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Objectives/Hypothesis Acquired laryngotracheal stenosis is a challenging problem for otolaryngologists. Several studies suggest tacrolimus may inhibit post-transplant airway stenosis that occurs with coronary drug-eluting stents. The objective of the present study was to determine whether tacrolimus modulates wound healing of the airway mucosa and prevents laryngotracheal stenosis in an acute injury animal model. Study Design Basic science. Methods The laryngotracheal mucosa of rats was scraped with a nylon brush through the tracheostoma. Tacrolimus (0.2 mg/kg or 1.0 mg/kg) was systemically administered intramuscularly for 5 days. Nine days after scraping, the pathological changes and the degree of stenosis were assessed by hematoxylin and eosin staining or by immunohistochemical staining for nuclear factor of activated T cell and interleukin 2. Results Lumen stenosis resulted from hyperplasia of the airway epithelium and a thickened submucosal layer with extensive fibrosis, angiogenesis, and collagen deposition. There was a significant preventive effect on airway stenosis at the tracheal and cricoid levels in the low-dose (0.2 mg/kg) tacrolimus-treated animals, compared to the untreated animals ( P < .05). This effect was insignificant with treatment by high-dose tacrolimus (1.0 mg/kg). Immunohistochemistry showed that, after tacrolimus treatment, the expressions of nuclear factor of activated T cell and interleukin 2 were downregulated in submucosal fibroblasts, neovascular cells, and glandular cells. Conclusions This study suggests that low-dose systemic tacrolimus has a preventive effect on laryngotracheal stenosis by inhibiting the activation of immune cells in the injured airway mucosa via the calcineurin/nuclear factor of activated T cell/interleukin 2 pathway. Level of Evidence NA Laryngoscope, 125:E210-E215, 2015 [ABSTRACT FROM AUTHOR]

This study was to evaluate the pharmacokinetics and bioequivalence of two tacrolimus formulations which had different in vitro drug release profiles. Dynamic solubility, in vitro dissolution profiles of the two formulations, and their influence on pharmacokinetics were examined. The male volunteers were randomly assigned to receive a single 1-mg capsule of the test or reference formulation and pharmacokinetic parameters were determined using a noncompartmental method. The two formulations released >85 % of tacrolimus in water within 30 min, which passed the criterion of evaluating the test formulation. However, the test formulation produced a faster initial release rate and plateaued in about 15 min, while the reference showed almost zero order initial release profiles. The AUC values were 145.92 (reference) and 140.49 ng h/mL (test). The mean C was 15.70 (reference) and 16.08 ng/mL (test) with T values of 1.63 and 1.60 h, respectively. The t for the reference and test formulations was 29.12 and 27.85 h, respectively. Relative bioavailability was calculated to be 96.28 %. The point estimates for the mean ratio of the test to reference for the AUC and C were 0.969 and 1.026, respectively, satisfying the criterion for bioequivalence. The results suggest that the test formulation is pharmacokinetically equivalent to the reference in terms of both rate and extent of absorption. Even though the in vitro dissolution profiles of the formulations might not be equivalent, the pharmacokinetics indicated bioequivalence. Therefore, when developing poorly soluble drugs, it might be beneficial to pay attention to the dynamic solubility as well as dissolution profiles. [ABSTRACT FROM AUTHOR]

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Background Non-compliance with immunosuppressive drugs has been reported as the most significant cause of graft loss. Since non-compliance with immunosuppressive drugs is preventable, certain approaches based on the risk factors and causes of non-compliance can help eliminate this problem. Aims The purpose of this study is to assess the effectiveness of patient education and interviews in improving medication adherence of renal-transplant recipients. Materials and methods This study was designed as a randomized controlled trial. Using the G*Power program, the sample size was calculated as 60 subjects, with 30 in both the intervention group and control group. Data collection tools included a patient information form, a pretest-posttest, a drug monitoring form for kidney transplant patients, the Immunosuppressive Therapy Adherence Scale, measurement of tacrolimus blood levels, and a training booklet.  Results The mean knowledge score in the intervention group was 12.17±3.39 at baseline, and it increased to 20.73±1.57 after the intervention. The mean scores on the Immunosuppressant Therapy Adherence Scale were 11.67±0.55 and 10.70±0.99 in the intervention group and control group, respectively. There was a statistically significant difference between the pre-test and post-test means on the Immunosuppressant Therapy Adherence Scale in the intervention group. The mean Immunosuppressant Therapy Adherence Scale score was higher in the intervention group. In the measurement of tacrolimus blood levels, medication adherence was found the be higher in the intervention group. The difference between the groups was statistically significant. There was a positive correlation between the tacrolimus blood levels and the Immunosuppressant Therapy Adherence Scale scores in both groups. Conclusions To conclude, our results have demonstrated that patient education and interviews improve immunosuppressant medication adherence in renal transplant recipients. Using direct or indirect methods proved similar outcomes, suggesting that both evaluation methods are safe., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Akşit et al.)

Context: The promising efficacy of Toll-like receptor 9 (TLR9) agonists for use against pathogenic infections, allergies, malignant neoplasms and autoimmunity have been demonstrated well in clinical studies, but the safety of TLR9 agonists is controversial. Objective: In light of the safety concerns, we conducted a systematic review and meta-analysis of clinical studies of TLR9 agonists. Methods: A systematic literature search was conducted. We selected studies in which the subjects were treated with a TLR9 agonist and in which the safety of the TLR9 agonist was monitored. We extracted data on adverse events (AEs) when available. A meta-analysis was performed to determine the commonest and clinical significant AEs observed in the controlled studies. Results: Nine single-arm studies and 12 controlled studies met our selection criteria. Subjects treated with TLR9 agonists were at a higher risk of anemia (risk ratio [RR] 1.04, 95% confidence interval [CI]: 1.02-1.06), neutropenia (RR 1.16, 95% CI: 1.11-1.21), leukopenia (RR 1.16, 95% CI: 1.11-1.22), lymphopenia (RR 1.17, 95% CI: 1.10-1.25), thrombocytopenia (RR 1.20, 95% CI: 1.14-1.27), flu-like symptoms (RR 10.59, 95% CI: 3.66-30.66), diarrhea (RR 1.40, 95% CI: 1.18-1.67) and headache (RR 1.61, 95% CI: 1.26-2.06). Injection-site reactions, such as erythema, pain, pruritus and swelling, were mild to moderate. TLR9 agonist therapies have not been associated with clinically significant autoimmune diseases, and few deaths potentially attributable to TLR9 agonists have been reported. Conclusion: The toxicity of TLR9 agonists is generally acceptable, except when the agonist is combined with immunosuppressive agents in patients with advanced non-small-cell lung cancer. [ABSTRACT FROM AUTHOR]

Background Central venous catheterization is recognized as a lifeline that is important for chemotherapy or nutritional support in pediatric patients with malignant disease and intestinal failure. This study analyzed the risk of infection with Broviac line use among these patients at a single Japanese center. Methods Two hundred and four Broviac lines were inserted in patients in the pediatric ward from January 2003 to October 2011. We analyzed the risk of catheter-related bloodstream infection ( CR-BSI) using clinical characteristics including underlying disease, sepsis history, inserted situation, drug use, and laboratory data at the time of Broviac insertion or before CR-BSI. Results During the study period, data from a total of 15 lines were excluded because of missing blood culture data. In the remaining 189 Broviac lines, 52 lines developed CR-BSI. On univariate analysis, leukemia, infantile Crohn's disease, sepsis history before Broviac insertion, existence of a stoma opening, and immunosuppressant use before CR-BSI were risk factors for CR-BSI. On multivariate logistic regression analysis infantile Crohn's disease, sepsis history before Broviac insertion, and immunosuppressant use before CR-BSI were independently associated with CR-BSI ( P = 0.015, P = 0.045, and P = 0.043, respectively). Conclusions Infantile Crohn's disease carries a high risk for CR-BSI because of its pathological condition, the therapeutic drugs required, and surgical intervention. [ABSTRACT FROM AUTHOR]

An adequate level of tacrolimus in serum should be obtained to prevent acute rejection following liver transplantation. Because of good gastrointestinal absorption of oral tacrolimus, adequate trough levels can be achieved even in patients with short bowel syndrome. Rarely, adequate through levels cannot be obtained by oral administration of the drug for several reasons such as inadequate absorption, having a discordant patient, laboratory error, and/or interactions with other drugs and foods. Here, we described a 16-year-old patient who had undergone massive intestinal resection due to mesenteric torsion 5 years previously and required liver transplantation for cryptogenic cirrhosis. Her remnant small bowel length was 90 cm. After a successful living donor liver transplantation, oral tacrolimus administration resulted in inadequate through levels in some parts of the postoperative period. We checked up all the potential reasons but could not identify any cause. An intravenous tacrolimus including immunosuppressive regimen was temporarily required. She maintained adequate blood levels of tacrolimus by parenteral route for a while; thereafter, oral administration resulted in enough blood drug levels. She was discharged with oral tacrolimus therapy. We concluded that very rarely, adequate blood levels of tacrolimus cannot be achieved by oral administration for unexplained reasons. In such cases, temporary administration of parenteral tacrolimus can be life-saving. [ABSTRACT FROM AUTHOR]

Objective: The calcineurin inhibitor tacrolimus has been approved in Japan for the treatment of interstitial pneumonia (IP) in patients with polymyositis (PM) and dermatomyositis (DM). Postmarketing surveillance was initiated to examine long-term outcomes of immunosuppressive regimens containing tacrolimus in real-world settings., Methods: Observational, prospective, postmarketing surveillance is ongoing in 179 patients with PM/DM-associated IP initiating treatment with tacrolimus. We report interim findings after 2 years of follow-up. Cumulative overall survival was assessed using Kaplan-Meier analysis. Potential prognostic factors for mortality were assessed by univariate Cox proportional hazards analysis., Results: A total of 170 patients were included in this analysis. At the time of starting treatment with tacrolimus, almost all patients were receiving corticosteroids (98.8%), and cyclophosphamide was additionally used in 42 patients (24.7%). Forty-nine patients (28.8%) discontinued tacrolimus during follow-up, mainly due to loss to follow-up, patient death, and adverse events. Mean (SD) oral corticosteroid dose decreased from 32.4 (21.6) mg/day at baseline to 7.6 (4.2) mg/day at 2 years. Overall survival at 2 years was 90.3%; corresponding progression-free survival was 62.5%. Factors found to be associated with all-cause mortality included diagnosis of clinically amyopathic DM (hazard ratio [HR] 9.04, 95% CI 1.18-69.51 vs PM), ferritin level 500 to < 1500 ng/mL (HR 8.61, 95% CI 2.51-29.45 vs < 500 ng/mL), and presence of antimelanoma differentiation-associated gene 5 antibodies (HR 8.16, 95% CI 1.03-64.47 vs absence)., Conclusion: Immunosuppressive regimens containing tacrolimus appear useful for the management of IP in patients with PM/DM. [ClinicalTrials.gov: NCT02159651]., (Copyright © 2022 by the Journal of Rheumatology.)

Cyclosporine A (CsA) is an immunosuppressive drug used in organ transplantation and treatment of autoimmune diseases. Effects of CsA on determining the direction of the immune response and pathogenesis of infections by altering immune responses particulary T cells functions have always been questionable. We evaluated the effect of different doses of CsA on course of infection in BALB/c mice infected with live Bacillus Calmette Guérin (BCG) (as an example of Mycobacterial infections). Four groups of mice (n = 5) receiving 5, 25, 125, and 0 mg/kg of CsA, three times a week, were infected with BCG aerosolly. Before BCG inhalation and 40-/60- days post-infection, cell proliferation and CD4+CD25+ cell percentage were evaluated in splenocytes of mice after culture and stimulation with PHA or BCG lysate. The histopathological alterations and bacterial burden were assessed in lung tissue. Cells showed a dose-dependent decrease in proliferation and the percentage of CD4+ CD25+ cells. After BCG infection, in presence of dose 125 mg/kg, there were some exceptions. The number of bacteria and histopathological lesions and inflammation in lung tissues increased in a dose-dependent manner. CsA immunosuppressed BCG infected mice can be used as a safe model for studying Mycobacterium species pathogenesis and related cellular immune responses. [ABSTRACT FROM AUTHOR]

Because of biological rhythms, drug efficiency and toxicity vary according to the time of administration of the drug. This study investigates whether the haematological toxicity of the immunosuppressive agent Mycophenolate Mofetil varies according to the circadian dosing-time in rats. 300 mg/kg of Mycophenolate Mofetil was injected by i.p. route to different groups of animals at six different circadian stages (1, 7, 13, and 19 hours after light onset, i.e., HALO). Mycophenolate Mofetil treatment induced a significant decrease at 7 HALO in red blood cells (-18%), in haemoglobin rate (-15%) and in white blood cells (-54%). These parameters followed a circadian rhythm with an acrophase located at the end of the light-rest phase. A significant thrombocytopenia was observed according to Mycophenolate Mofetil the circadian dosing-time. In the controls, the number of platelets followed a circadian rhythm. Mycophenolate Mofetil modified this rhythm which became an 8-h ultradian rhythm. The data indicate that, the Mycophenolate Mofetil-induced haematological toxicity was maximum when the drug was administered in the middle of the light-rest phase, which is physiologically analogous to the end of the activity of the diurnal phase in human patients. [ABSTRACT FROM AUTHOR]

We recently demonstrated that the insect peptide CopA3 (LLCIALRKK), a disulfide-linked dimeric peptide, exerts antimicrobial and anti-inflammatory activities in a mouse colitis model. Here, we examined whether CopA3 inhibited activation of macrophages by LPS. Exposure of an unseparated mouse peritoneal cell population or isolated peritoneal macrophages to LPS markedly increased secretion of IL-6 and TNF-α; these effects were significantly inhibited by CopA3 treatment. The inhibitory effect of CopA3 was also evident in murine macrophage cell line, RAW 264.7. Western blotting revealed that LPS-induced activation of STAT1 and STAT5 in macrophages was significantly inhibited by CopA3. Inhibition of JAK (STAT1/STAT5 kinase) with AG490 markedly reduced the production of IL-6 and TNF-α in macrophages. Collectively, these observations suggest that CopA3 inhibits macrophage activation by inhibiting activating phosphorylations of the transcription factors, STAT1 and STAT5, and blocking subsequent production of IL-6 and TNF-α and indicate that CopA3 may be useful as an immune-modulating agent. Copyright © 2012 European Peptide Society and John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

We evaluated the effectiveness of mizoribine, a newly developed immunosuppressive agent, as an adjuvant therapy in the treatment of both pemphigus vulgaris and pemphigus foliaceus. Eleven pemphigus patients (eight pemphigus vulgaris and three pemphigus foliaceus) received the combination therapy of prednisolone and mizoribine. Complete remission was observed in three of the eight patients with pemphigus vulgaris and in one of the three patients with pemphigus foliaceus. The four patients with complete remission had a rapid clinical response and achieved remission at a median of 11.8 months. Partial remission was achieved in two of the three patients with pemphigus foliaceus. The median time to achieve partial remission was 16.0 months. Six (55.6%) of the 11 patients with pemphigus had complete or partial remission and were able to taper their prednisolone. The cumulative probability of having a complete remission was 64.3% at 19 months of follow-up using Kaplan- Meier analysis. The effectiveness of the additional mizoribine therapy could be attributed to its corticosteroid-sparing properties as well as its immunosuppressive effects. The serum concentration titer of mizoribine was around 1.0 μg/ mL 2 hours after administration. Patients who were not improved by the additional mizoribine might require a continuously higher dose of mizoribine to achieve effective therapy. [ABSTRACT FROM AUTHOR]

Abstract: Sphingosine 1-phosphate (S1P) regulates lymphocyte trafficking via type-1 S1P receptor (S1P1) and participates in many pathological conditions. We developed a novel type S1P1-selective antagonist, TASP0251078, which is structurally unrelated to S1P. This competitive antagonist inhibited binding of S1P to S1P1 resulting in reduced signaling downstream of S1P1, including GTPγS-binding and cAMP formation. TASP0251078 also inhibited S1P-induced cellular responses such as chemotaxis and receptor-internalization. Furthermore, when administered in vivo, TASP0251078 induced lymphopenia in blood, which is different from previously reported effects of other S1P1-antagonists. In a mouse contact hypersensitivity model, TASP0251078 effectively suppressed ear swelling, leukocyte infiltration, and hyperplasia. These findings provide the chemical evidence that S1P1 antagonism is responsible for lymphocyte sequestration from the blood, and suggest that the effect of S1P1 agonists on lymphocyte sequestration results from their functional antagonism. [Copyright &y& Elsevier]

Abstract: A series of oxazolidin-2-one-4-carboxylic amide compounds (1a–f) were designed and synthesized as the non-phosphate S1P1 receptor agonists. The single crystal of 1e was prepared and solved to elucidate the structure of 1a–f. EC50 of 1a–d were about 1.1–3.6μM in S1P1 Redistribution® assay, and their cytotoxicity was 8–40-fold lower than FTY720. Though its S1P1 agonist activities in vitro were about 1000-folds weaker than (S)-FTY720-P, at a dose of 10mg/Kg, the immunosuppressive effects of 1a were comparable to FTY720. So oxazolidin-2-one-4-carboxylic amide derivatives were found as potential immunomodulator, compound 1a could be considered as a lead compound, rational modifications of 1a are anticipated using medicinal chemistry techniques and molecular modeling to obtain analogs with higher affinity and better clinical therapeutic properties. [Copyright &y& Elsevier]

Cyclophosphamide (CP) has been used for over 40 years in patients with steroid-sensitive nephrotic syndrome (SSNS) presenting frequent relapses or steroid dependence (SD). We evaluated retrospectively and tried to identify parameters possibly associated with a prolonged and sustained remission (PSR+) ≥5 years in 108 children with steroid-dependent nephrotic syndrome (SDNS) treated with oral CP. Patients had a follow-up time ≥5 years and were divided into two groups according to achievement of PSR (+ and -). Gender, histological injury, cumulative doses of CP, age of onset of illness, and start of treatment and prednisone dose on the occasion of relapse were analyzed. The overall cumulative sustained remission for 5 and 10 years was 25 and 21.6%, respectively. The only factor that influenced a PSR was the degree of SD: the group PSR+ relapsed at prednisone dose of 0.96 ± 0.51 mg/kg vs. 1.29 ± 0.59 mg/kg in group PSR- ( p = 0.01). Also, patients who relapsed in the presence of prednisone doses ≤1.4 mg/kg showed a cumulative sustained remission of 43, 35, and 32.7% at 2, 5, and 10 years, respectively, versus 22.5, 12.5, and 5% in those with prednisone >1.4 mg/kg ( p = 0.001). Our findings suggest that patients with SDNS who relapse on prednisone dose >1.4 mg/kg are especially prone to an unfavorable response to CP use. [ABSTRACT FROM AUTHOR]

Abstract: Four fluorinated derivatives of the immunosuppressive drug FTY720 were synthesized by a convergent strategy, using the Sonogashira coupling as the key reaction to assemble the two major fragments. [Copyright &y& Elsevier]

The syntheses of two diastereoisomers of 2-acetyl-5-(1,2,3,4,5,6-hexahydroxyhexyl)thiazole are reported. The synthesis of these diastereoisomers involved the coupling of 5-metallated 2-(1,1-dimethoxyethyl)thiazole with a Weinreb amide derived from δ-gluconolactone, followed by asymmetric reduction of the ketone thus prepared. The stereochemistries and structures of some key compounds were determined by single-crystal X-ray structural analysis. Graphical abstract: [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]