humans; however, causality has not been established. For this reason, drug-induced BSEP interference is best considered a susceptibility factor for liver injury as other host- or drug-related properties may contribute to the development of hepatotoxicity. To better understand the association between BSEP interference and liver injury in humans, over 600 marketed or withdrawn drugs were evaluated in BSEP expressing membrane vesicles. The example of a compound that failed during phase 1 human trials is also described, AMG 009. AMG 009 showed evidence of liver injury in humans that was not predicted by preclinical safety studies, and BSEP inhibition was implicated. For 109 of the drugs with some effect on in vitro BSEP function, clinical use, associations with hepatotoxicity, pharmacokinetic data, and other information were annotated. A steady state concentration (C(ss)) for each of these annotated drugs was estimated, and a ratio between this value and measured IC₅₀ potency values were calculated in an attempt to relate exposure to in vitro potencies. When factoring for exposure, 95% of the annotated compounds with a C(ss)/BSEP IC₅₀ ratio ≥ 0.1 were associated with some form of liver injury. We then investigated the relationship between clinical evidence of liver injury and effects to multidrug resistance-associated proteins (MRPs) believed to play a role in BA homeostasis. The effect of 600+ drugs on MRP2, MRP3, and MRP4 function was also evaluated in membrane vesicle assays. Drugs with a C(ss)/BSEP IC₅₀ ratio ≥ 0.1 and a C(ss)/MRP IC₅₀ ratio ≥ 0.1 had almost a 100% correlation with some evidence of liver injury in humans. These data suggest that integration of exposure data, and knowledge of an effect to not only BSEP but also one or more of the MRPs, is a useful tool for informing the potential for liver injury due to altered BA transport.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Biological Transport; Chemical and Drug Induced Liver Injury; Cluster Analysis; Drug-Related Side Effects and Adverse Reactions; Humans; Liver; Male; Multidrug Resistance-Associated Proteins; Pharmacokinetics; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Risk Assessment; Risk Factors; Toxicity Tests

Topics: Child; Child, Preschool; Diarrhea; Drug-Related Side Effects and Adverse Reactions; Humans; Immunosuppressive Agents; Nephrotic Syndrome; Tacrolimus

The topical calcineurin antagonist tacrolimus plays an important role in the treatment of different forms of eczema because of its favorable risk profile. In addition, different off-label indications have been clinically tested where tacrolimus ointment has achieved clinical improvement. This article discusses off-label treatment of vitiligo, seborrheic dermatitis, steroid rosacea, perioral dermatitis, rosacea and lichen sclerosus.

Topics: Administration, Topical; Chronic Disease; Dermatologic Agents; Drug-Related Side Effects and Adverse Reactions; Evidence-Based Medicine; Humans; Immunosuppressive Agents; Off-Label Use; Skin Diseases; Tacrolimus; Treatment Outcome

Thymomas and thymic carcinomas, although uncommon, constitute a significant proportion of anterior mediastinal tumours. Systemic chemotherapy is the mainstay of treatment for inoperable or recurrent disease, but immunosuppressive therapy may provide an alternative treatment strategy.. We present a series of 18 patients diagnosed with unresectable thymic tumours, of which eight received immunosuppressive therapy following relapse after chemotherapy.. Eight individuals were treated with primary immunotherapy after a median of 3.5 lines of chemotherapy (range 2-6 lines), of which 3 had confirmed myasthenia gravis (MG). After 3 months, 2 patients achieved a radiological partial response and 4 had stable disease. The median time to progression measured 6.8 months (CI 1.4-19.3 months). Two of the 4 patients who progressed on tacrolimus and prednisolone received sirolimus. One of these patients has stable disease (SD) at 21 months, and the other has SD at 3 months.. Although previous case reports have related tacrolimus therapy with tumour shrinkage in patients with MG-associated invasive thymomas, these data are the first to demonstrate the efficacy of such immunosuppressive agents in a larger cohort of heavily pre-treated patients with thymic tumours. Our experience adds to the limited anecdotal evidence in the literature, and suggests that immunosuppressive agents represent a valuable additional treatment for thymic tumours.

Topics: Aged; Combined Modality Therapy; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Neoplasm Recurrence, Local; Sirolimus; Tacrolimus; Thymectomy; Thymus Neoplasms

Drug-induced liver injury (DILI) is a leading cause of drugs failing during clinical trials and being withdrawn from the market. Comparative analysis of drugs based on their DILI potential is an effective approach to discover key DILI mechanisms and risk factors. However, assessing the DILI potential of a drug is a challenge with no existing consensus methods. We proposed a systematic classification scheme using FDA-approved drug labeling to assess the DILI potential of drugs, which yielded a benchmark dataset with 287 drugs representing a wide range of therapeutic categories and daily dosage amounts. The method is transparent and reproducible with a potential to serve as a common practice to study the DILI of marketed drugs for supporting drug discovery and biomarker development.

Topics: Animals; Benchmarking; Biomarkers, Pharmacological; Chemical and Drug Induced Liver Injury; Drug Design; Drug Labeling; Drug-Related Side Effects and Adverse Reactions; Humans; Pharmaceutical Preparations; Reproducibility of Results; United States; United States Food and Drug Administration

Drug-induced liver injury (DILI) is a significant concern in drug development due to the poor concordance between preclinical and clinical findings of liver toxicity. We hypothesized that the DILI types (hepatotoxic side effects) seen in the clinic can be translated into the development of predictive in silico models for use in the drug discovery phase. We identified 13 hepatotoxic side effects with high accuracy for classifying marketed drugs for their DILI potential. We then developed in silico predictive models for each of these 13 side effects, which were further combined to construct a DILI prediction system (DILIps). The DILIps yielded 60-70% prediction accuracy for three independent validation sets. To enhance the confidence for identification of drugs that cause severe DILI in humans, the "Rule of Three" was developed in DILIps by using a consensus strategy based on 13 models. This gave high positive predictive value (91%) when applied to an external dataset containing 206 drugs from three independent literature datasets. Using the DILIps, we screened all the drugs in DrugBank and investigated their DILI potential in terms of protein targets and therapeutic categories through network modeling. We demonstrated that two therapeutic categories, anti-infectives for systemic use and musculoskeletal system drugs, were enriched for DILI, which is consistent with current knowledge. We also identified protein targets and pathways that are related to drugs that cause DILI by using pathway analysis and co-occurrence text mining. While marketed drugs were the focus of this study, the DILIps has a potential as an evaluation tool to screen and prioritize new drug candidates or chemicals, such as environmental chemicals, to avoid those that might cause liver toxicity. We expect that the methodology can be also applied to other drug safety endpoints, such as renal or cardiovascular toxicity.

Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Chemical and Drug Induced Liver Injury; Databases, Factual; Drug-Related Side Effects and Adverse Reactions; Humans; Liver; Models, Biological; Predictive Value of Tests

Children with severe corticosteroid-resistant ulcerative colitis either need to undergo surgery or be treated with more intensive immunosuppression. Our aim was to characterize the short- and long-term outcomes and adverse events associated with the use of tacrolimus in a steroid-refractory pediatric population.. We retrospectively reviewed the medical records of 46 children with steroid-refractory colitis treated with tacrolimus at Children's Hospital Boston between 1994 and 2008. Oral tacrolimus was initiated at a dose of 0.1 mg/kg twice a day and titrated to yield trough levels of 10-15 ng/mL for induction, and 5-10 ng/mL once in remission. The Pediatric Ulcerative Colitis Activity Index (PUCAI) and other measures of disease activity, adverse events, and long-term outcomes were assessed. Statistical analysis of outcomes was performed using SAS statistical software.. Ninety-three percent of patients were discharged without undergoing surgery. The median length of stay after starting tacrolimus was 10 days (range 4-37 days). The mean PUCAI score was 68 ± 13 prior to initiating tacrolimus, and 27 ± 18 at the time of hospital discharge. The probability of avoiding colectomy after starting tacrolimus was 40% at 26 months. The most common adverse events included hypertension (52%) and tremor (44%). There was one seizure and no deaths.. Tacrolimus is useful as induction therapy in pediatric patients with corticosteroid-refractory colitis and side effects are generally mild and reversible. Despite these findings, many patients develop exacerbations of colitis upon transition to maintenance therapies. The long-term colectomy rate in this challenging population remains ≈60% over time.

Topics: Acute-Phase Proteins; Adolescent; Adrenal Cortex Hormones; Adult; Child; Child, Preschool; Cohort Studies; Colitis, Ulcerative; Drug Resistance; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Retrospective Studies; Tacrolimus; Treatment Outcome; Young Adult

The objective of this study was to assess the usefulness of tacrolimus (TAC) for rheumatoid arthritis (RA) patients. The first 101 consecutive RA patients in whom TAC treatment was initiated were prospectively registered and their data analyzed. Clinical variables were extracted from the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) database. The 101 patients included 85 females and 16 males. Average doses of TAC were 1.62 mg/day at entry and 2.13 mg/day at month 12. The average doses of concomitantly prescribed prednisolone (6.92 mg/day) and methotrexate (MTX; 8.59 mg/week) were higher than those in all RA patients in the IORRA cohort. At month 12, 57 patients remained on TAC therapy; 18 patients had discontinued TAC due to side effects, and 16 patients had discontinued due to inefficacy. Adverse reactions responsible for discontinuation included gastrointestinal symptoms, renal dysfunction, and infection. According to the European League Against Rheumatism (EULAR) response criteria, 56.5% of the patients who continued TAC at 12 months experienced "good" or "moderate" responses. Through the use of last observation carried forward (LOCF) methodology, the average Disease Activity Score (DAS) 28 significantly improved. We confirmed the usefulness of TAC for the treatment of RA and found that TAC is suitable for RA patients who are unable to use biologic agents or to tolerate a high dose of MTX because of their complications or background factors.

Topics: Arthritis, Rheumatoid; Drug Resistance; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Health Status; Humans; Immunosuppressive Agents; Male; Methotrexate; Middle Aged; Prednisolone; Prospective Studies; Severity of Illness Index; Tacrolimus; Treatment Outcome

Vitiligo is an acquired, pigmentary skin disorder which is disfiguring and difficult to treat. Phototherapy and application of topical corticosteroids are most commonly prescribed. However, these therapies are often not effective and use of corticosteroids on the face may lead to cutaneous atrophy, telangiectasia, and ocular complications.. We sought to assess the efficacy of topical tacrolimus ointment in the treatment of vitiligo.. A prospective pilot study was performed of 30 patients with vitiligo. Patients were treated with tacrolimus ointment for at least 4 months. Clinical responses were documented during clinic visits, and by pretacrolimus and post-tacrolimus photography.. Twenty-five (83.3%) patients showed some repigmentation at the end of 4 months. Patients with vitiligo for more than 5 years also responded well to tacrolimus ointment. Repigmentation in active vitiligo was superior to that in stable vitiligo. 80% of patients with segmental vitiligo of the head and neck showed some response to tacrolimus, but there was no statistical significance between segmental and vulgaris vitiligo. The mean percentage of repigmentation on the head and neck was greater than that on the trunk and extremities. Four patients initially experienced burning on application.. Topical tacrolimus ointment is an effective and well-tolerated alternative therapy for vitiligo especially involving the head and neck.

Topics: Administration, Topical; Adolescent; Adult; Analysis of Variance; Child; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug-Related Side Effects and Adverse Reactions; Emollients; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Pilot Projects; Prospective Studies; Severity of Illness Index; Tacrolimus; Treatment Outcome; Vitiligo; Young Adult

Renal disease is commonly encountered by primary care physicians during their day-to-day visits with patients. Common renal disorders include hypertension, proteinuria, kidney stones, and chronic kidney disease. Despite their prevalence, many physicians may be unfamiliar with the diagnosis and initial treatment of these common renal disorders. Early recognition and intervention are important in slowing the progression of chronic kidney disease and preventing its complications. The evidence-based pearls in this article will help primary care physicians avoid common pitfalls in the recognition and treatment of such disorders and guide their decision to refer their patients to a specialist.

Topics: Aluminum; Anemia; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antacids; Blood Pressure; Blood Urea Nitrogen; Cardiovascular Diseases; Cathartics; Chronic Disease; Contraindications; Creatinine; Cyclosporine; Disease Progression; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Evidence-Based Medicine; Glomerular Filtration Rate; Humans; Hypertension; Immunosuppressive Agents; Kidney Diseases; Magnesium; Nephrolithiasis; Nephrology; Phosphates; Primary Health Care; Proteinuria; Recombinant Proteins; Referral and Consultation; Tacrolimus; Urinalysis

This article reports changes in tacrolimus (FK506) blood levels connected with carbamazepine (CBZ). A drug interaction between FK506 and CBZ was investigated in a woman, who was in her 40s, who underwent heart transplantation. Pharmacokinetic parameters were measured, including dose and trough blood levels (C(0)), area under the serum concentration-time curve from 0 to 12 hours (AUC(0-12h)), and apparent clearance of oral FK506 (CL/F) for FK506 alone (about 3 months before starting CBZ) and combined with CBZ (11 days and about 3 months after starting CBZ). FK506 C(0) levels were decreased within 7 days of CBZ treatment. FK506 dosing required a 1.3- to 1.4-fold increase to maintain adequate blood levels while taking 200 mg CBZ daily. The AUC(0-12h)/dose 11 days after CBZ treatment was about 50% of the value before CBZ, and was about 70% at 3 months after CBZ treatment. The CL/F at 11 days and about 3 months after starting CBZ treatment was about 2 times higher than before CBZ therapy. FK506 C(0) levels are decreased by CBZ treatment, and blood levels should be closely monitored.

Topics: Adult; Anticonvulsants; Carbamazepine; Cardiomyopathy, Dilated; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Heart Transplantation; Humans; Immunosuppressive Agents; Tacrolimus; Treatment Outcome

Oral posaconazole (PSZ), an azole antifungal drug, was recently introduced for the treatment of invasive fungal infections. The prescription of PSZ together with the immunosuppressant tacrolimus (TRL) was evaluated in 14 lung transplant patients with cystic fibrosis. PSZ inhibited CYP3A4 TRL metabolism, resulting in a decrease of TRL dose by a factor of 3, with tapering to a mean of 2 mg/d. Previous studies with itraconazole and voriconazole showed that TRL dose could be decreased by factors of 5 and 4, respectively. Joint therapeutic drug monitoring of TRL and PSZ was carried out to investigate the high risk of interindividual variability associated with this coprescription in such patients.

Topics: Adult; Antifungal Agents; Aspergillosis; Candidiasis; Cystic Fibrosis; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Drug Monitoring; Drug-Related Side Effects and Adverse Reactions; Enzyme Inhibitors; Female; Graft Rejection; Humans; Immunosuppressive Agents; Itraconazole; Lung Transplantation; Male; Microbial Sensitivity Tests; Mycoses; Prescriptions; Pyrimidines; Tacrolimus; Triazoles; Voriconazole

Pharmacists play an important role in prescription analysis. They are involved in therapeutic drug monitoring, particularly for drugs with a narrow therapeutic index, prevention and management of drug interactions, and may be called in to identify side effects and adverse events related to drug therapy. For the polymedicated patient, the medical file, the list of prescribed drugs and the history of their administration may be insufficient to adequately assign the responsibility of a given adverse effect to one or more drugs. Graphical representations can sometimes be useful to describe and clarify a sequence of events. In addition, as part of their academic course, students have many occasions to hear about "side effects" and "drug interactions". However, in the academic setting, there are few opportunities to observe the evolution and the consequences of these events. In the course of their hospital training, these students are required to perform patient follow-up for pharmacotherapeutic or educational purposes and to comment case reports to physicians. The aim of this paper is to present a tool facilitating the graphic display of drug interaction consequences and side effects. This tool can be a useful aid for causality assessment. It structures the students' training course and helps them better understand the commentaries pharmacists provide for physicians. Further development of this tool should contribute to the prevention of adverse drug events.

Topics: Antifungal Agents; Audiovisual Aids; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Education, Pharmacy, Continuing; Immunosuppressive Agents; Leukocyte Count; Pharmacists; Pyrimidines; Software; Students, Pharmacy; Tacrolimus; Triazoles; Voriconazole

Topics: Drug-Related Side Effects and Adverse Reactions; Humans; Immunosuppressive Agents; Medication Errors; Pharmaceutical Preparations; Tacrolimus

Topics: Administration, Cutaneous; Administration, Oral; Cord Blood Stem Cell Transplantation; Drug-Related Side Effects and Adverse Reactions; Graft vs Host Disease; Humans; Immunosuppressive Agents; Infant; Male; Severe Combined Immunodeficiency; Skin Diseases; Tacrolimus; Time Factors; Transplantation, Homologous

The visual cortex may be involved in adverse drug reactions, leading to three different clinical presentations: cortical blindness, visual hallucinations and visual aura without headache. The drugs with potential visual cortex toxicity are described.

Topics: Anti-Bacterial Agents; Anti-Inflammatory Agents; Blindness, Cortical; Carmustine; Cathartics; Cholinergic Antagonists; Cisplatin; Cyclosporine; Dopamine Agents; Drug-Related Side Effects and Adverse Reactions; Hallucinations; Humans; Interferons; Serotonin Agents; Tacrolimus; Vidarabine; Vincristine; Visual Cortex

Topics: Administration, Topical; Calcineurin Inhibitors; Child; Child, Preschool; Clinical Trials as Topic; Dermatitis, Atopic; Drug-Related Side Effects and Adverse Reactions; Humans; Risk Assessment; Tacrolimus; United States; United States Food and Drug Administration

Selected immunophilin ligands (IPLs) are not only potent immunosuppressants but also modulate hair growth. Their considerable side effects, however, justify at best topical applications of these drugs for the management of clinical hair growth disorders. Therefore, we have explored hair growth manipulation by topical cyclosporin A (CsA) and FK 506 in previously established murine models that mimic premature hair follicle regression (catagen) or chemotherapy-induced alopecia, two major pathomechanisms underlying human hair loss. We confirm that topical CsA and FK 506 induce active hair growth (anagen) in the back skin of C57BL/6 mice with all follicles in the resting stage (telogen) and show that both IPLs also inhibit massive, dexamethasone-induced, premature catagen development in these mice. Furthermore, we demonstrate that CsA and FK 506 provide relative protection from alopecia and follicle dystrophy induced by cyclophosphamide, possibly by favoring the dystrophic anagen pathway of follicle response to chemical damage. Although it remains to be established whether these IPLs exert the same effects on human hair follicles, our study provides proof of the principle that topical IPLs can act as potent manipulators of clinically relevant hair-cycling pathomechanisms. This strongly encourages one to explore the use of topical IPLs in the management of human hair growth disorders.

Topics: Administration, Topical; Alopecia; Animals; Cyclophosphamide; Cyclosporine; Dexamethasone; Drug-Related Side Effects and Adverse Reactions; Female; Hair Follicle; Ligands; Mice; Mice, Inbred C57BL; Tacrolimus