Improved prediction of tacrolimus concentrations early after kidney transplantation using theory-based pharmacokinetic modelling.

PubMed

Størset, Elisabet; Holford, Nick; Hennig, Stefanie; Bergmann, Troels K; Bergan, Stein; Bremer, Sara; Åsberg, Anders; Midtvedt, Karsten; Staatz, Christine E

2014-09-01

The aim was to develop a theory-based population pharmacokinetic model of tacrolimus in adult kidney transplant recipients and to externally evaluate this model and two previous empirical models. Data were obtained from 242 patients with 3100 tacrolimus whole blood concentrations. External evaluation was performed by examining model predictive performance using Bayesian forecasting. Pharmacokinetic disposition parameters were estimated based on tacrolimus plasma concentrations, predicted from whole blood concentrations, haematocrit and literature values for tacrolimus binding to red blood cells. Disposition parameters were allometrically scaled to fat free mass. Tacrolimus whole blood clearance/bioavailability standardized to haematocrit of 45% and fat free mass of 60 kg was estimated to be 16.1 l h−1 [95% CI 12.6, 18.0 l h−1]. Tacrolimus clearance was 30% higher (95% CI 13, 46%) and bioavailability 18% lower (95% CI 2, 29%) in CYP3A5 expressers compared with non-expressers. An Emax model described decreasing tacrolimus bioavailability with increasing prednisolone dose. The theory-based model was superior to the empirical models during external evaluation displaying a median prediction error of −1.2% (95% CI −3.0, 0.1%). Based on simulation, Bayesian forecasting led to 65% (95% CI 62, 68%) of patients achieving a tacrolimus average steady-state concentration within a suggested acceptable range. A theory-based population pharmacokinetic model was superior to two empirical models for prediction of tacrolimus concentrations and seemed suitable for Bayesian prediction of tacrolimus doses early after kidney transplantation.

Conversion from twice-daily tacrolimus to once-daily extended release tacrolimus (LCPT): the phase III randomized MELT trial.

PubMed

Bunnapradist, S; Ciechanowski, K; West-Thielke, P; Mulgaonkar, S; Rostaing, L; Vasudev, B; Budde, K

2013-03-01

Phase III noninferiority trial examining efficacy and safety of converting stable renal transplant recipients from twice-daily tacrolimus to a novel extended-release once-daily tacrolimus formulation (LCPT) with a controlled agglomeration technology. Controls maintained tacrolimus twice daily. The primary efficacy endpoint was proportion of patients with efficacy failures (death, graft failure, locally read biopsy-proven acute rejection [BPAR], or loss to follow-up) within 12 months. Starting LCPT dose was 30% lower (15% for blacks) than preconversion tacrolimus dose; target trough levels were 4-15 ng/mL. A total of 326 patients were randomized; the mITT population (n = 162 each group) was similar demographically in the two groups. Mean daily dose of LCPT was significantly (p < 0.0001) lower than preconversion tacrolimus dose at each visit; mean trough levels between groups were similar. There were four efficacy failures in each group; safety outcomes were similar between groups. Frequency of premature study drug discontinuation was LCPT: 12% versus tacrolimus twice daily: 5% (p = 0.028). LCPT demonstrated noninferiority to tacrolimus twice daily in efficacy failure rates. LCPT may offer a safe and effective alternative for converting patients to a once-daily formulation. Compared to currently available tacrolimus formulation, LCPT requires lower doses to achieve target trough levels. © Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.

Mechanisms of lower maintenance dose of tacrolimus in obese patients.

PubMed

Sawamoto, Kazuki; Huong, Tran T; Sugimoto, Natsumi; Mizutani, Yuka; Sai, Yoshimichi; Miyamoto, Ken-ichi

2014-01-01

A retrospective analysis suggested that blood tacrolimus concentrations were consistent among patients with a body mass index (BMI) that was lean (<18.5), normal (≥ 18.5 and <25) or overweight/obese (≥ 25). The average maintenance dose of tacrolimus in patients with BMI ≥ 25 was significantly lower compared with that in patients with a BMI of less than 25. Lean and obese Zucker rats fed a normal diet were given tacrolimus intravenously or orally. The blood concentrations of tacrolimus in obese rats were significantly higher than those in lean rats after administration via both routes. The moment analysis has suggested that CLtot and Vdss of tacrolimus were not significantly different between lean and obese rats. The bioavailability was higher in obese rats, compared with that in lean rats. The protein expression of Cyp3a2 in the liver was significantly decreased in obese rats, compared with lean rats, while P-gp in the small intestine was also significantly decreased in obese rats. These results suggested that the steady-state trough concentration of tacrolimus in obese patients was well maintained by a relatively low dose compared with that in normal and lean patients, presumably due to increased bioavailability.

High Intrapatient Variability of Tacrolimus Levels and Outpatient Clinic Nonattendance Are Associated With Inferior Outcomes in Renal Transplant Patients

PubMed Central

Goodall, Dawn L.; Willicombe, Michelle; McLean, Adam G.; Taube, David

2017-01-01

Background Nonadherence to immunosuppressants is associated with rejection and allograft loss. Intrapatient variability (IPV) of immunosuppression levels is a marker of nonadherence. This study describes the impact of IPV of tacrolimus levels in patients receiving a tacrolimus monotherapy immunosuppression protocol. Methods We retrospectively analyzed the outpatient tacrolimus levels of kidney-only transplant patients taken between 6 and 12 months posttransplant. IPV was determined using the coefficient of variance. Results Six hundred twenty-eight patients with a mean number of 8.98 ± 3.81 tacrolimus levels and a mean follow-up of 4.72 ± 2.19 years were included. Multivariate analysis showed death was associated with increasing age (1.04 [1.01-1.07], P = 0.0055), diabetes at time of transplant (2.79 [1.44-5.41], P = 0.0024), and rejection (2.34 [1.06-5.19], P = 0.036). Variables associated with graft loss included the highest variability group (2.51 [1.01-6.27], P = 0.048), mean tacrolimus level less than 5 ng/mL (4.32 [1.94-9.63], P = 0.0003), a high clinic nonattendance rate (1.10 [1.01-1.20], P = 0.03), and rejection (9.83 [4.62-20.94], P < 0.0001). Independent risk factors for rejection were de novo donor-specific antibody (3.15 [1.84-5.39], P < 0.0001), mean tacrolimus level less than 5 ng/mL (2.57 [1.27-5.19], P = 0.00860, and a high clinic nonattendance rate (1.11 [1.05-1.18], P = 0.0005). Conclusions This study shows that high tacrolimus IPV and clinic nonattendance are associated with inferior allograft survival. Interventions to minimize the causes of high variability, particularly nonadherence are essential to improve long-term allograft outcomes. PMID:28795143

A Randomized Pharmacokinetic Study of Generic Tacrolimus Versus Reference Tacrolimus in Kidney Transplant Recipients

PubMed Central

Alloway, R R; Sadaka, B; Trofe-Clark, J; Wiland, A; Bloom, R D

2012-01-01

Pharmacokinetic analyses comparing generic tacrolimus preparations versus the reference drug in kidney transplant patients are lacking. A prospective, multicenter, open-label, randomized, two-period (14 days per period), two-sequence, crossover and steady-state pharmacokinetic study was undertaken to compare twice-daily generic tacrolimus (Sandoz) versus reference tacrolimus (Prograf®) in stable renal transplant patients. AUC0–12h and peak concentration (Cmax) were calculated from 12 h pharmacokinetic profiles at the end of each period (days 14 and 28). Of 71 patients enrolled, 68 provided evaluable pharmacokinetic data. The ratios of geometric means were 1.02 (90% CI 97–108%, p = 0.486) for AUC0–12h and 1.09 (90% CI 101–118%, p = 0.057) for Cmax. Mean (SD) C0 was 7.3(1.8) ng/mL for generic tacrolimus versus 7.0(2.1) ng/mL for reference tacrolimus based on data from days 14 and 28. Correlations between 12 h trough levels and AUC were r = 0.917 for generic tacrolimus and r = 0.887 for reference drug at day 28. These data indicate that generic tacrolimus (Sandoz) has a similar pharmacokinetic profile to the reference drug and is bioequivalent in kidney transplant recipients according to US Food and Drug Administration and European Medicines Agency guidelines. PMID:22759200

Multi-site analytical evaluation of the Abbott ARCHITECT tacrolimus assay.

PubMed

Wallemacq, Pierre; Goffinet, Jean-Sebastien; O'Morchoe, Susan; Rosiere, Thomas; Maine, Gregory T; Labalette, Myriam; Aimo, Giuseppe; Dickson, Diana; Schmidt, Ed; Schwinzer, Reinhard; Schmid, Rainer W

2009-04-01

The objective of this study was to evaluate the analytical performance of the Abbott ARCHITECT Tacrolimus immunoassay. Proficiency panels and specimens from a population of organ transplant recipients were analyzed in 6 clinical laboratories in Europe and the United States, and the results were compared with other methods. The ARCHITECT assay requires a whole blood specimen pretreatment step with methanol/zinc sulfate to precipitate protein and extract the drug, followed by a 30-minute immunoassay using anti-tacrolimus antibody-coated paramagnetic microparticles and an acridinium-tacrolimus tracer. The assay was free from hematocrit interference in the range 25%-55% and from interference by extremes of cholesterol, triglycerides, bilirubin, total protein, and uric acid. The total percent of coefficient of variations of the assay were 4.9%-7.6% at 3 ng/mL, 2.9%-4.6% at 8.6 ng/mL, and 3.1%-8.2% at 15.5 ng/mL. Limit of detection was < or =0.5 ng/mL and limit of quantification (LOQ) ranged from 0.69 to 1.07 ng/mL across the 6 sites (based on the upper 95% confidence interval concentrations). The 2007 European Consensus Conference on Tacrolimus Optimization recommended the use of assay methods with an LOQ around 1 ng/mL, based upon the need to measure trough tacrolimus blood concentrations precisely down to 3 ng/mL during low-dose tacrolimus regimens. Tacrolimus International Proficiency Testing Scheme samples were measured by the ARCHITECT immunoassay at 5 sites and showed an average bias of -0.28 to +0.85 ng/mL versus IMx Tacrolimus II immunoassay historical values and -0.21 to +0.68 ng/mL versus liquid chromatography/tandem mass spectrometry (LC-MSMS) Tacrolimus historical values. Method comparison studies were performed with the ARCHITECT Tacrolimus immunoassay on patient specimens with the following results: ARCHITECT Tacrolimus assay versus the Abbott IMx Tacrolimus II immunoassay (4 sites) yielded average biases between -0.94 and +0.26 ng/mL; ARCHITECT assay

A randomized pharmacokinetic study of generic tacrolimus versus reference tacrolimus in kidney transplant recipients.

PubMed

Alloway, R R; Sadaka, B; Trofe-Clark, J; Wiland, A; Bloom, R D

2012-10-01

Pharmacokinetic analyses comparing generic tacrolimus preparations versus the reference drug in kidney transplant patients are lacking. A prospective, multicenter, open-label, randomized, two-period (14 days per period), two-sequence, crossover and steady-state pharmacokinetic study was undertaken to compare twice-daily generic tacrolimus (Sandoz) versus reference tacrolimus (Prograf®) in stable renal transplant patients. AUC(0-12h) and peak concentration (C(max) ) were calculated from 12 h pharmacokinetic profiles at the end of each period (days 14 and 28). Of 71 patients enrolled, 68 provided evaluable pharmacokinetic data. The ratios of geometric means were 1.02 (90% CI 97-108%, p = 0.486) for AUC(0-12h) and 1.09 (90% CI 101-118%, p = 0.057) for C(max) . Mean (SD) C(0) was 7.3(1.8) ng/mL for generic tacrolimus versus 7.0(2.1) ng/mL for reference tacrolimus based on data from days 14 and 28. Correlations between 12 h trough levels and AUC were r = 0.917 for generic tacrolimus and r = 0.887 for reference drug at day 28. These data indicate that generic tacrolimus (Sandoz) has a similar pharmacokinetic profile to the reference drug and is bioequivalent in kidney transplant recipients according to US Food and Drug Administration and European Medicines Agency guidelines. © Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.

Application of Biodegradable Nanoparticles in Liver Targeting of Tacrolimus

NASA Astrophysics Data System (ADS)

Affifi, Nagia N.; Heikal, Ola A.; Hanafi, Rasha S.; Tammam, Salma N.

2011-06-01

Tacrolimus is a potent immunosuppressant used in liver transplantation to avoid graft rejection. Tacrolimus has a narrow therapeutic index and variable pharmacokinetics, making dose adjustment and therapeutic drug monitoring a complicated task. Increasing the occurrence of adverse effects, especially nephrotoxicity are another concerns. In graft rejection, antigen presentation occurs in the graft and lymphatics. Therefore, by targeting tacrolimus to the liver and spleen, graft survival could be achieved with a decrease in nephrotoxicity. Poly(lactide) tacrolimus nanoparticles (PLA-TAC-NP) were formulated and characterized with the aim of targeting tacrolimus to the liver and spleen and therefore decreasing its nephrotoxicity. To evaluate the targeting efficiency of PLA-TAC-NP, rats were divided into two groups. They were intravenously injected either PLA-TAC-NP or free tacrolimus. At assigned time intervals, blood, liver, spleen and kidney samples were collected from each rat. Drug extraction and HPLC analysis were used to evaluate tacrolimus tissue distribution and consequently the targeting efficiency of the prepared PLA-TAC-NP. PLA-TAC-NP proved their success in targeting liver and spleen, by showing significantly higher drug amounts compared to the rats injected with free tacrolimus. PLA-TAC-NP increased tacrolimus concentration in the liver 24 fold and in the spleen 1.94 fold whereas tacrolimus concentration in the kidneys decreased by 7.12 fold. Transmission electron microscopy (TEM) was used to examine a liver section, obtained from a rat that has received PLA-TAC-NP. TEM images showed PLA-TAC-NP in a Kupffer cell and in the liver sinusoids. Therefore, PLA-TAC-NP are promising drug delivery systems for achieving localized immunosuppression and minimizing nephrotoxicity in liver transplant patients.

Distinct effects of omeprazole and rabeprazole on the tacrolimus blood concentration in a kidney transplant recipient.

PubMed

Takahashi, Kazushige; Yano, Ikuko; Fukuhara, Yuga; Katsura, Toshiya; Takahashi, Takeshi; Ito, Noriyuki; Yamamoto, Shingo; Ogawa, Osamu; Inui, Ken-ichi

2007-12-01

Proton-pump inhibitors (PPIs, e.g. omeprazole and rabeprazole) are often administered to transplant patients as a treatment or prophylaxis for ulcers after surgery. Since tacrolimus and PPIs share the CYP3A4 system for metabolism, pharmacokinetic interactions are anticipated when they are administered simultaneously. We present a Japanese male patient who underwent a living-donor kidney transplantation having received tacrolimus, mycophenolate mofetil, and prednisolone for immunosuppression. The concentration/dose (C/D) ratio for tacrolimus was markedly higher during the period of treatment with omeprazole than ranitidine or rabeprazole. The results of liver functional tests were within the normal range during the use of these three antacid drugs. Since the higher C/D ratio for tacrolimus when omeprazole was being administered did not result from a decrease in the elimination of tacrolimus due to hepatic dysfunction, drug interaction between omeprazole and tacrolimus was strongly suspected. The present case indicates that rabeprazole can be used safely in place of omeprazole in kidney transplant recipients receiving tacrolimus.

Limited interaction between tacrolimus and P-glycoprotein in the rat small intestine.

PubMed

Saitoh, Hiroshi; Saikachi, Yuko; Kobayashi, Mikako; Yamaguchi, Michiko; Oda, Masako; Yuhki, Yoshimitsu; Achiwa, Kazuhito; Tadano, Koji; Takahashi, Yasushi; Aungst, Bruce J

2006-05-01

The significance of intestinal P-glycoprotein (P-gp) in determining the oral bioavailability of tacrolimus has been still controversial. In this study, we reevaluated the interaction of tacrolimus with P-gp in the rat small intestine, by evaluating its absorption from the rat small intestine and its modulating effect on the absorption of known P-gp substrates (digoxin, methylprednisolone, and vinblastine). Intestinal absorption of tacrolimus itself was as extensive as other P-gp modulators such as cyclosporine and verapamil. While cyclosporine and verapamil significantly increased the absorption of methylprednisolone and vinblastine through potent inhibition of intestinal P-gp, tacrolimus failed to achieve this. When cyclosporine and tacrolimus were intravenously administered to rats, digoxin absorption was significantly increased by cyclosporine but not by tacrolimus. When tacrolimus was coadministered with clotrimazole, a specific CYP3A inhibitor, into the rat small intestine, the area under the curve of tacrolimus blood concentrations increased more than seven-fold compared with that of tacrolimus alone. Our present results strongly suggest that the interaction between tacrolimus and P-gp is limited in the rat small intestine and that extensive metabolism by CYP3A enzymes is more responsible for the low oral bioavailability of tacrolimus. It was considered that the extensive absorption of cyclosporine and verapamil was closely associated with their potent ability to inhibit intestinal P-gp.

Tacrolimus Optic Neuropathy.

PubMed

Rasool, Nailyn; Boudreault, Katherine; Lessell, Simmons; Prasad, Sashank; Cestari, Dean M

2018-06-01

Tacrolimus (FK506, Prograf) is a potent immunosuppressant, which inhibits cytokine synthesis and blocks T-cell development. Optic neuropathy from tacrolimus toxicity is very uncommon but, when present, can result in severe vision loss. Case series and review of the literature. We present 3 patients with tacrolimus optic neuropathy after bone marrow transplantation complicated by graft-vs-host disease and demonstrate the differing clinical and radiologic presentation of this presumed toxic optic neuropathy. Tacrolimus optic neuropathy can manifest in a multitude of clinical presentations and can have devastating visual consequences.

Systematic conversion to generic tacrolimus in stable kidney transplant recipients.

PubMed

Rosenborg, Staffan; Nordström, Annica; Almquist, Tora; Wennberg, Lars; Bárány, Peter

2014-04-01

Tacrolimus (Prograf ® ) is a key drug in the immunosuppressive treatment of renal transplant patients. Since the expiration of the patent for Prograf ® , generic preparations have been approved in Europe as bioequivalence has been shown in healthy volunteers. However, few studies have investigated whether patients can be successfully converted from Prograf ® to generic tacrolimus. Tacrolimus drug costs are by far the largest single item in the total drug expenditure for patients with renal disease in the Stockholm area. Considerable reductions in drug costs could be achieved if generic tacrolimus were to be used. The aim of this quality assurance study was to evaluate whether a switch from Prograf ® to generic tacrolimus (Tacrolimus Sandoz ® ) could be safely performed in renal transplant patients. It further aimed to investigate changes of renal function (measured in estimated glomerular filtration rate, eGFR), need for dose changes and to calculate potential drug cost savings as a result of the conversion. We planned to recruit at least 50 patients. Plasma creatinine levels and trough concentrations of tacrolimus were collected from patients with renal transplants at three occasions during treatment with Prograf ® and three times after conversion to Tacrolimus Sandoz ® . The eGFR was calculated before and after the conversion. Sixty-three of 67 enrolled patients (69% males, age 28-80 years) are included in this analysis. The ratio of mean trough concentrations of tacrolimus after comparison with before conversion was 1.02 (90% confidence interval 0.95-1.09). Fourteen patients experienced a change in tacrolimus levels >20% compared with baseline, no patients changed >20% in eGFR. The drug cost saving per daily dose was 33.40 SEK (∼€3.60, -23%). Stable kidney transplant patients treated with Prograf ® can be converted to Tacrolimus Sandoz ® if trough concentrations of tacrolimus and plasma creatinine levels are closely monitored. The conversion brought

Systematic conversion to generic tacrolimus in stable kidney transplant recipients

PubMed Central

Rosenborg, Staffan; Nordström, Annica; Almquist, Tora; Wennberg, Lars; Bárány, Peter

2014-01-01

Background Tacrolimus (Prograf®) is a key drug in the immunosuppressive treatment of renal transplant patients. Since the expiration of the patent for Prograf®, generic preparations have been approved in Europe as bioequivalence has been shown in healthy volunteers. However, few studies have investigated whether patients can be successfully converted from Prograf® to generic tacrolimus. Tacrolimus drug costs are by far the largest single item in the total drug expenditure for patients with renal disease in the Stockholm area. Considerable reductions in drug costs could be achieved if generic tacrolimus were to be used. The aim of this quality assurance study was to evaluate whether a switch from Prograf® to generic tacrolimus (Tacrolimus Sandoz®) could be safely performed in renal transplant patients. It further aimed to investigate changes of renal function (measured in estimated glomerular filtration rate, eGFR), need for dose changes and to calculate potential drug cost savings as a result of the conversion. Methods We planned to recruit at least 50 patients. Plasma creatinine levels and trough concentrations of tacrolimus were collected from patients with renal transplants at three occasions during treatment with Prograf® and three times after conversion to Tacrolimus Sandoz®. The eGFR was calculated before and after the conversion. Results Sixty-three of 67 enrolled patients (69% males, age 28–80 years) are included in this analysis. The ratio of mean trough concentrations of tacrolimus after comparison with before conversion was 1.02 (90% confidence interval 0.95–1.09). Fourteen patients experienced a change in tacrolimus levels >20% compared with baseline, no patients changed >20% in eGFR. The drug cost saving per daily dose was 33.40 SEK (∼€3.60, −23%). Conclusions Stable kidney transplant patients treated with Prograf® can be converted to Tacrolimus Sandoz® if trough concentrations of tacrolimus and plasma creatinine levels are closely

Donor CYP3A5 genotype influences tacrolimus disposition on the first day after paediatric liver transplantation.

PubMed

Calvo, Pier Luigi; Serpe, Loredana; Brunati, Andrea; Nonnato, Antonello; Bongioanni, Daniela; Olio, Dominic Dell'; Pinon, Michele; Ferretti, Carlo; Tandoi, Francesco; Carbonaro, Giulia; Salizzoni, Mauro; Amoroso, Antonio; Romagnoli, Renato; Canaparo, Roberto

2017-06-01

The aim of the present study was to investigate the influence of the cytochrome P450 (CYP) 3A4/5 genotype in paediatric liver transplant recipients and donors, and the contribution of age and gender to tacrolimus disposition on the first day after transplantation. The contribution of the CYP3A4/5 genotype in paediatric liver transplant recipients and donors to the tacrolimus blood trough concentrations (C 0 ) and the tacrolimus concentration/weight-adjusted dose ratio on day 1 was evaluated in 67 liver-transplanted children: 33 boys and 34 girls, mean age 4.5 years. Donor CYP3A5 genotype appears to be significantly associated with tacrolimus disposition on the first day after liver transplantation (P < 0.0002). Other physiological factors, such as recipient age and donor gender may also play a role and lead to significant differences in tacrolimus C 0 and tacrolimus concentration/weight-adjusted dose ratio on day 1. However, according to the general linear model, only recipient age appears to be independently associated with tacrolimus disposition on the first day after liver transplantation (P < 0.03). Indeed, there was a faster tacrolimus metabolism in children under 6 years of age (P < 0.02). Donor CYP3A5 genotype, recipient age and, to a lesser extent, donor gender appear to be associated with tacrolimus disposition on day 1 after transplant. This suggests that increasing the starting tacrolimus doses in paediatric patients under 6 years of age who receive a graft from a male extensive metabolizer may enhance the possibility of their tacrolimus levels reaching the therapeutic range sooner. © 2017 The British Pharmacological Society.

Quantitation of tacrolimus in whole blood using high performance liquid chromatography-tandem mass spectrometry (HPLC-MS-MS).

PubMed

Donaldson, Keri J; Shaw, Leslie M

2010-01-01

We describe a multiple reaction monitoring positive ion HPLC/tandem mass spectrometric method for quantification of tacrolimus in human whole blood with online extraction and cleanup. Included in this procedure: API 2000 triple quadrupole mass spectrometer with turbo-ion spray source (Applied Biosystems, Foster City, CA); 10-port diverter/switching valve (Valco, Houston, TX); HPLC system (Agilent Technologies series 1100, Wilmington, DE); 10 mm (C(18)) guard cartridge (Perkin Elmer, Norwalk, CT) used as an extraction column; a Nova-Pak C18 analytical column (2.1 x 150 mm I.D., 4 microm, Waters Corp, Milford, MA); washing solution, methanol: 30 mM ammonium acetate pH 5.1 (80:20); eluting solution, methanol:30 mM ammonium acetate pH 5.1 (97:3); flow rate 0.8 mL/min; and a run-time of 2.8 min. The first and third quadrupoles were set to detect the ammonium adduct ion and a high mass fragment of tacrolimus (m/z 821.5-->768.3), and of an internal standard (ascomycin) (m/z 901.8-->834.4). The lower limit of quantification of this method is 3.75 mg/L. The concentration of drug is determined by comparing peak-area ratios for tacrolimus and internal standard to a standard curve constructed using non-weighted linear through zero regression.

A multicenter experience with generic tacrolimus conversion.

PubMed

McDevitt-Potter, Lisa M; Sadaka, Basma; Tichy, Eric M; Rogers, Christin C; Gabardi, Steven

2011-09-27

The first generic tacrolimus product gained Food and Drug Administration approval in August 2009. This prospective, observational trial sought to determine the need for dose titrations and measure drug cost savings on conversion to generic tacrolimus. Transplant recipients on stable tacrolimus doses were converted from brand to generic tacrolimus on a mg:mg basis. Data were collected at the time of generic conversion (study arm) and at a time point exactly 6 months before conversion (control arm) for all subjects. Seventy conversions from four centers are reported. Subjects were a mean of 70 months after kidney (n=37), liver (n=28), or multiorgan (n=5) transplant. In the study arm, mean tacrolimus doses were 4.4 and 4.5 mg/d and mean tacrolimus trough concentrations were 5.8 and 5.9 ng/mL before and after conversion, respectively. In the control arm, mean tacrolimus doses were 4.6 and 4.6 mg/d and mean tacrolimus trough concentrations were 6.1 and 5.9 ng/mL before and after the control time point, respectively. Dose titrations occurred in five patients (7%) in the control arm and 15 patients (21%) in the study arm (P=0.028). Mean monthly drug costs were $645 for brand, $593 for generic, and $595 for generic after dose titrations. Mean monthly patient copays were $38 for brand and $15 for generic. These cumulative data show that dose requirements and trough levels are similar between brand and generic tacrolimus and that generic substitution allows for savings. However, postconversion monitoring is prudent as patients may require dose titration.

A differential impact of mycophenolic acid, prednisolone, and tacrolimus exposure on sCD30 levels in adult kidney transplant recipients.

PubMed

Barraclough, Katherine A; Staatz, Christine E; Johnson, David W; Gillis, David; Lee, Katie J; McWhinney, Brett C; Ungerer, Jacobus P J; Campbell, Scott B; Isbel, Nicole M

2013-04-01

Soluble CD30 (sCD30) has been associated with rejection and graft loss in kidney transplantation, leading to the suggestion that sCD30 might be a useful biomarker to adjust immunosuppressant medication dosing. However, there has been minimal study of the influence of individual immunosuppressive drugs on sCD30 levels. To evaluate the influence of mycophenolic acid (MPA), prednisolone, and tacrolimus exposure on sCD30 levels in adult kidney transplant recipients. The sCD30 levels were measured pretransplant and 30 days posttransplant. Area under the concentration-time curve (AUC) for each drug was estimated on day 30 using validated, multiple regression-derived limited sampling strategies. One hundred twenty-five subjects were included. Median (interquartile range) sCD30 levels were lower on day 30 posttransplant compared with pretransplant [10.7 (3.7-20.1) pg/mL versus 66.5 (46.0-95.1) pg/mL; P < 0.0001]. On univariate analyses, day 30 sCD30 levels were negatively correlated with MPA exposure and positively correlated with tacrolimus exposure. Using multivariate logistic regression, higher tacrolimus exposure was independently associated with higher day 30 sCD30 levels (2.2 change in odds for an SD increase in tacrolimus AUC 0-12, P = 0.01; 5.5 change in odds for an SD increase in tacrolimus predose concentration, P < 0.0001). In contrast, MPA and total and free prednisolone exposures were not independently associated with sCD30 levels. The sCD30 levels are significantly reduced in the presence of combination immunosuppression but are differentially affected by different immunosuppressant agents. More research is required before introduction of sCD30 measurement into clinical practice can be considered.

Switching Stable Kidney Transplant Recipients to a Generic Tacrolimus Is Feasible and Safe, but It Must Be Monitored.

PubMed

González, Fernando; López, René; Arriagada, Elizabeth; Carrasco, René; Gallardo, Natalia; Lorca, Eduardo

2017-01-01

Background . Tacrolimus is the primary immunosuppressive drug used in kidney transplant patients. Replacing brand name products with generics is a controversial issue that we studied after a Chilean Ministry of Health mandate to implement such a switch. Methods . Forty-one stable Prograf (Astellas) receiving kidney transplant patients were switched to a generic tacrolimus (Sandoz) in a 1 : 1 dose ratio and were followed up for up to 8 months. All other drugs were maintained as per normal practice. Results . Neither tacrolimus doses nor their trough blood levels changed significantly after the switch, but serum creatinine did: 1.62 ± 0.90 versus 1.75 ± 0.92 mg/dL ( p < 0.001). At the same time, five graft biopsies were performed, and two of them showed cellular acute rejection. There were nine infectious episodes treated satisfactorily with proper therapies. No patient or graft was lost during the follow-up time period. Conclusion . Switching from brand name tacrolimus to a generic tacrolimus (Sandoz) is feasible and appears to be safe, but it must be monitored carefully by treating physicians.

The effect of CYP3A5 and ABCB1 single nucleotide polymorphisms on tacrolimus dose requirements in Caucasian liver transplant patients.

PubMed

Provenzani, Alessio; Notarbartolo, Monica; Labbozzetta, Manuela; Poma, Paola; Biondi, Filippo; Sanguedolce, Rosario; Vizzini, Giovanni; Palazzo, Ugo; Polidori, Piera; Triolo, Fabio; Gridelli, Bruno; D'Alessandro, Natale

2009-01-01

Tacrolimus is a substrate of cytochrome P-450 (CYP) 3A enzyme and of the drug transporter ABCB1. We have investigated the effects of possible relevant CYP3A5 and ABCB1 single nucleotide polymorphisms (SNPs) present in both donors and recipients on tacrolimus blood levels achieved in a population of 32 Caucasian liver transplant patients. At 1, 3 and 6 months after transplantation, tacrolimus doses (mg/kg/day) and trough blood levels (C(0)) were determined. Polymerase chain reaction followed by restriction fragment length polymorphism analysis was used for genotyping CYP3A5*3 [6986A>G] as well as ABCB1 at exons 21 [2677G>T] and 26 [3435C>T]. 87.5% of the population showed a CYP3A5*3/*3 genotype. For the ABCB1 SNPs, in the case of 3435C>T the total frequency observed for the allelic variant was 50%. For the 2677G>T, the total frequency of the allelic variant was 12.5%, lower than in other Caucasian populations and without any significant linkage with 3435C>T. At 3 and 6 months after transplantation, tacrolimus dose requirements were significantly higher in patients receiving a liver with one copy of the *1 allele compared to those homozygous for the *3 allele (0.111+/-0.057 vs. 0.057+/-0.030 [P<0.05] at 3 month and 0.086+/-0.051 vs. 0.044+/-0.025 [P<0.05] at 6 month). For the recipients' genotypes, the presence of at least one *1 copy tended, though not statistically significantly, to increase tacrolimus doses. With regard to the ABCB1 SNPs, they did not show any influence on tacrolimus dosing requirements. Pharmacogenetic analysis of CYP3A5 in the donor could contribute to determine the appropriate initial dosage of tacrolimus in liver transplant patients.

Rectal and sublingual administration of tacrolimus: a single-dose pharmacokinetic study in healthy volunteers.

PubMed

Stifft, Frank; Vanmolkot, Floris; Scheffers, Ingrid; van Bortel, Luc; Neef, Cees; Christiaans, Maarten

2014-11-01

The immunosuppressant tacrolimus is usually administered orally. When this is not feasible, other routes of administration may be useful. Previous research suggested that tacrolimus may be applied sublingually or rectally. Pharmacokinetic data are sparse. The aim of this study was to investigate and compare the pharmacokinetics of these alternative formulations with orally administered tacrolimus. Three single, fixed-dose formulations of tacrolimus were administered in a random sequence in 18 healthy subjects, using a cross-over study design. For sublingual administration, 3 mg of powder obtained from oral capsules was applied under the tongue for a period of 15 min without swallowing, with mouth rinsing afterwards. For rectal administration, a suppository containing 15 mg of the oral powder was used. Oral administration consisted of 7 mg of instant-release tacrolimus capsules (Prograf). Main pharmacokinetic outcome parameters were compared by anova. Sublingual administration showed no clinically significant exposure, contrary to rectal administration, where all subjects had clinically relevant exposure, with a lower relative bioavailability (78%), a lower maximal blood concentration and a later time of maximal blood concentration compared with oral administration. Sublingual administration of a single dose of tacrolimus does not result in systemic exposure if care is taken not to swallow saliva and to rinse the oral cavity afterwards. Rectal administration of tacrolimus results in clinically relevant systemic exposure and might represent an alternative formulation in case oral administration is not feasible. When used as a topical agent, systemic side-effects should be considered. © 2014 The British Pharmacological Society.

Rectal and sublingual administration of tacrolimus: a single-dose pharmacokinetic study in healthy volunteers

PubMed Central

Stifft, Frank; Vanmolkot, Floris; Scheffers, Ingrid; van Bortel, Luc; Neef, Cees; Christiaans, Maarten

2014-01-01

Aims The immunosuppressant tacrolimus is usually administered orally. When this is not feasible, other routes of administration may be useful. Previous research suggested that tacrolimus may be applied sublingually or rectally. Pharmacokinetic data are sparse. The aim of this study was to investigate and compare the pharmacokinetics of these alternative formulations with orally administered tacrolimus. Methods Three single, fixed-dose formulations of tacrolimus were administered in a random sequence in 18 healthy subjects, using a cross-over study design. For sublingual administration, 3 mg of powder obtained from oral capsules was applied under the tongue for a period of 15 min without swallowing, with mouth rinsing afterwards. For rectal administration, a suppository containing 15 mg of the oral powder was used. Oral administration consisted of 7 mg of instant-release tacrolimus capsules (Prograf). Main pharmacokinetic outcome parameters were compared by anova. Results Sublingual administration showed no clinically significant exposure, contrary to rectal administration, where all subjects had clinically relevant exposure, with a lower relative bioavailability (78%), a lower maximal blood concentration and a later time of maximal blood concentration compared with oral administration. Conclusions Sublingual administration of a single dose of tacrolimus does not result in systemic exposure if care is taken not to swallow saliva and to rinse the oral cavity afterwards. Rectal administration of tacrolimus results in clinically relevant systemic exposure and might represent an alternative formulation in case oral administration is not feasible. When used as a topical agent, systemic side-effects should be considered. PMID:24809233

Influence of CYP3A5 and ABCB1 gene polymorphisms and other factors on tacrolimus dosing in Caucasian liver and kidney transplant patients.

PubMed

Provenzani, Alessio; Notarbartolo, Monica; Labbozzetta, Manuela; Poma, Paola; Vizzini, Giovanni; Salis, Paola; Caccamo, Chiara; Bertani, Tullio; Palazzo, Ugo; Polidori, Piera; Gridelli, Bruno; D'Alessandro, Natale

2011-12-01

Tacrolimus is a substrate of cytochrome P4503A (CYP3A) enzymes as well as of the drug transporter ABCB1. We have investigated the possible influence of CYP3A5 and ABCB1 single nucleotide polymorphisms (SNPs) and other factors (e.g. albumin, hematocrit and steroids) on tacrolimus blood levels achieved in a population of Caucasian liver (n=51) and kidney (n=50) transplant recipients. At 1, 3 and 6 months after transplantation, tacrolimus doses (mg/kg/day) and trough blood levels (C0) were recorded and the weight-adjusted tacrolimus dosage (mg/kg/day) was calculated. Polymerase chain reaction followed by restriction fragment length polymorphism analysis was used for genotyping CYP3A5*1 and *3 [6986A>G] as well as ABCB1 at exons 21 [2677G>T/A] and 26 [3435C>T] in both liver transplant donors and recipients and in kidney transplant recipients. Of the 152 subjects studied, 84.9% showed a CYP3A5*3/*3 genotype. The total frequency of the allelic variant *3 was 93%. For the G2677T/A and C3435T polymorphisms the total frequencies of the allelic variants T/A and T were 44.7 and 46.7%, respectively. At 1, 3 and 6 months after transplantation the dose-adjusted C0 levels were significantly lower in patients with one copy of the *1 allele compared to those homozygous for the *3 allele. In the case of liver transplant patients the tacrolimus dose requirements were dominantly influenced by the polymorphisms of the CYP3A5 gene in the donors. With regard to the ABCB1 SNPs, in general they did not show any appreciable influence on tacrolimus dosing requirements; however, kidney transplant recipients carrying the 2677T/A allele required significantly higher daily tacrolimus doses than subjects homozygous for the wild-type allele. Identification of CYP3A5 single nucleotide polymorphisms prior to transplantation could contribute to evaluate the appropriate initial dosage of tacrolimus in the patients.

Pharmacokinetics of prolonged-release tacrolimus and implications for use in solid organ transplant recipients.

PubMed

Tanzi, Maria G; Undre, Nasrullah; Keirns, James; Fitzsimmons, William E; Brown, Malcolm; First, M Roy

2016-08-01

Prolonged-release tacrolimus was developed as a once-daily formulation with ethylcellulose as the excipient, resulting in slower release and reduction in peak concentration (Cmax ) for a given dose compared with immediate-release tacrolimus, which is administered twice daily. This manuscript reviews pharmacokinetic information on prolonged-release tacrolimus in healthy subjects, in transplant recipients converted from immediate-release tacrolimus, and in de novo kidney and liver transplant recipients. As with the immediate-release formulation, prolonged-release tacrolimus shows a strong correlation between trough concentration (Cmin ) and area under the 24-hour time-concentration curve (AUC24 ), indicating that trough whole blood concentrations provide an accurate measure of drug exposure. We present the pharmacokinetic similarities and differences between the two formulations, so that prescribing physicians will have a better understanding of therapeutic drug monitoring in patients receiving prolonged-release tacrolimus. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Topical tacrolimus for atopic dermatitis.

PubMed

Cury Martins, Jade; Martins, Ciro; Aoki, Valeria; Gois, Aecio F T; Ishii, Henrique A; da Silva, Edina M K

2015-07-01

SCORAD (SCORing Atopic Dermatitis), the EASI (Eczema Area and Severity Index), and BSA (Body Surface Area) scores. We included 20 studies, with 5885 participants. The variability of drug doses, outcomes, and follow-up periods made it difficult to carry out meta-analyses.A single trial showed that tacrolimus 0.1% was better than low-potency TCS by the physician's assessment (risk ratio (RR) 3.09, 95% confidence interval (CI) 2.14 to 4.45, 1 study, n = 371, moderate-quality evidence). It was also marginally better than low-potency TCS on face and neck areas and moderate-potency TCS on the trunk and extremities by the physician's assessment (RR 1.32, 95% CI 1.17 to 1.49, 1 study, n = 972, moderate level of evidence) and for some of the secondary outcomes. Compared with pimecrolimus 1%, people treated with tacrolimus were almost twice as likely to improve by the physician's assessment (RR 1.80, 95% CI 1.34 to 2.42, 2 studies, n = 506, moderate quality of evidence). Compared with the lower concentration of 0.03%, the tacrolimus 0.1% formulation reduced the risk of not having an improvement by 18% as evaluated by the physician's assessment (RR 0.82, 95% CI 0.72 to 0.92, 6 studies, n = 1640, high-quality evidence). Tacrolimus 0.1% compared with moderate-to-potent TCS showed no difference by the physician's assessment, and 2 secondary outcomes (1 study, 377 participants) and a marginal benefit favouring tacrolimus 0.1% was found by the participant's assessment (RR 1.21, 95% CI 1.13 to 1.29, 1 study, n = 974, low quality of evidence) and SCORAD.Based on data from 2 trials, tacrolimus 0.03% was superior to mild TCS for the physician's assessment (RR 2.58, 95% CI 1.96 to 3.38, 2 studies, n = 790, moderate-quality evidence) and the participant's self-assessment (RR 1.64, 95% CI 1.41 to 1.90, 1 study, n = 416, moderate quality of evidence). One trial showed moderate benefit of tacrolimus 0.03% compared with pimecrolimus 1% on the physician's assessment (RR 1.42, 95% CI 1.02 to 1

The evaluation of potential pharmacokinetic interaction between sirolimus and tacrolimus in healthy volunteers.

PubMed

Tortorici, Michael A; Parks, Virginia; Matschke, Kyle; Korth-Bradley, Joan; Patat, Alain

2013-04-01

Sirolimus and tacrolimus are immunosuppressive compounds that have been used concomitantly in renal transplant patients. Both drugs are dosed orally and have common intestinal and hepatic metabolism and intestinal transport mechanisms. As such, there is a potential for pharmacokinetic drug interaction. A single-dose, open-label, four-period, four-treatment, randomized crossover study was conducted in 27 healthy fasting volunteers. Each subject received a 15-mg oral dose of sirolimus alone, a 10-mg oral dose of tacrolimus alone, sirolimus and tacrolimus administered simultaneously, and tacrolimus administered 4 h before sirolimus. Whole blood and plasma samples for sirolimus and tacrolimus testing were analyzed by liquid chromatography/tandem mass spectrometry. Pharmacokinetic parameters were assessed using noncompartmental methods and were compared using analysis of variance (ANOVA). The geometric mean ratio and 90 % confidence interval (CI) area under the concentration-time curve from time 0 to infinity (AUCinf) for sirolimus administered simultaneously with tacrolimus versus sirolimus alone were 97 and 89-106, respectively, and, when administered in a staggered approach versus sirolimus alone, 107 and 98-117, respectively. The geometric mean ratio (%) and 90 % CI AUCinf for tacrolimus administered simultaneously with sirolimus versus tacrolimus alone were 92 and 82-102, respectively, and, when administered in a staggered approach versus tacrolimus alone, 94 and 84-105, respectively. The results of this study demonstrate a lack of any clinically important drug interaction between sirolimus and tacrolimus in healthy subjects after single-dose administration. However, due to the complexity of anti-rejection immunosuppressive therapy dosing, we suggest that sirolimus and tacrolimus concentration monitoring be performed when changes in dosing are made for either drug regimen.

Switching Stable Kidney Transplant Recipients to a Generic Tacrolimus Is Feasible and Safe, but It Must Be Monitored

PubMed Central

López, René; Arriagada, Elizabeth; Carrasco, René; Gallardo, Natalia; Lorca, Eduardo

2017-01-01

Background. Tacrolimus is the primary immunosuppressive drug used in kidney transplant patients. Replacing brand name products with generics is a controversial issue that we studied after a Chilean Ministry of Health mandate to implement such a switch. Methods. Forty-one stable Prograf (Astellas) receiving kidney transplant patients were switched to a generic tacrolimus (Sandoz) in a 1 : 1 dose ratio and were followed up for up to 8 months. All other drugs were maintained as per normal practice. Results. Neither tacrolimus doses nor their trough blood levels changed significantly after the switch, but serum creatinine did: 1.62 ± 0.90 versus 1.75 ± 0.92 mg/dL (p < 0.001). At the same time, five graft biopsies were performed, and two of them showed cellular acute rejection. There were nine infectious episodes treated satisfactorily with proper therapies. No patient or graft was lost during the follow-up time period. Conclusion. Switching from brand name tacrolimus to a generic tacrolimus (Sandoz) is feasible and appears to be safe, but it must be monitored carefully by treating physicians. PMID:28246556

Effects of traditional chinese medicine Wuzhi capsule on pharmacokinetics of tacrolimus in rats.

PubMed

Wei, Hua; Tao, Xia; Di, Peng; Yang, Yingbo; Li, Jingxian; Qian, Xiaofeng; Feng, Jin; Chen, Wansheng

2013-07-01

Wuzhi capsule (WZC) is a preparation of an ethanol herbal extract of Schisandra sphenanthera (Nan-Wuweizi), with its main active ingredients that include schisandrin, schizandrol B, schisantherin A, schisanhenol, and deoxyschizandrin. WZC and tacrolimus are often coadministered for the treatment of drug-induced hepatitis in organ transplant recipients in China. Recently, it was reported that WZC could significantly increase the blood concentration of tacrolimus. The purpose of this study was to investigate whether and how WZC affects the pharmacokinetics of tacrolimus in rats. Liquid chromatography-tandem mass spectrometry method was used to determine the plasma concentration of tacrolimus. The results showed that WZC increased the mean plasma concentration of tacrolimus. Compared with administration of tacrolimus alone [maximum plasma concentration (C(max)), 18.87 ± 10.29 ng/ml; area under the plasma concentration-time curve from time zero to last sampling time (AUC(0→t)), 40.98 ± 37.07 ng h/ml], a single intragastric administered dose of WZC increased the pharmacokinetic parameters of tacrolimus (C(max), 59.42 ± 30.32 ng/ml; AUC(0→t), 239.71 ± 28.86 ng h/ml) by 5-fold in rat plasma. After pretreatment with WZC for 12 days, there were still significant increases in AUC(0→t) (from 40.98 ± 37.07 to 89.21 ± 26.39 ng h/ml; P < 0.05) and C(max) (from 18.87 ± 10.29 to 43.16 ± 10.61 ng/ml; P < 0.05) of tacrolimus, compared with oral of tacrolimus alone, suggesting that WZC increased the exposure of tacrolimus by one or more mechanisms. The increase in tacrolimus C(max) by WZC was dose-dependent. The effect of WZC on tacrolimus AUC(0→t) also increased with dose, with a maximal effect observed at 450 mg/kg (825.34 ng h/ml). No further increases in tacrolimus AUC(0→t) were observed at WZC dose above 450 mg/kg. It is suggested that, because of the effect of WZC on the pharmacokinetics of tacrolimus, the herb-drug interaction between WZC and tacrolimus

Nationwide conversion to generic tacrolimus in pediatric kidney transplant recipients.

PubMed

Naicker, Derisha; Reed, Peter W; Ronaldson, Jane; Kara, Tonya; Wong, William; Prestidge, Chanel

2017-11-01

Bioequivalence between Tacrolimus Prograf® and generic tacrolimus formulations has been demonstrated in adult populations, however clinical experience and safety data regarding generic tacrolimus in pediatric transplant recipients is limited. This study aimed to evaluate conversion from Tacrolimus Prograf® to Sandoz® in pediatric renal transplant recipients nationwide. The primary outcome was a change in mean trough tacrolimus concentration. Additionally, changes in tacrolimus intra-patient coefficient of variation (CoV), allograft function, requirement for dose adjustments, and episodes of biopsy-proven rejection were evaluated. Retrospective cohort study in 37 pediatric renal transplant recipients who switched to Tacrolimus Sandoz®. Each patient had three pre-conversion tacrolimus trough and creatinine concentrations within the 4 months prior and three post-conversion concentrations on day 3, 10, and the next subsequent level. Mean pre- and post-conversion tacrolimus trough concentrations and glomerular filtration rate (eGFR) were calculated. Tacrolimus concentration, CoV, and creatinine differences were compared by paired t test. Thirty-seven patients (41% females, age 3-18 years) were included. Average intra-patient difference in trough tacrolimus concentration was 0.05μg/l (95% CI -0.37 to 0.47). Average intra-patient difference in eGFR was -1.20 ml/min/1.73 2 (95% CI -3.53 to 1.13). Three patients had acute rejection during 12 months post-conversion compared to none during 12 months pre-conversion. Pediatric renal transplant recipients can be converted from Tacrolimus Prograf® to Sandoz® with negligible change in trough concentration, dose adjustments, or immediate allograft function. Of concern was the number of acute rejection episodes, however non-adherence contributed to at least one episode and this difference was determined clinically and statistically not significant.

Development of extended-release solid dispersion granules of tacrolimus: evaluation of release mechanism and human oral bioavailability.

PubMed

Tsunashima, Daisuke; Yamashita, Kazunari; Ogawara, Ken-Ichi; Sako, Kazuhiro; Hakomori, Tadashi; Higaki, Kazutaka

2017-12-01

We aimed to prepare a once-daily modified-release oral formulation of tacrolimus by utilizing an extended-release granules (ERG). Extended-release granules were prepared using ethylcellulose (EC), hydroxypropylmethylcellulose (HPMC) and lactose via a solvent evaporation method with ethanol. Physicochemical and biopharmaceutical studies were performed to determine the formulation with optimum release profile of tacrolimus from ERG. Tacrolimus existed in an amorphous state in ERG. Tacrolimus release from ERG was attenuated by EC and facilitated by lactose, suggesting that drug release kinetics could adequately be regulated by these components. Those release profiles were consistent with Higuchi's equation, suggesting a diffusion-type release mechanism. Smooth surface of ERG changed to the structure with pores after the release test, likely derived from the dissolution of HPMC and lactose. But ERG structure formed by EC was still maintained after the release test, leading to the longer maintenance of diffusion-type release. Two ERG formulations selected by blood concentration simulation successfully provided long-term retention of tacrolimus in blood in a human absorption study. We successfully developed the formulation exhibiting a significant reduction in C max , the longer mean residence time and AUC close to that of an immediate-release tacrolimus formulation, being preferred from the viewpoint of safe and effective immunosuppressant pharmacotherapy. © 2017 Royal Pharmaceutical Society.

A high performance liquid chromatography tandem mass spectrometry for the quantification of tacrolimus in human bile in liver transplant recipients.

PubMed

Tron, Camille; Rayar, Michel; Petitcollin, Antoine; Beaurepaire, Jean-Marie; Cusumano, Caterina; Verdier, Marie-Clémence; Houssel-Debry, Pauline; Camus, Christophe; Boudjema, Karim; Bellissant, Eric; Lemaitre, Florian

2016-12-02

Tacrolimus whole-blood concentrations imperfectly reflect concentrations at the effect site. Tacrolimus concentrations in the transplanted organ could be more relevant to predict rejection events. Because liver biopsy cannot be repeatedly performed after liver transplantation, we suggested measuring tacrolimus in the bile to have a cost-effective and clinically implementable surrogate marker of intra-hepatic tacrolimus concentration. We developed and fully validated a liquid chromatography-tandem mass spectrometry method for the determination of tacrolimus in human bile. Sample purification was achieved using protein precipitation and liquid-liquid extraction with ethyl-acetate. Gradient elution was performed using a C18 analytical column with a 5min run-time. The method was linear from 0.5ng/mL to 20ng/mL. In this concentration range, within-day and between-day precisions as well as overall bias were within ±15%. Matrix effect was fully corrected by the internal standard (ascomycin). The assay was optimized to achieve good selectivity in this complex biological matrix. Tacrolimus was found to be stable in bile stored 6 months at -80°C, after 3 freeze and thaw cycles, 20h at room temperature and 24h in extracts kept at 15°C in the auto-sampler. The method was applied to quantify tacrolimus in bile from liver transplant recipients. It allowed getting preliminary data about tacrolimus excretion profile in bile and showed the lack of correlation between tacrolimus whole blood concentration and tacrolimus liver exposition. This alternative and innovative analytical approach of tacrolimus bio-analysis appears suitable for further studies evaluating relevance of biliary tacrolimus concentration as a new pharmacological marker of immunosuppressive activity. Copyright © 2016 Elsevier B.V. All rights reserved.

Tacrolimus Increases the Effectiveness of Itraconazole and Fluconazole against Sporothrix spp.

PubMed

Borba-Santos, Luana P; Reis de Sá, Leandro F; Ramos, Juliene A; Rodrigues, Anderson M; de Camargo, Zoilo P; Rozental, Sonia; Ferreira-Pereira, Antonio

2017-01-01

Calcineurin inhibitors - such as the clinically used drug tacrolimus - are active against important fungal pathogens, particularly when combined with azoles. However, tacrolimus has not been tested against sporotrichosis, an endemic subcutaneous mycosis with worldwide distribution. Here, we evaluated the activity of tacrolimus and cyclosporine A in vitro - as monotherapy and in combination with itraconazole or fluconazole - against yeasts of Sporothrix brasiliensis and S. schenckii , the main sporotrichosis agents in Brazil. We also analyzed the effect of tacrolimus treatment on intracellular neutral lipid levels, which typically increase after azole treatment. Tacrolimus inhibited the growth of yeasts from S. brasiliensis and S. schenckii reference isolates, with minimum inhibitory concentration (MIC) values (required for ≥50% growth inhibition) of 1 and 2 mg/L, respectively. Importantly, the combination of tacrolimus and azoles exhibited high synergy toward reference Sporothrix isolates. Tacrolimus combined with itraconazole significantly increased neutral lipid accumulation in S. brasiliensis , but not in S. schenckii . Clinical isolates of S. brasiliensis and S. schenckii were more sensitive to tacrolimus as monotherapy than feline-borne isolates, however, synergy between tacrolimus and azoles was only observed for feline-borne isolates. Cyclosporine A was effective against S. brasiliensis and S. schenckii as monotherapy (MIC = 1 mg/L), but exhibited no synergy with itraconazole and fluconazole. We conclude that tacrolimus has promising antifungal activity against sporotrichosis agents, and also increases the activity of the current anti-sporotrichosis therapy (itraconazole and fluconazole) in combination assays against S. brasiliensis feline-borne isolates.

Population pharmacokinetic and pharmacogenetic analysis of tacrolimus in paediatric liver transplant patients

PubMed Central

Abdel Jalil, Mariam H; Hawwa, Ahmed F; McKiernan, Patrick J; Shields, Michael D; McElnay, James C

2014-01-01

Aims To build a population pharmacokinetic model that describes the apparent clearance of tacrolimus and the potential demographic, clinical and genetically controlled factors that could lead to inter-patient pharmacokinetic variability within children following liver transplantation. Methods The present study retrospectively examined tacrolimus whole blood pre-dose concentrations (n = 628) of 43 children during their first year post-liver transplantation. Population pharmacokinetic analysis was performed using the non-linear mixed effects modelling program (nonmem) to determine the population mean parameter estimate of clearance and influential covariates. Results The final model identified time post-transplantation and CYP3A5*1 allele as influential covariates on tacrolimus apparent clearance according to the following equation: where TVCL is the typical value for apparent clearance, TPT is time post-transplantation in days and the CYP3A5 is 1 where *1 allele is present and 0 otherwise. The population estimate and inter-individual variability (%CV) of tacrolimus apparent clearance were found to be 0.977 l h−1 kg−1 (95% CI 0.958, 0.996) and 40.0%, respectively, while the residual variability between the observed and predicted concentrations was 35.4%. Conclusion Tacrolimus apparent clearance was influenced by time post-transplantation and CYP3A5 genotypes. The results of this study, once confirmed by a large scale prospective study, can be used in conjunction with therapeutic drug monitoring to recommend tacrolimus dose adjustments that take into account not only body weight but also genetic and time-related changes in tacrolimus clearance. PMID:23738951

Generic tacrolimus in solid organ transplantation.

PubMed

Taube, D; Jones, G; O'Beirne, J; Wennberg, L; Connor, A; Rasmussen, A; Backman, L

2014-05-01

The availability of a wide range of immunosuppressive therapies has revolutionized the management of patients who have undergone solid organ transplantation (SOT). However, the cost of immunosuppressive drugs remains high. This situation has led to the development of generic equivalents, which are similar in quality, safety, and efficacy to their approved innovator drugs. There are data available for three generic brands, tacrolimus (Intas), tacrolimus (PharOS), and tacrolimus (Sandoz). Bioequivalence has been demonstrated for generic tacrolimus (Sandoz) within a narrow therapeutic range to its innovator tacrolimus drug (Prograf) in both healthy volunteers and kidney transplant patients. Clinical experience with this generic tacrolimus formulation has also been established in both de novo and conversion patients who have undergone kidney and liver transplantation, as well as in conversion of other SOT patients, including lung and heart recipients. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Tacrolimus Increases the Effectiveness of Itraconazole and Fluconazole against Sporothrix spp.

PubMed Central

Borba-Santos, Luana P.; Reis de Sá, Leandro F.; Ramos, Juliene A.; Rodrigues, Anderson M.; de Camargo, Zoilo P.; Rozental, Sonia; Ferreira-Pereira, Antonio

2017-01-01

Calcineurin inhibitors – such as the clinically used drug tacrolimus – are active against important fungal pathogens, particularly when combined with azoles. However, tacrolimus has not been tested against sporotrichosis, an endemic subcutaneous mycosis with worldwide distribution. Here, we evaluated the activity of tacrolimus and cyclosporine A in vitro – as monotherapy and in combination with itraconazole or fluconazole – against yeasts of Sporothrix brasiliensis and S. schenckii, the main sporotrichosis agents in Brazil. We also analyzed the effect of tacrolimus treatment on intracellular neutral lipid levels, which typically increase after azole treatment. Tacrolimus inhibited the growth of yeasts from S. brasiliensis and S. schenckii reference isolates, with minimum inhibitory concentration (MIC) values (required for ≥50% growth inhibition) of 1 and 2 mg/L, respectively. Importantly, the combination of tacrolimus and azoles exhibited high synergy toward reference Sporothrix isolates. Tacrolimus combined with itraconazole significantly increased neutral lipid accumulation in S. brasiliensis, but not in S. schenckii. Clinical isolates of S. brasiliensis and S. schenckii were more sensitive to tacrolimus as monotherapy than feline-borne isolates, however, synergy between tacrolimus and azoles was only observed for feline-borne isolates. Cyclosporine A was effective against S. brasiliensis and S. schenckii as monotherapy (MIC = 1 mg/L), but exhibited no synergy with itraconazole and fluconazole. We conclude that tacrolimus has promising antifungal activity against sporotrichosis agents, and also increases the activity of the current anti-sporotrichosis therapy (itraconazole and fluconazole) in combination assays against S. brasiliensis feline-borne isolates. PMID:28966608

A Low Concentration of Tacrolimus/Semifluorinated Alkane (SFA) Eyedrop Suppresses Intraocular Inflammation in Experimental Models of Uveitis.

PubMed

De Majumdar, S; Subinya, M; Korward, J; Pettigrew, A; Scherer, D; Xu, H

2017-01-01

Corticosteroids remain the mainstay therapy for uveitis, a major cause of blindness in the working age population. However, a substantial number of patients cannot benefit from the therapy due to steroids resistance or intolerance. Tacrolimus has been used to treat refractory uveitis through systemic administration. The aim of this study was to evaluate the therapeutic potential of 0.03% tacrolimus eyedrop in mouse models of uveitis. 0.03% tacrolimus in perfluorobutylpentane (F4H5) (0.03% Tacrolimus/SFA) was formulated using a previously published protocol. Tacrolimus suspended in PBS (0.03% Tacrolimus/PBS) was used as a control. In addition, 0.1% dexamethasone (0.1% DXM) was used as a standard therapy control. Endotoxin-induced uveitis (EIU) and experimental autoimmune uveoretinitis (EAU) were induced in adult C57BL/6 mice using protocols described previously. Mice were treated with eyedrops three times/day immediately after EIU induction for 48 h or from day 14 to day 25 post-immunization (for EAU). Clinical and histological examinations were conducted at the end of the experiment. Pharmacokinetics study was conducted in mice with and without EIU. At different times after eyedrop treatment, ocular tissues were collected for tacrolimus measurement. The 0.03% Tacrolimus/SFA eyedrop treatment reduced the clinical scores and histological scores of intraocular inflammation in both EIU and EAU to the levels similar to 0.1% DXM eyedrop treatment. The 0.03% Tacrolimus/PBS did not show any suppressive effect in EIU and EAU. Pharmacokinetic studies showed that 15 min after topical administration of 0.03% Tacrolimus/SFA, low levels of tacrolimus were detected in the retina (48 ng/g tissue) and vitreous (2.5 ng/ml) in normal mouse eyes, and the levels were significantly higher in EIU eyes (102 ng/g tissue in the retina and 24 ng/ml in the vitreous). Tacrolimus remained detectable in intraocular tissues of EIU eyes 6 h after topical administration (68 ng/g retinal tissue, 10

Gut Microbiota and Tacrolimus Dosing in Kidney Transplantation

PubMed Central

Lee, John R.; Muthukumar, Thangamani; Dadhania, Darshana; Taur, Ying; Jenq, Robert R.; Toussaint, Nora C.; Ling, Lilan; Pamer, Eric; Suthanthiran, Manikkam

2015-01-01

Tacrolimus dosing to establish therapeutic levels in recipients of organ transplants is a challenging task because of much interpatient and intrapatient variability in drug absorption, metabolism, and disposition. In view of the reported impact of gut microbial species on drug metabolism, we investigated the relationship between the gut microbiota and tacrolimus dosing requirements in this pilot study of adult kidney transplant recipients. Serial fecal specimens were collected during the first month of transplantation from 19 kidney transplant recipients who either required a 50% increase from initial tacrolimus dosing during the first month of transplantation (Dose Escalation Group, n=5) or did not require such an increase (Dose Stable Group, n=14). We characterized bacterial composition in the fecal specimens by deep sequencing of the PCR amplified 16S rRNA V4-V5 region and we investigated the hypothesis that gut microbial composition is associated with tacrolimus dosing requirements. Initial tacrolimus dosing was similar in the Dose Escalation Group and in the Stable Group (4.2±1.1 mg/day vs. 3.8±0.8 mg/day, respectively, P=0.61, two-way between-group ANOVA using contrasts) but became higher in the Dose Escalation Group than in the Dose Stable Group by the end of the first transplantation month (9.6±2.4 mg/day vs. 3.3±1.5 mg/day, respectively, P<0.001). Our systematic characterization of the gut microbial composition identified that fecal Faecalibacterium prausnitzii abundance in the first week of transplantation was 11.8% in the Dose Escalation Group and 0.8% in the Dose Stable Group (P=0.002, Wilcoxon Rank Sum test, P<0.05 after Benjamini-Hochberg correction for multiple hypotheses). Fecal Faecalibacterium prausnitzii abundance in the first week of transplantation was positively correlated with future tacrolimus dosing at 1 month (R=0.57, P=0.01) and had a coefficient±standard error of 1.0±0.6 (P=0.08) after multivariable linear regression. Our novel

A Markov chain model to evaluate the effect of CYP3A5 and ABCB1 polymorphisms on adverse events associated with tacrolimus in pediatric renal transplantation.

PubMed

Sy, Sherwin K B; Heuberger, Jules; Shilbayeh, Sireen; Conrado, Daniela J; Derendorf, Hartmut

2013-10-01

The SNP A6986G of the CYP3A5 gene (*3) results in a non-functional protein due to a splicing defect whereas the C3435T was associated with variable expression of the ABCB1 gene, due to protein instability. Part of the large interindividual variability in tacrolimus efficacy and toxicity can be accounted for by these genetic factors. Seventy-two individuals were examined for A6986G and C3435T polymorphism using a PCR-RFLP-based technique to estimate genotype and allele frequencies in the Jordanian population. The association of age, hematocrit, platelet count, CYP3A5, and ABCB1 polymorphisms with tacrolimus dose- and body-weight-normalized levels in the subset of 38 pediatric renal transplant patients was evaluated. A Markov model was used to evaluate the time-dependent probability of an adverse event occurrence by CYP3A5 phenotypes and ABCB1 genotypes. The time-dependent probability of adverse event was about double in CYP3A5 non-expressors compared to the expressors for the first 12 months of therapy. The CYP3A5 non-expressors had higher corresponding normalized tacrolimus levels compared to the expressors in the first 3 months. The correlation trend between probability of adverse events and normalized tacrolimus concentrations for the two CYP3A5 phenotypes persisted for the first 9 months of therapy. The differences among ABCB1 genotypes in terms of adverse events and normalized tacrolimus levels were only observed in the first 3 months of therapy. The information on CYP3A5 genotypes and tacrolimus dose requirement is important in designing effective programs toward management of tacrolimus side effects particularly for the initial dose when tacrolimus blood levels are not available for therapeutic drug monitoring.

De novo use of generic tacrolimus in liver transplantation - a single center experience with one-yr follow-up.

PubMed

Dannhorn, E; Cheung, M; Rodrigues, S; Cooper, H; Thorburn, D; Patch, D; Burroughs, A K; O'Beirne, J

2014-12-01

Use of generic tacrolimus in liver transplantation (LT) could result in cost savings. Generic tacrolimus has been shown to be bioequivalent to innovator tacrolimus in healthy volunteers and renal transplant patients. There are limited data on the de novo use of generic tacrolimus in LT. This study aimed to determine whether the de novo use of generic tacrolimus (Adoport, Sandoz,UK) was associated with differences in outcomes, safety, and cost compared with innovator tacrolimus (Prograf, Astellas, Japan). Patients were studied before and after a programmatic change from de novo IS with Prograf to Adoport. Outcomes, tacrolimus levels, doses, and costs were compared for the first-yr post-LT. Ninety-four patients were studied, 46 Prograf, 48 Adoport. No significant differences in rejection, cytomegalovirus infection, acute kidney injury, sepsis, or graft loss were observed between groups. Tacrolimus costs were significantly reduced with the de novo use of Adoport. Day 14 dose normalized levels in Adoport patients showed significant variation but at the day 30 and one yr, there were no significant differences in the doses or levels of tacrolimus between groups. Adoport is safe and effective compared to Prograf when used de novo in LT patients. Tacrolimus costs were significantly reduced by the use of Adoport. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Lactobacillus Fermentum Improves Tacrolimus-Induced Hypertension by Restoring Vascular Redox State and Improving eNOS Coupling.

PubMed

Toral, Marta; Romero, Miguel; Rodríguez-Nogales, Alba; Jiménez, Rosario; Robles-Vera, Iñaki; Algieri, Francesca; Chueca-Porcuna, Natalia; Sánchez, Manuel; de la Visitación, Néstor; Olivares, Mónica; García, Federico; Pérez-Vizcaíno, Francisco; Gálvez, Julio; Duarte, Juan

2018-05-30

Our aim was to analyse whether the probiotic Lactobacillus fermentum CECT5716 (LC40) could prevent endothelial dysfunction and hypertension induced by tacrolimus in mice. Tacrolimus increased systolic blood pressure (SBP) and impaired endothelium-dependent relaxation to acetylcholine and these effects were partially prevented by LC40. Endothelial dysfunction induced by tacrolimus was related to both increased NADPH oxidase (NOX2) and uncoupled eNOS driven-superoxide production and Rho-kinase mediated eNOS inhibition. LC40 treatment prevented all the aortic changes induced by tacrolimus. LC40 restored the imbalance between T-helper 17 (Th17)/ regulatory T (Treg) cells induced by tacrolimus in mesenteric lymph nodes and spleen. Tacrolimus induced gut dysbiosis, i.e. it decreased microbial diversity, increased Firmicutes/Bacteroidetes ratio and decreased acetate- and butyrate-producing bacteria and these effects were prevented by LC40. Fecal microbiota transplantation from LC40 treated mice to control mice prevented the increase in SBP and the impaired relaxation to acetylcholine induced by tacrolimus. LC40 treatment prevented hypertension and endothelial dysfunction induced by tacrolimus by inhibiting gut dysbiosis. These effects were associated with a reduction in vascular oxidative stress, mainly through NOX2 down-regulation and prevention of eNOS-uncoupling, and inflammation possibly because of decreased Th17 and increased Treg cells polarization in mesenteric lymph nodes. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Multi-center Performance Evaluations of Tacrolimus and Cyclosporine Electrochemiluminescence Immunoassays in the Asia-Pacific Region

PubMed Central

Qin, Xuzhen; Rui, Jianzhong; Xia, Yong; Mu, Hong; Song, Sang Hoon; Raja Aziddin, Raja Elina; Miles, Gabrielle; Sun, Yuli

2018-01-01

Background The immunosuppressant drugs (ISDs), tacrolimus and cyclosporine, are vital for solid organ transplant patients to prevent rejection. However, toxicity is a concern, and absorption is highly variable across patients; therefore, ISD levels need to be precisely monitored. In the Asia-Pacific (APAC) region, tacrolimus and cyclosporine concentrations are typically measured using immunoassays. The objective of this study was to assess the analytical performance of Roche Elecsystacrolimus and cyclosporinee electrochemiluminescence immunoassays (ECLIAs). Methods This evaluation was performed in seven centers across China, South Korea, and Malaysia. Imprecision (repeatability and reproducibility), assay accuracy, and lot-to-lot reagent variability were tested. The Elecsys ECLIAs were compared with commercially available immunoassays (Architect, Dimension, and Viva-E systems) using whole blood samples from patients with various transplant types (kidney, liver, heart, and bone marrow). Results Coefficients of variation for repeatability and reproducibility were ≤5.4% and ≤12.4%, respectively, for the tacrolimus ECLIA, and ≤5.1% and ≤7.3%, respectively, for the cyclosporine ECLIA. Method comparisons of the tacrolimus ECLIA with Architect, Dimension, and Viva-E systems yielded slope values of 1.01, 1.14, and 0.897, respectively. The cyclosporine ECLIA showed even closer agreements with the Architect, Dimension, and Viva-E systems (slope values of 1.04, 1.04, and 1.09, respectively). No major differences were observed among the different transplant types. Conclusions The tacrolimus and cyclosporine ECLIAs demonstrated excellent precision and close agreement with other immunoassays tested. These results show that both assays are suitable for ISD monitoring in an APAC population across a range of different transplant types. PMID:29214751

Overview of extended release tacrolimus in solid organ transplantation

PubMed Central

Patel, Neha; Cook, Abigail; Greenhalgh, Elizabeth; Rech, Megan A; Rusinak, Joshua; Heinrich, Lynley

2016-01-01

Tacrolimus (Prograf©, Astellas Pharma Europe Ltd, Staines, United Kingdom; referred to as tacrolimus-BID) is an immunosuppressive agent to prevent and treat allograft rejection in kidney transplant recipients in combination with mycophenolate mofetil, corticosteroids, with or without basiliximab induction. The drug has also been studied in liver, heart and lung transplant; however, these are currently off-label indications. An extended release tacrolimus formulation (Advagraf©, Astagraf XL©) allows for once-daily dosing, with the potential to improve adherence. Extended release tacrolimus has similar absorption, distribution, metabolism and excretion to tacrolimus-BID. Phase I pharmacokinetic trials comparing extended release tacrolimus and tacrolimus-BID have demonstrated a decreased maximum concentration (Cmax) and delayed time to maximum concentration (tmax) with the extended release formulation; however, AUC0-24 was comparable between formulations. Overall extended release tacrolimus has a very similar safety and efficacy profile to tacrolimus-BID. It is not recommended in the use of liver transplant patient’s due to the increased risk of mortality in female recipients. There has been minimal data regarding the use of extended release tacrolimus in heart and lung transplant recipients. With the current data available for all organ groups the extended release tacrolimus should be dosed in a 1:1 fashion, the exception may be the cystic fibrosis population where their initial dose may need to be higher. PMID:27011912

Overview of extended release tacrolimus in solid organ transplantation.

PubMed

Patel, Neha; Cook, Abigail; Greenhalgh, Elizabeth; Rech, Megan A; Rusinak, Joshua; Heinrich, Lynley

2016-03-24

Tacrolimus (Prograf(©), Astellas Pharma Europe Ltd, Staines, United Kingdom; referred to as tacrolimus-BID) is an immunosuppressive agent to prevent and treat allograft rejection in kidney transplant recipients in combination with mycophenolate mofetil, corticosteroids, with or without basiliximab induction. The drug has also been studied in liver, heart and lung transplant; however, these are currently off-label indications. An extended release tacrolimus formulation (Advagraf(©), Astagraf XL(©)) allows for once-daily dosing, with the potential to improve adherence. Extended release tacrolimus has similar absorption, distribution, metabolism and excretion to tacrolimus-BID. Phase I pharmacokinetic trials comparing extended release tacrolimus and tacrolimus-BID have demonstrated a decreased maximum concentration (Cmax) and delayed time to maximum concentration (tmax) with the extended release formulation; however, AUC0-24 was comparable between formulations. Overall extended release tacrolimus has a very similar safety and efficacy profile to tacrolimus-BID. It is not recommended in the use of liver transplant patient's due to the increased risk of mortality in female recipients. There has been minimal data regarding the use of extended release tacrolimus in heart and lung transplant recipients. With the current data available for all organ groups the extended release tacrolimus should be dosed in a 1:1 fashion, the exception may be the cystic fibrosis population where their initial dose may need to be higher.

Conversion From Twice-Daily Tacrolimus Capsules to Once-Daily Extended-Release Tacrolimus (LCPT): A Phase 2 Trial of Stable Renal Transplant Recipients

PubMed Central

Gaber, A. Osama; Alloway, Rita R.; Bodziak, Kenneth; Kaplan, Bruce; Bunnapradist, Suphamai

2013-01-01

Background LCP-Tacro is an extended-release formulation of tacrolimus designed for once-daily dosing. Phase 1 studies demonstrated greater bioavailability to twice-daily tacrolimus capsules and no new safety concerns. Methods In this phase 2 study, adult stable kidney transplant patients on tacrolimus capsules (Prograf) twice-daily were converted to tacrolimus tablets (LCP-Tacro) once-daily; patients continued on LCP-Tacro once-daily for days 8 to 21; trough levels were to be maintained between 5 and 15 ng/mL; 24-hr pharmacokinetic assessments were done on days 7 (baseline pre-switch), 14, and 21. Results Forty-seven patients completed LCP-Tacro dosing per protocol. The mean conversion ratio was 0.71. Pharmacokinetic data demonstrated consistent exposure (AUC) at the lower conversion dose. Cmax (P=0.0001), Cmax/Cmin ratio (P<0.001), percent fluctuation (P<0.0001), and swing (P=0.0004) were significantly lower and Tmax significantly (P<0.001) longer for LCP-Tacro versus Prograf. AUC24 and Cmin correlation coefficients after 7 and 14 days of therapy were 0.86 or more, demonstrating a robust correlation between LCP-Tacro tacrolimus exposure and trough levels. There were three serious adverse events; none were related to study drug and all were resolved. Conclusions Stable kidney transplant patients can be safely converted from Prograf twice-daily to LCP-Tacro. The greater bioavailability of LCP-Tacro allows for once-daily dosing and similar (AUC) exposure at a dose approximately 30% less than the total daily dose of Prograf. LCP-Tacro displays flatter kinetics characterized by significantly lower peak-trough fluctuations. PMID:23715050

Tacrolimus Topical

MedlinePlus

... ointment is used to treat the symptoms of eczema (atopic dermatitis; a skin disease that causes the ... use other medications for their condition or whose eczema has not responded to another medication. Tacrolimus is ...

ATG-Fresenius treatment and low-dose tacrolimus: results of a randomized controlled trial in liver transplantation.

PubMed

Benítez, C E; Puig-Pey, I; López, M; Martínez-Llordella, M; Lozano, J J; Bohne, F; Londoño, M C; García-Valdecasas, J C; Bruguera, M; Navasa, M; Rimola, A; Sánchez-Fueyo, A

2010-10-01

We report the results of a prospective randomized controlled trial in liver transplantation assessing the efficacy and safety of antithymocyte globulin (ATG-Fresenius) plus tacrolimus monotherapy at gradually decreasing doses. Patients were randomized to either: (a) standard-dose tacrolimus plus steroids;or (b) peritransplant ATG-Fresenius plus reduced-dose tacrolimus monotherapy followed by weaning of tacrolimus starting 3 months after transplantation. The primary end-point was the achievement of very low-dose tacrolimus (every-other-day or once daily dose with <5 ng/mL trough levels) at 12 months after transplantation. Acute rejection occurring during the first 3 months after transplantation was more frequent in the ATG group (52.4% vs. 25%). Moreover, late acute rejection episodes occurred in all recipients in whom weaning was attempted and no recipients reached the primary end-point. This motivated the premature termination of the trial. Tacrolimus trough levels were lower in the ATG-Fresenius group but no benefits in terms of improved renal function, lower metabolic complications or increased prevalence of tolerance-related biomarkers were observed. In conclusion, the use of ATG-Fresenius and tacrolimus at gradually decreasing doses was associated with a high rate of rejection, did not allow for the administration of very low doses of tacrolimus and failed to provide detectable clinical benefits. ClinicalTrials.gov identifier: NCT00436722. © 2010 The Authors Journal compilation © 2010 The American Society of Transplantation and the American Society of Transplant Surgeons.

Safety and efficacy of conversion from twice-daily tacrolimus to once-daily tacrolimus one month after transplantation: randomized controlled trial in adult renal transplantation.

PubMed

Oh, Chang-Kwon; Huh, Kyu Ha; Lee, Jong Soo; Cho, Hong Rae; Kim, Yu Seun

2014-09-01

The purpose of this study was to compare once-daily tacrolimus with twice-daily tacrolimus in terms of safety, efficacy, and patient satisfaction. This prospective, randomized, open-label, multicenter study was conducted at three institutes. Patients in the investigational group were converted from tacrolimus twice daily to the same dose of extended-release tacrolimus once daily at 1 month post-transplantation, while patients in the control group were maintained on tacrolimus twice daily. The efficacies, safeties, and patient satisfaction for the two drugs at 6 months post-transplantation were compared. Sixty patients were enrolled and randomized to the investigational group (28 of 29 patients completed the study) or the control group (26 of 31 patients completed the study). At 6 months post-transplantation, composite efficacy failure rates including the incidences of biopsy-confirmed acute rejection in the investigational and control groups were 0% and 10.7%, respectively; patient survival was 100% in each group. No difference in estimated glomerular filtration rate values were observed at 6 months post-transplantation (p=0.97). The safety and satisfaction profile (immunosuppressant therapy barrier scale) of once-daily tacrolimus was comparable with that of twice-daily tacrolimus (p=0.35). Conversion from twice-daily tacrolimus to once-daily tacrolimus one month after transplantation is safe and effective.

Development of a Simple and Rapid Method to Measure the Free Fraction of Tacrolimus in Plasma Using Ultrafiltration and LC-MS/MS.

PubMed

Stienstra, Nicolaas A; Sikma, Maaike A; van Dapperen, Anouk L; de Lange, Dylan W; van Maarseveen, Erik M

2016-12-01

Tacrolimus is an immunosuppressant mainly used in the prophylaxis of solid organ transplant rejection. Therapeutic drug monitoring of tacrolimus is essential for avoiding toxicity related to overexposure and transplant rejection from underexposure. Previous studies suggest that unbound tacrolimus concentrations in the plasma may serve as a better predictor of tacrolimus-associated nephrotoxicity and neurotoxicity compared to tacrolimus concentration in whole blood. Monitoring the plasma concentrations of unbound tacrolimus might be of interest in preventing tacrolimus-related toxicity. Therefore, the aim was to develop a method for the measurement of total and unbound tacrolimus concentrations in plasma. The sample preparation for the determination of the plasma concentrations of unbound tacrolimus consisted of an easy-to-use ultrafiltration method followed by solid-phase extraction. To determine the total concentration of tacrolimus in plasma, a simple method based on protein precipitation was developed. The extracts were injected into a Thermo Scientific HyPurity C18 column using gradient elution. The analytes were detected by liquid chromatography-tandem mass spectrometry with positive ionization. The method was validated over a linear range of 1.00-200 ng/L for unbound tacrolimus concentrations in plasma and 100-3200 ng/L for total plasma concentrations. The lower limit of quantification was 1.00 ng/L in ultrafiltrate and 100 ng/L in plasma. The inaccuracy and imprecision for the determination of unbound tacrolimus concentrations in ultrafiltrate and plasma showed a maximum coefficients of variation (CV) of 11.7% and a maximum bias of 3.8%. A rapid and easy method based on ultrafiltration and liquid chromatography-tandem mass spectrometry was established to measure the total and unbound tacrolimus concentrations in plasma. This method can facilitate further investigations on the relationship between plasma concentrations of unbound tacrolimus and clinical

CYP3A5 and ABCB1 polymorphisms influence tacrolimus concentrations in peripheral blood mononuclear cells after renal transplantation.

PubMed

Capron, Arnaud; Mourad, Michel; De Meyer, Martine; De Pauw, Luc; Eddour, Djamila Chaib; Latinne, Dominique; Elens, Laure; Haufroid, Vincent; Wallemacq, Pierre

2010-05-01

This prospective study investigated the effect of genetic polymorphisms in a biotransformation enzyme (CYP3A5) and a transporter protein (ABCB1) on tacrolimus (Tac) whole blood concentrations in renal transplantation, and more specifically on peripheral blood mononuclear cell (PBMC) drug concentrations, after renal transplantation. A total of 96 renal transplant recipients were genotyped for the exon 11 (1199G>A), 21 (3435C>T) and 26 (2677G>T/A) polymorphisms in the ABCB1 gene and for the intron 3 polymorphism in the CYP3A5 gene. Tac blood and PBMC concentrations were determined at day 7 after transplantation and at steady state, and then compared with recipient genotypes. The ABCB1 1199G>A, 3435C>T and 2677G>T/A SNPs, appeared to reduce the activity of P-glycoprotein towards Tac, increasing Tac PBMC concentrations. The impact of ABCB1 genetic polymorphisms on Tac blood concentrations was negligible. As increased Tac intracellular concentrations might in turn enhance immunosuppressive status and prevention or rejection, ABCB1 recipient genotyping might be useful to better individualize the Tac immunosuppressive therapy in renal transplantation.

The calcineurin inhibitor tacrolimus as a new therapy in severe cherubism.

PubMed

Kadlub, Natacha; Vazquez, Marie-Paule; Galmiche, Louise; L'Herminé, Aurore Coulomb; Dainese, Linda; Ulinski, Tim; Fauroux, Brigitte; Pavlov, Ioana; Badoual, Cécile; Marlin, Sandrine; Deckert, Marcel; Leboulanger, Nicolas; Berdal, Ariane; Descroix, Vianney; Picard, Arnaud; Coudert, Amélie E

2015-05-01

Cherubism is a rare genetic disorder characterized by extensive growth of a bilateral granuloma of the jaws, resulting in facial disfigurement. Cherubism is caused by gain-of-function mutations in the SH3BP2 gene, leading to overactivation of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1)-dependent osteoclastogenesis. Recent findings in human and mouse cherubism have suggested that calcineurin inhibitors might be drug candidates in cherubism medical treatment. A 4-year-old boy with aggressive cherubism was treated with the calcineurin inhibitor tacrolimus for 1 year, and clinical, radiological, and molecular data were obtained. Immunohistologic analysis was performed to compare preoperative and postoperative NFATc1 staining and tartrate resistant acid phosphatase (TRAP) activity. Real-time PCR was performed to analyze the relative expression levels of OPG and RANKL. After tacrolimus therapy, the patient showed significant clinical improvement, including stabilization of jaw size and intraosseous osteogenesis. Immunohistologic analyses on granuloma showed that tacrolimus caused a significant reduction in the number of TRAP-positive osteoclasts and NFATc1 nuclear staining in multinucleated giant cells. Molecular analysis showed that tacrolimus treatment also resulted in increased OPG expression. We present the first case of effective medical therapy in cherubism. Tacrolimus enhanced bone formation by stimulating osteogenesis and inhibiting osteoclastogenesis. © 2014 American Society for Bone and Mineral Research.

Evaluation of gingival alterations in rats medicated with cyclosporine A, tacrolimus and sirolimus: a stereological study.

PubMed

Pamuk, F; Cetinkaya, B O; Ayas, B; Keles, G C; Gacar, A

2015-10-01

It has previously been shown that both cyclosporine A and tacrolimus cause gingival overgrowth in the rat. We proposed that sirolimus may play an important role in decreasing the severity of gingival overgrowth. Therefore, the aim of this study was to evaluate the gingival changes induced by immunosuppressants, in the presence and absence of sirolimus, using histopathology and stereological methods. Thirty-six male Sprague-Dawley rats were distributed into six treatment groups, each containing six rats, as follows: (i) cyclosporine A for 8 wk; (ii) tacrolimus for 8 wk; (iii) sirolimus for 8 wk; (iv) cyclosporine A + sirolimus for 8 wk; (v) tacrolimus + sirolimus for 8 wk; and (vi) distilled water for 8 wk. Histomorphometric analyses included measurements of epithelial thickness and connective tissue width and height. Stereological analyses included measurements of volumetric densities of fibroblasts (Vf ), collagen fibers (Vcf ) and blood vessels (Vbv ). Connective tissue width and height were significantly increased in cyclosporine A, tacrolimus and cyclosporine A + sirolimus groups compared with the control group (p < 0.05), and epithelial thickness was significantly increased in the cyclosporine A group and tacrolimus group compared with the control group (p < 0.05). Vf was significantly increased in the cyclosporine A group and the tacrolimus group compared with the control group (p < 0.05), whereas Vcf and Vbv were significantly increased in the cyclosporine A, tacrolimus and cyclosporine A + sirolimus groups compared with the control group (p < 0.05). The results of the study suggest that sirolimus seems not to be associated with gingival overgrowth, and combined usage of sirolimus and immunosuppressants decreases the severity of gingival overgrowth. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Tacrolimus is a class II low-solubility high-permeability drug: the effect of P-glycoprotein efflux on regional permeability of tacrolimus in rats.

PubMed

Tamura, Shigeki; Ohike, Atsuo; Ibuki, Rinta; Amidon, Gordon L; Yamashita, Shinji

2002-03-01

The objective of this study is to investigate the role of P-glycoprotein (P-gp), a membrane efflux pump associated with multidrug resistance (MDR) and a known substrate for tacrolimus, in determining the regional intestinal permeability of tacrolimus in rats. Thus, isolated segments of rat jejunum, ileum, or colon were perfused with tacrolimus solutions containing polyethoxylated hydrogenated castor oil 60 surfactant, and with or without verapamil, a P-gp substrate used to reverse the MDR phenotype. The results indicated that the intrinsic permeability of tacrolimus in the jejunum, calculated on the basis of the concentration of non-micellized free tacrolimus, was quite high ( approximately 1.4 x 10(-4) cm/s). The apparent permeability (P(app)) in the jejunum was unaffected by the presence of verapamil; however, the P(app) in the ileum and the colon increased significantly in the presence of verapamil and were similar to the values observed in the jejunum. The results suggest that systemic absorption of tacrolimus from the gastrointestinal tract could be significantly affected by P-gp efflux mechanisms. It is also possible that differences in P-gp function at various intestinal sites in a subject or at a given intestinal site in various subjects could lead to large intra- and interindividual variability in bioavailability of tacrolimus following oral administration. Copyright 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association .

21 CFR 862.1678 - Tacrolimus test system.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Tacrolimus test system. 862.1678 Section 862.1678 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... quantitatively determine tacrolimus concentrations as an aid in the management of transplant patients receiving...

Sirolimus and tacrolimus trough concentrations and dose requirements after kidney transplantation in relation to CYP3A5 and MDR1 polymorphisms and steroids.

PubMed

Mourad, Michel; Mourad, Georges; Wallemacq, Pierre; Garrigue, Valérie; Van Bellingen, Christophe; Van Kerckhove, Valérie; De Meyer, Martine; Malaise, Jacques; Eddour, Djamila Chaib; Lison, Dominique; Squifflet, Jean Paul; Haufroid, Vincent

2005-10-15

CYP3A5 and MDR1 polymorphisms have been shown to influence tacrolimus blood concentrations and dose requirements. The aim is to determine whether these polymorphisms also affect sirolimus trough concentrations and dose requirements after kidney transplantation. Eighty-five renal transplant recipients receiving sirolimus were included. Twenty-four were treated with a combined sirolimus-tacrolimus regimen. Eighty-one patients received steroids. Sirolimus and tacrolimus were adjusted to a target therapeutic window. CYP3A5 (intron 3) and MDR1 (exons 12, 21, 26) genotypes were correlated to the adjusted trough concentrations and dose requirements for both sirolimus and tacrolimus. There were no significant correlation between adjusted sirolimus trough concentrations or dose requirements and genetic polymorphisms. In a multiple regression model, adjusted-prednisone dose was involved with a positive or negative effect when considering sirolimus dose requirements or adjusted concentrations, respectively. In the subgroup of patients treated by tacrolimus and sirolimus, adjusted tacrolimus doses were higher in patients carrying at least one CYP3A5 *1 allele (median 0.083 vs. 0.035 mg/kg for CYP3A5*3/*3 patients, P<0.05). Adjusted-prednisolone dose and CYP3A5 polymorphism explained up to 61% of the variability in tacrolimus dose requirements. Unlike tacrolimus, sirolimus adjusted trough concentrations and dose requirements seem not affected by CYP3A5 and MDR1 polymorphisms. Adjusted-prednisone dose has a significant impact on tacrolimus and sirolimus dose requirements.

Dyslipidaemia among renal transplant recipients: cyclosporine versus tacrolimus.

PubMed

Fazal, Muhammad Asim; Idrees, Muhammad Khalid; Akhtar, Syed Fazal

2014-05-01

To compare new onset dyslipidaemia in live-related renal transplant recipients taking cyclosporine versus tacrolimus after 3 months of therapy. The randomised controlled trial was conducted at the Sindh Institute of Urology and Transplantation (SIUT) Karachi, from September 2010 to April 2011, and included 182 End Stage Renal Disease patients on maintenance haemodialysis with pre-transplant normal lipid profile. The patients, who had live-related renal transplant, were randomly allocated to two equal groups using lottery. Group A received cyclosporine (3 mg/kg) and group B was treated with tacrolimus (0.1 mg/kg). All patients had pre-transplant fasting lipid profile checked when they were on maintenance haemodialysis and 3 months after renal transplantation. Serum fasting lipid profile was collected by taking 5 ml blood by venipuncture after an overnight fast of 9-12 hours. SPSS 10 was used for statistical analyses. Of the 182 patients, 144 (79.1%) were males and 38 (20.9%) were females. The overall mean age was 30.18 +/- 9.57 years, and the mean weight was 54.41 +/- 11.144 kg. Significant difference was not observed between the two groups regarding age and weight of the patients. Dyslipidaemia was found in 115(63.2%) subjects; 61(67%) in group A and 54 (59.3%) in group B. There was no statistical difference (p=0.28) when comparison was done after 3 months of therapy. The occurrence of new onset hyperlipidaemia is similar in renal transplant recipients receiving either cyclosporine or tacrolimus in first 3 months post-transplant, but there is room for more research in this field as dyslipidaemia following successful renal transplantation is a frequent and persistent complication.

Stability of tacrolimus solutions in polyolefin containers.

PubMed

Lee, Jun H; Goldspiel, Barry R; Ryu, Sujung; Potti, Gopal K

2016-02-01

Results of a study to determine the stability of tacrolimus solutions stored in polyolefin containers under various temperature conditions are reported. Triplicate solutions of tacrolimus (0.001, 0.01, and 0.1 mg/mL) in 0.9% sodium chloride injection or 5% dextrose injection were prepared in polyolefin containers. Some samples were stored at room temperature (20-25 °C); others were refrigerated (2-8 °C) for 20 hours and then stored at room temperature for up to 28 hours. The solutions were analyzed by stability-indicating high-performance liquid chromatography (HPLC) assay at specified time points over 48 hours. Solution pH was measured and containers were visually inspected at each time point. Stability was defined as retention of at least 90% of the initial tacrolimus concentration. All tested solutions retained over 90% of the initial tacrolimus concentration at all time points, with the exception of the 0.001-mg/mL solution prepared in 0.9% sodium chloride injection, which was deemed unstable beyond 24 hours. At all evaluated concentrations, mean solution pH values did not change significantly over 48 hours; no particle formation was detected. During storage in polyolefin bags at room temperature, a 0.001-mg/mL solution of tacrolimus was stable for 24 hours when prepared in 0.9% sodium chloride injection and for at least 48 hours when prepared in 5% dextrose injection. Solutions of 0.01 and 0.1 mg/mL prepared in either diluent were stable for at least 48 hours, and the 0.01-mg/mL tacrolimus solution was also found to be stable throughout a sequential temperature protocol. Copyright © 2016 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

Renal Function in De Novo Liver Transplant Recipients Receiving Different Prolonged-Release Tacrolimus Regimens-The DIAMOND Study.

PubMed

TruneČka, P; Klempnauer, J; Bechstein, W O; Pirenne, J; Friman, S; Zhao, A; Isoniemi, H; Rostaing, L; Settmacher, U; Mönch, C; Brown, M; Undre, N; Tisone, G

2015-07-01

DIAMOND: multicenter, 24-week, randomized trial investigating the effect of different once-daily, prolonged-release tacrolimus dosing regimens on renal function after de novo liver transplantation. Arm 1: prolonged-release tacrolimus (initial dose 0.2mg/kg/day); Arm 2: prolonged-release tacrolimus (0.15-0.175mg/kg/day) plus basiliximab; Arm 3: prolonged-release tacrolimus (0.2mg/kg/day delayed until Day 5) plus basiliximab. All patients received MMF plus a bolus of corticosteroid (no maintenance steroids). eGFR (MDRD4) at Week 24. Secondary endpoints: composite efficacy failure, BCAR and AEs. Baseline characteristics were comparable. Tacrolimus trough levels were readily achieved posttransplant; initially lower in Arm 2 versus 1 with delayed initiation in Arm 3. eGFR (MDRD4) was higher in Arms 2 and 3 versus 1 (p = 0.001, p = 0.047). Kaplan-Meier estimates of composite efficacy failure-free survival were 72.0%, 77.6%, 73.9% in Arms 1-3. BCAR incidence was significantly lower in Arm 2 versus 1 and 3 (p = 0.016, p = 0.039). AEs were comparable. Prolonged-release tacrolimus (0.15-0.175mg/kg/day) immediately posttransplant plus basiliximab and MMF (without maintenance corticosteroids) was associated with lower tacrolimus exposure, and significantly reduced renal function impairment and BCAR incidence versus prolonged-release tacrolimus (0.2mg/kg/day) administered immediately posttransplant. Delayed higher-dose prolonged-release tacrolimus initiation significantly reduced renal function impairment compared with immediate posttransplant administration, but BCAR incidence was comparable. © 2015 The Authors. American Journal of Transplantation published by Wiley Periodicals Inc.

[The therapeutic drug monitoring network server of tacrolimus for Chinese renal transplant patients].

PubMed

Deng, Chen-Hui; Zhang, Guan-Min; Bi, Shan-Shan; Zhou, Tian-Yan; Lu, Wei

2011-07-01

This study is to develop a therapeutic drug monitoring (TDM) network server of tacrolimus for Chinese renal transplant patients, which can facilitate doctor to manage patients' information and provide three levels of predictions. Database management system MySQL was employed to build and manage the database of patients and doctors' information, and hypertext mark-up language (HTML) and Java server pages (JSP) technology were employed to construct network server for database management. Based on the population pharmacokinetic model of tacrolimus for Chinese renal transplant patients, above program languages were used to construct the population prediction and subpopulation prediction modules. Based on Bayesian principle and maximization of the posterior probability function, an objective function was established, and minimized by an optimization algorithm to estimate patient's individual pharmacokinetic parameters. It is proved that the network server has the basic functions for database management and three levels of prediction to aid doctor to optimize the regimen of tacrolimus for Chinese renal transplant patients.

Early alteration of kidney function in nonuremic type 1 diabetic islet transplant recipients under tacrolimus-mycophenolate therapy.

PubMed

Gillard, Pieter; Rustandi, Maria; Efendi, Achmad; Lee, Da Hae; Ling, Zhidong; Hilbrands, Robert; Kuypers, Dirk; Mathieu, Chantal; Jacobs-Tulleneers-Thevissen, Daniel; Gorus, Frans; Pipeleers, Daniel; Keymeulen, Bart

2014-08-27

Transplant patients on tacrolimus therapy exhibit a reduced glomerular filtration rate (GFR). The type of graft and immune treatment protocol may influence the extent and reversibility of this side effect. The present single-center study is conducted in 48 nonuremic type 1 diabetic recipients of an intraportal islet-cell graft under maintenance immunosuppression (IS) with tacrolimus and mycophenolate mofetil. Estimated GFR (eGFR) and albuminuria were followed up to 5 years posttransplantation. Mean eGFR values decreased by 19 mL/min/1.73 m after 1 to 2 weeks of IS (P<0.0001) and then remained stable throughout the complete treatment period. The decrease was related to predose trough tacrolimus concentrations or doses and disappeared upon its discontinuation; it was also associated with the presence of albuminuria at the time of transplantation. Tacrolimus treatment resulted in a reduction of albuminuria; its discontinuation restored albuminuria to the initial levels. The use of tacrolimus in our islet-cell transplant protocol caused an initial 20% reduction in eGFR, which was reversible following its discontinuation, at least within the 5-year follow-up period. The associated reduction in albuminuria was also reversible, compatible with a tacrolimus-induced preglomerular vasoconstriction. These observations support further use of our tacrolimus regimen in this patient population.

Trends in the biosynthesis and production of the immunosuppressant tacrolimus (FK506).

PubMed

Barreiro, Carlos; Martínez-Castro, Miriam

2014-01-01

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

Tacrolimus Improves Symptoms of Children With Myasthenia Gravis Refractory to Prednisone.

PubMed

Liu, Chanchan; Gui, Mengcui; Cao, Yayun; Lin, Jing; Li, Yue; Ji, Suqiong; Bu, Bitao

2017-12-01

Myasthenia gravis tends to affect children in China. Oral pyridostigmine and prednisone could effectively improve the symptoms, but multiple side effects become a major concern after long-term oral prednisone. To avoid the long-term complications of prednisone therapy and to obtain more satisfactory improvement, we tested the efficacy and safety of tacrolimus in children with myasthenia gravis. Children with myasthenia gravis who had not achieved satisfactory improvement or who experienced severe side effects after prednisone therapy were recruited between January 2015 and December 2016 at Tongji Hospital. All the children were treated with tacrolimus 1 mg to 2 mg daily and the dose was adjusted on the basis of the clinical response and the serum concentration. The dosage of prednisone, the severity of symptoms, blood samples, the serum concentration of tacrolimus, and titers of antiacetylcholine receptor antibodies were evaluated every four weeks. Fourteen children were enrolled. One child withdrew two weeks after the enrollment. Thirteen children have completed the therapy for one year. At the end point, the dosage of prednisone was significantly decreased (P < 0.05), the symptoms were evaluated by the quantitative myasthenia gravis score, and myasthenia gravis-specific manual muscle testing and myasthenia gravis-activities of daily living scores were significantly improved (P < 0.05, P < 0.05, and P < 0.01, respectively). More importantly, ten (76.9%) patients had completely discontinued prednisone, and the major side effects were nearly reversed. The mean titer of antiacetylcholine receptor antibodies significantly dropped from 1.96±2.62 nmol/L to 0.70±1.04 nmol/L (P < 0.05). No severe adverse events were reported. Our results suggest that tacrolimus is a promising agent for children with refractory myasthenia gravis. Randomized clinical trials are needed to confirm the observation. Copyright © 2017 Elsevier Inc. All rights reserved.

Successful treatment of oral lichen planus-like chronic graft-versus-host disease with topical tacrolimus: a case report.

PubMed

Sánchez, Andrés R; Sheridan, Phillip J; Rogers, Roy S

2004-04-01

Bone marrow transplantation (BMT) is a common treatment used for deficiencies of host marrow or in the control of blood malignancies. Post-allogeneic BMT complications include graft-versus-host disease (GVHD). GVHD occurs when immunologically active T lymphocytes are transplanted into an immunosuppressed recipient who is genetically disparate from the donor. In this case report we describe the occurrence of oral lichen planus-like lesions as the first manifestation of chronic GVHD (c-GVHD) and the subsequent management of this disease with topical tacrolimus. Diagnostic aids included routine histology and direct immunofluorescence studies to rule out immunobullous diseases and to confirm the c-GVHD. Treatment consisted of topical application of 0.1% tacrolimus ointment three times a day. Routine histology confirmed the clinical diagnosis of oral lichen planus-like c-GVHD. Treatment with tacrolimus ointment completely resolved the oral lesions after 2 months of therapy. Topical tacrolimus at low concentrations (0.1%) shows promise in the management of oral lichen planus-like c-GVHD. Controlled studies are necessary to assess the efficacy, the duration of therapy required for effective results, and the safety of this treatment over the long-term.

Cobicistat Significantly Increases Tacrolimus Serum Concentrations in a Renal Transplant Recipient with Human Immunodeficiency Virus Infection.

PubMed

Han, Zhe; Kane, Brenna M; Petty, Lindsay A; Josephson, Michelle A; Sutor, Jozefa; Pursell, Kenneth J

2016-06-01

Cobicistat is a pharmacokinetic booster in several fixed-dose combination products for treatment of human immunodeficiency virus (HIV) infection. As a potent inhibitor of cytochrome P450 (CYP) 3A enzymes, significant drug-drug interactions are expected between cobicistat and medications that are metabolized primarily through the CYP3A pathway, including calcineurin inhibitors (e.g., tacrolimus and cyclosporine). We describe a case of tacrolimus toxicity due to supratherapeutic tacrolimus concentrations when Stribild (elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate) was initiated for newly diagnosed HIV infection in a 50-year-old renal transplant recipient who was previously receiving a stable tacrolimus regimen. Drug-drug interaction via CYP3A inhibition was acknowledged, and weekly labs were ordered to allow for close monitoring of renal function and tacrolimus serum concentrations as recommended by Stribild prescribing information. The patient reported headache, insomnia, stomachache, and decreased urine output within 1 week of starting Stribild and was found to have acute kidney injury (serum creatinine [S cr ]concentration increasing from 1.5-2.3 mg/dl) and a serum tacrolimus concentration of 111.2 ng/ml at 1 week follow-up (goal trough level 4-6 ng/ml). Both tacrolimus and Stribild were withheld. In 15 days, the patient's tacrolimus serum concentration returned to goal. In the interim, he required twice/week clinic visits for laboratory assessments and an emergency department visit for management of hyperkalemia (potassium 6.5 mEq/L). Triumeq (abacavir, dolutegravir, and lamivudine) was started about 4 weeks later after S cr returned to baseline, and his tacrolimus serum trough concentrations subsequently remained stable. To our knowledge, this is the first case report describing the extent, significance, and onset of cobicistat and tacrolimus drug-drug interaction in clinical practice. As more fixed-dose combination products

Inappropriate amounts of topical tacrolimus applied on Korean patients with eczema.

PubMed

Jin, Hyunju; Kim, Jeong-Min; Kim, Gun-Wook; Kim, Hoon-Soo; Ko, Hyun-Chang; Kim, Moon-Bum; Kim, Byung-Soo

2017-06-01

The limited efficacy of topical tacrolimus may result from insufficient frequency of application or amount applied in eczema patients. To investigate the frequency of application and amount of use of topical tacrolimus in patients with various types of eczema. The frequency of application and the applied amount of topical tacrolimus were assessed over two weeks. A total of 200 eczema patients completed this study. The average number of applications per day was 1.75 ± 0.53, despite instructions to apply the topical tacrolimus twice daily. With respect to the frequency of application, 147 (73.5%) and 122 (61.0%) of patients followed the prescription in the first and second weeks, respectively. The average amount applied per 2% of total body surface area (TBSA) was 0.54 ± 0.52 g. Only 53 (26.5%) patients applied between 80 and 120% of expected amount of topical tacrolimus. The frequency of application was self-reported, possibly resulting in limited accuracy. Korean patients with eczema tend to apply topical tacrolimus less frequently and in inappropriate amounts. Clear instructions regarding both the frequency and amount of application are needed to improve the therapeutic outcome with treatment with topical tacrolimus.

A simple and highly sensitive on-line column extraction liquid chromatography-tandem mass spectrometry method for the determination of protein-unbound tacrolimus in human plasma samples.

PubMed

Bittersohl, Heike; Schniedewind, Björn; Christians, Uwe; Luppa, Peter B

2018-04-27

Therapeutic drug monitoring (TDM) of the immunosuppressive drug tacrolimus is essential to avoid side effects and rejection of the allograft after transplantation. In the blood circulation, tacrolimus is largely located inside erythrocytes or bound to plasma proteins and less than 0.1% is protein-unbound (free). One basic principle of clinical pharmacology is that only free drug is pharmacologically active and monitoring this portion has the potential to better reflect the drug effect than conventional measurements of total tacrolimus in whole blood. To address this, a highly sensitive and straightforward on-line liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed, validated and applied to patient plasma samples. The sample preparation included ultracentrifugation and addition of the stable isotope labeled drug analogue D2,13C-tacrolimus, followed by on-line sample extraction and measurement using a Sciex QTRAP ® 6500 in the multiple reaction monitoring mode. Due to very low concentrations of protein-unbound tacrolimus, it was important to develop a highly sensitive, precise and accurate assay. Here, we first report the efficient formation of tacrolimus lithium adduct ions, which greatly increased assay sensitivity. A lower limit of quantification (LLOQ) of 1 pg/mL (10 fg on column) was achieved and the assay was linear between 1 and 200 pg/mL. There was no carry-over detected. The inaccuracy ranged from -9.8 to 7.4% and the greatest imprecision was 7.5%. The matrix factor was found to be smaller than 1.1%. In summary, this method represents a suitable tool to investigate the potential clinical value of free tacrolimus monitoring in organ transplant recipients. Copyright © 2018 Elsevier B.V. All rights reserved.

Ranolazine, tacrolimus, and diltiazem might be a hazardous combination in a transplant patient.

PubMed

Patni, Hitesh; Gitman, Michael; Hazzan, Azzour; Jhaveri, Kenar D

2012-01-01

We report a case of a renal transplant patient who was maintained on tacrolimus and diltiazem therapy and developed tacrolimus toxicity leading to reversible acute kidney injury when started on ranolazine. A 62-year-old Caucasian male status post renal transplant in 2009 (on prednisone and tacrolimus) was evaluated for ischemic heart disease and was initiated on ranolazine 500 mg tablets twice daily, which was later increased to 1000 mg twice daily. After 2 weeks, he developed fatigue, loss of appetite, tremors, and decreased urine output and was admitted to our hospital. His other significant medications included enalapril 2.5 mg and diltiazem 240 mg daily. The patient was awake and alert, but lethargic. He was found to be bradycardic with a heart rate of 42/min. The rest of his physical examination was benign. His electrocardiogram revealed sinus bradycardia. Laboratory studies revealed serum creatinine of 2.4 mg/dL from a baseline of 1.5 mg/dL (stable for the past 2 years). The tacrolimus trough was elevated at 14 ng/mL, which decreased after stopping ranolazine, reaching 7 ng/mL after 3 days, while continuing the same dose of tacrolimus. His creatinine trended downward and reached his baseline of 1.5 mg/dL over the next 2 days. His bradycardia and other symptoms resolved after cessation of ranolazine. He was discharged to follow up, to initiate an alternate agent for ischemic heart disease. Specific pharmacokinetic studies are warranted to study these drug interactions, and tacrolimus levels should be closely monitored in transplant patients who initiate ranolazine treatment.

Tacrolimus for the treatment of systemic lupus erythematosus with pure class V nephritis.

PubMed

Szeto, C-C; Kwan, B C-H; Lai, F M-M; Tam, L-S; Li, E K-M; Chow, K-M; Gang, W; Li, P K-T

2008-11-01

The treatment of pure membranous (class V) lupus nephropathy remains unsatisfactory. We studied the efficacy and safety of tacrolimus in the treatment of membranous nephritis secondary to SLE. We recruited 18 consecutive SLE patients (tacrolimus group) with recently confirmed biopsy-proven class V lupus nephritis. They were treated with a tailing dose of oral prednisolone and tacrolimus 0.1-0.2 mg/kg/day for 6 months, followed by maintenance prednisolone and AZA. The rate of resolution of proteinuria and SLEDAI were compared with 19 historical controls treated with oral cyclophosphamide or AZA (control group). All patients were followed for 12 months. Baseline clinical characteristics were comparable between the groups. For the tacrolimus group, the complete and partial remission rates were 27.8 and 50.0%, respectively at 12 weeks; for the control group, they were 15.8 and 47.4%, respectively (overall chi-square test, P = 0.5). However, tacrolimus group had faster resolution of proteinuria than the control group by the general linear model with repeated measures (P = 0.032). At 12 weeks, proteinuria was reduced by 76.2 +/- 17.0% for the tacrolimus group and 47.1 +/- 51.1% for the control group (P = 0.028). Serial change in renal function and SLEDAI score did not differ between the groups. During the study period, four patients of the tacrolimus group, and 11 of the control group, developed lupus flare (P = 0.027). There was no serious adverse effect in the tacrolimus group. A 6-month course of tacrolimus is a safe and effective treatment of pure class V (membranous) lupus nephritis. As compared with conventional cytotoxic treatment, tacrolimus possibly results in a faster resolution of proteinuria, and a lower risk of lupus flare within 1 yr. The long-term effect and optimal regimen of tacrolimus require further study.

Development of novel fast-dissolving tacrolimus solid dispersion-loaded prolonged release tablet.

PubMed

Cho, Jung Hyun; Kim, Yong-Il; Kim, Dong-Wuk; Yousaf, Abid Mehmood; Kim, Jong Oh; Woo, Jong Soo; Yong, Chul Soon; Choi, Han-Gon

2014-04-11

The goal of this research was to develop a novel prolonged release tablet bioequivalent to the commercial sustained release capsule. A number of tacrolimus-loaded fast-dissolving solid dispersions containing various amounts of DOSS were prepared using the spray drying technique. Their solubility, dissolution and pharmacokinetics in rats were studied. DOSS increased drug solubility and dissolution in the solid dispersions. Compared with the drug powder, the solubility, dissolution and bioavailability of tacrolimus with the fast-dissolving solid dispersion containing tacrolimus/HP-β-CD/DOSS in the weight ratio of 5:40:4 were boosted by approximately 700-, 30- and 2-fold, respectively. Several tablet formulations were accomplished with this solid dispersion in combination with various ratios of HPMC/ethylcellulose. The release behaviour and pharmacokinetic studies in beagle dogs were assessed compared with the commercial prolonged release capsule. A decrease in HPMC/ethylcellulose ratios reduced the dissolution of tacrolimus from the tablets. Particularly, the tacrolimus-loaded prolonged release tablet consisting of fast-dissolving tacrolimus solid dispersion, HPMC, ethylcellulose and talc at the weight ratio of 20:66:112:2 exhibited a dissolution profile similar to that produced by the commercial prolonged release capsule. Furthermore, there were no significant differences in the AUC, Cmax, Tmax and MRT values between them in beagle dogs. Consequently, this tacrolimus-loaded prolonged release tablet might be bioequivalent to the tacrolimus-loaded commercial capsule. Copyright © 2013 Elsevier B.V. All rights reserved.

Design and physicochemical characterization of advanced spray-dried tacrolimus multifunctional particles for inhalation

PubMed Central

Wu, Xiao; Hayes, Don; Zwischenberger, Joseph B; Kuhn, Robert J; Mansour, Heidi M

2013-01-01

The aim of this study was to design, develop, and optimize respirable tacrolimus microparticles and nanoparticles and multifunctional tacrolimus lung surfactant mimic particles for targeted dry powder inhalation delivery as a pulmonary nanomedicine. Particles were rationally designed and produced at different pump rates by advanced spray-drying particle engineering design from organic solution in closed mode. In addition, multifunctional tacrolimus lung surfactant mimic dry powder particles were prepared by co-dissolving tacrolimus and lung surfactant mimic phospholipids in methanol, followed by advanced co-spray-drying particle engineering design technology in closed mode. The lung surfactant mimic phospholipids were 1,2-dipalmitoyl-sn-glycero-3-phosphocholine and 1,2-dipalmitoyl-sn-glycero-3-[phosphor-rac-1-glycerol]. Laser diffraction particle sizing indicated that the particle size distributions were suitable for pulmonary delivery, whereas scanning electron microscopy imaging indicated that these particles had both optimal particle morphology and surface morphology. Increasing the pump rate percent of tacrolimus solution resulted in a larger particle size. X-ray powder diffraction patterns and differential scanning calorimetry thermograms indicated that spray drying produced particles with higher amounts of amorphous phase. X-ray powder diffraction and differential scanning calorimetry also confirmed the preservation of the phospholipid bilayer structure in the solid state for all engineered respirable particles. Furthermore, it was observed in hot-stage micrographs that raw tacrolimus displayed a liquid crystal transition following the main phase transition, which is consistent with its interfacial properties. Water vapor uptake and lyotropic phase transitions in the solid state at varying levels of relative humidity were determined by gravimetric vapor sorption technique. Water content in the various powders was very low and well within the levels necessary

Potential differentiation ability of gingiva originated human mesenchymal stem cell in the presence of tacrolimus

PubMed Central

Ha, Dong-Ho; Pathak, Shiva; Yong, Chul Soon; Kim, Jong Oh; Jeong, Jee-Heon; Park, Jun-Beom

2016-01-01

The aim of the present study is to evaluate the potential differentiation ability of gingiva originated human mesenchymal stem cell in the presence of tacrolimus. Tacrolimus-loaded poly(lactic-co-glycolic acid) microspheres were prepared using electrospraying technique. In vitro release study of tacrolimus-loaded poly(lactic-co-glycolic acid) microspheres was performed in phosphate-buffered saline (pH 7.4). Gingiva-derived stem cells were isolated and incubated with tacrolimus or tacrolimus-loaded microspheres. Release study of the microspheres revealed prolonged release profiles of tacrolimus without any significant initial burst release. The microsphere itself did not affect the morphology of the mesenchymal stem cells, and cell morphology was retained after incubation with microspheres loaded with tacrolimus at 1 μg/mL to 10 μg/mL. Cultures grown in the presence of microspheres loaded with tacrolimus at 1 μg/mL showed the highest mineralization. Alkaline phosphatase activity increased with an increase in incubation time. The highest expression of pSmad1/5 was achieved in the group receiving tacrolimus 0.1 μg/mL every third day, and the highest expression of osteocalcin was achieved in the group receiving 1 μg/mL every third day. Biodegradable poly(lactic-co-glycolic acid)-based microspheres loaded with tacrolimus promoted mineralization. Microspheres loaded with tacrolimus may be applied for increased osteoblastic differentiation. PMID:27721434

[Application of Fourier amplitude sensitivity test in Chinese healthy volunteer population pharmacokinetic model of tacrolimus].

PubMed

Guan, Zheng; Zhang, Guan-min; Ma, Ping; Liu, Li-hong; Zhou, Tian-yan; Lu, Wei

2010-07-01

In this study, we evaluated the influence of different variance from each of the parameters on the output of tacrolimus population pharmacokinetic (PopPK) model in Chinese healthy volunteers, using Fourier amplitude sensitivity test (FAST). Besides, we estimated the index of sensitivity within whole course of blood sampling, designed different sampling times, and evaluated the quality of parameters' and the efficiency of prediction. It was observed that besides CL1/F, the index of sensitivity for all of the other four parameters (V1/F, V2/F, CL2/F and k(a)) in tacrolimus PopPK model showed relatively high level and changed fast with the time passing. With the increase of the variance of k(a), its indices of sensitivity increased obviously, associated with significant decrease in sensitivity index for the other parameters, and obvious change in peak time as well. According to the simulation of NONMEM and the comparison among different fitting results, we found that the sampling time points designed according to FAST surpassed the other time points. It suggests that FAST can access the sensitivities of model parameters effectively, and assist the design of clinical sampling times and the construction of PopPK model.

Beneficial effects of topical tacrolimus on recalcitrant erosions of pemphigus vulgaris.

PubMed

Gach, J E; Ilchyshyn, A

2004-05-01

We report a case of pemphigus vulgaris in which a recalcitrant area of erosion on the cheek cleared only when topical tacrolimus was used in addition to a regime of systemic therapy consisting of cyclophosphamide and prednisolone. Clinical improvement occurred within 10 days of applying topical tacrolimus with healing of erosions and reduction in pain and burning sensations. Topical tacrolimus may inhibit local activation of T lymphocytes through altered expression of cytokines such as interleukin-1, -4 and -5, tumour necrosis factor-alpha and interferon-gamma. Some of these cytokines may also contribute directly to increasing keratinocyte fragility in the aetiology of pemphigus vulgaris erosions. This case illustrates that topical tacrolimus may be a useful adjunct in the management of patients with pemphigus vulgaris.

Large-Scale Variability of Inpatient Tacrolimus Therapeutic Drug Monitoring at an Academic Transplant Center: a Retrospective Study.

PubMed

Strohbehn, Garth W; Pan, Warren W; Petrilli, Christopher M; Heidemann, Lauren; Larson, Sophia; Aaronson, Keith D; Johnson, Matt; Ellies, Tammy; Heung, Michael

2018-04-30

Inpatient tacrolimus therapeutic drug monitoring (TDM) lacks standardized guidelines. In this study, the authors analyzed variability in the pre-analytical 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 one 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.

Post-Transplant Cyclophosphamide and Tacrolimus-Mycophenolate Mofetil Combination Prevents Graft-versus-Host Disease in Allogeneic Peripheral Blood Hematopoietic Cell Transplantation from HLA-Matched Donors.

PubMed

Carnevale-Schianca, Fabrizio; Caravelli, Daniela; Gallo, Susanna; Coha, Valentina; D'Ambrosio, Lorenzo; Vassallo, Elena; Fizzotti, Marco; Nesi, Francesca; Gioeni, Luisa; Berger, Massimo; Polo, Alessandra; Gammaitoni, Loretta; Becco, Paolo; Giraudo, Lidia; Mangioni, Monica; Sangiolo, Dario; Grignani, Giovanni; Rota-Scalabrini, Delia; Sottile, Antonino; Fagioli, Franca; Aglietta, Massimo

2017-03-01

Allogeneic hematopoietic cell transplant (HCT) remains the only curative therapy for many hematologic malignancies but it is limited by high nonrelapse mortality (NRM), primarily from unpredictable control of graft-versus-host disease (GVHD). Recently, post-transplant cyclophosphamide demonstrated improved GVHD control in allogeneic bone marrow HCT. Here we explore cyclophosphamide in allogeneic peripheral blood stem cell transplantation (alloPBSCT). Patients with high-risk hematologic malignancies received alloPBSCT from HLA-matched unrelated/related donors. GVHD prophylaxis included combination post-HCT cyclophosphamide 50 mg/kg (days +3 and +4) and tacrolimus/mofetil mycophenolate (T/MMF) (day +5 forward). The primary objective was the cumulative incidence of acute and chronic GVHD. Between March 2011 and May 2015, 35 consecutive patients received the proposed regimen. MMF was stopped in all patients at day +28; the median discontinuation of tacrolimus was day +113. Acute and chronic GVHD cumulative incidences were 17% and 7%, respectively, with no grade IV GVHD events, only 2 patients requiring chronic GVHD immunosuppression control, and no deaths from GVHD. Two-year NRM, overall survival, event-free survival, and chronic GVHD event-free survival rates were 3%, 77%, 54%, and 49%, respectively. The graft-versus-tumor effect was maintained as 5 of 15 patients (33%) who received HCT with evidence of disease experienced further disease response. A post-transplant cyclophosphamide + T/MMF combination strategy effectively prevented acute and chronic GVHD after alloPBSCT from HLA-matched donors and achieved an unprecedented low NRM without losing efficacy in disease control or impaired development of the graft-versus-tumor effect. This trial is registered at clinicaltrials.gov as NCT02300571. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Conversion from cyclosporine to tacrolimus improves renal function and lipid profile after cardiac transplantation.

PubMed

Garlicki, Mirosław; Czub, Paweł; Labuś, Krzysztof; Ehrlich, Marek P; Rdzanek, Hanna

2006-01-01

Calcineurin inhibitors (CNIs) have become the cornerstone of immunosuppressive regimens following heart transplantation, but their use is associated with nephrotoxicity. The impact on renal function after conversion from cyclosporine (CsA) to tacrolimus (TAC) is reported. Fifteen patients (men age 42 +/- 11 years) after cardiac transplantation (HTX) were switched from CsA to TAC (mean time after HTX 21 +/- 6 months). There were 13 male and 2 female patients. Mean cholesterol and LDL level at the time of conversion were 217 +/- 65 ml/dl and and 136 +/- 51 mg/100 ml respectively. Indication for HTX was ischemic cardiomyopathy (CMP) in 8, congenital in 3 and dilatative CMP in the remaining 4 patients. Mean tacrolimus level (microg/dl) at 1, 3, 6 and 12 months were 8.6 +/- 3.3, 8.6 +/- 1.4, 9.2 +/- 2.8 and 9.8 +/- 2.5 respectively. There was a statistically significant improvement in creatinine levels at 1, 3, 6 and 12 months after conversion from baseline 1.9 +/- 0.7 mg/dl to 1.4 +/- 0.5 mg/dl, 1.4 +/- 0.4 mg/dl, 1.3 +/- 0.4 mg/dl and 1.2 +/- 0.4 mg/dl, respectively (p < 0.05). Furthermore, TAC decreased cholesterol as well as LDL-levels during this one-year time frame. This study shows that conversion from CsA to tacrolimus after orthotopic heart transplantation improves renal function.

Intravenous tacrolimus and cyclosporine induced anaphylaxis: what is next?

PubMed Central

Kang, Sung-Yoon; Sohn, Kyoung-Hee; Lee, Jeong-Ok; Kim, Sae-Hoon; Cho, Sang-Heon

2015-01-01

Tacrolimus and cyclosporine have been used in various formulations, but their hypersensitivity reactions are rare in practice. Castor oil derivatives are nonionic surfactants used in aqueous preparations of hydrophobic active pharmaceutical ingredients. Castor oil derivatives that can be used as additives to tacrolimus and cyclosporine may play a role in the development of hypersensitivity reactions, especially anaphylaxis. Various immunologic and nonimmunologic mechanisms have been implicated in hypersensitivity reactions induced by castor oil derivatives. Physicians should be aware that not only the drug itself, but also its additives or metabolites could induce hypersensitivity reactions. We report a case of anaphylaxis caused by vitamin K (phytonadine), serotonin antagonist (granisetron), intravenous tacrolimus, and cyclosporine. Interestingly, the patient tolerated oral cyclosporine, which did not contain Cremophor EL or polysorbate 80. PMID:26240796

Efficacy and safety of tacrolimus treatment for rheumatoid arthritis patients undergoing hemodialysis.

PubMed

Yamashita, Misuzu; Natsumeda, Masamitsu; Takasugi, Koji; Ueno, Akiko; Ezawa, Kayo; Ezawa, Kazuhiko

2008-01-01

Rheumatoid arthritis (RA) is an autoimmune disorder characterized by progressive joint destruction that requires aggressive treatment using appropriate disease-modifying antirheumatic drugs (DMARDs). RA patients with renal failure, however, are intolerant to most DMARDs due to the potential toxicity. In Japan, tacrolimus was approved for the treatment of RA in 2005. Based on its pharmacokinetics, tacrolimus may be administered to the patients undergoing hemodialysis. We report two cases of RA patients on hemodialysis treated effectively and safely with tacrolimus.

Effects of tacrolimus on action potential configuration and transmembrane ion currents in canine ventricular cells.

PubMed

Szabó, László; Szentandrássy, Norbert; Kistamás, Kornél; Hegyi, Bence; Ruzsnavszky, Ferenc; Váczi, Krisztina; Horváth, Balázs; Magyar, János; Bányász, Tamás; Pál, Balázs; Nánási, Péter P

2013-03-01

Tacrolimus is a commonly used immunosuppressive agent which causes cardiovascular complications, e.g., hypertension and hypertrophic cardiomyopathy. In spite of it, there is little information on the cellular cardiac effects of the immunosuppressive agent tacrolimus in larger mammals. In the present study, therefore, the concentration-dependent effects of tacrolimus on action potential morphology and the underlying ion currents were studied in canine ventricular cardiomyocytes. Standard microelectrode, conventional whole cell patch clamp, and action potential voltage clamp techniques were applied in myocytes enzymatically dispersed from canine ventricular myocardium. Tacrolimus (3-30 μM) caused a concentration-dependent reduction of maximum velocity of depolarization and repolarization, action potential amplitude, phase-1 repolarization, action potential duration, and plateau potential, while no significant change in the resting membrane potential was observed. Conventional voltage clamp experiments revealed that tacrolimus concentrations ≥3 μM blocked a variety of ion currents, including I(Ca), I(to), I(K1), I(Kr), and I(Ks). Similar results were obtained under action potential voltage clamp conditions. These effects of tacrolimus developed rapidly and were fully reversible upon washout. The blockade of inward currents with the concomitant shortening of action potential duration in canine myocytes is the opposite of those observed previously with tacrolimus in small rodents. It is concluded that although tacrolimus blocks several ion channels at higher concentrations, there is no risk of direct interaction with cardiac ion channels when applying tacrolimus in therapeutic concentrations.

Successful treatment with tacrolimus in TAFRO syndrome: two case reports and literature review.

PubMed

Shirai, Taiichiro; Onishi, Akira; Waki, Daisuke; Saegusa, Jun; Morinobu, Akio

2018-06-01

TAFRO syndrome is a systemic inflammatory disorder characterized by thrombocytopenia, anasarca, fever, reticulin fibrosis, renal dysfunction, and organomegaly. In contrast to that in multicentric Castleman disease, interleukin-6 targeting strategies seem ineffective in some TAFRO syndrome cases; however, the optimal treatment remains unclear. Here, we report 2 cases of TAFRO syndrome, where 1 with cardiomyopathy, successfully treated with tacrolimus. This is the first case report of successful treatment with tacrolimus in TAFRO syndrome. Both patients (cases 1 and 2) developed fever, anasarca, thrombocytopenia, renal dysfunction, and mild hepatosplenomegaly. In both patients, lymph node pathology revealed mixed type Castleman disease-like features, and bone marrow showed reticulin myelofibrosis. TAFRO syndrome was diagnosed based on the patients' laboratory, clinical, and pathologic findings. In case 2, we observed a rare complication of cardiomyopathy with no evidence of takotsubo cardiomyopathy or viral myocarditis. In case 1, tocilizumab combined with glucocorticoids was ineffective and caused septic shock; additionally, cyclosporine A was discontinued because of hepatotoxicity. However, tacrolimus was effective in resolving TAFRO syndrome without any adverse events. In case 2, tacrolimus completely reversed TAFRO syndrome and was also effective in cardiomyopathy. This report suggests that tacrolimus is potentially effective and safe as an initial treatment and a glucocorticoid-sparing agent. Our literature review shows that calcineurin inhibitors, including tacrolimus, may be effective in TAFRO syndrome. Since previous studies indicate a role of Th1 inflammation in TAFRO syndrome pathogenesis, tacrolimus may, therefore, be effective in treating TAFRO syndrome.

Unraveling Nutritional Regulation of Tacrolimus Biosynthesis in Streptomyces tsukubaensis through omic Approaches.

PubMed

Ordóñez-Robles, María; Santos-Beneit, Fernando; Martín, Juan F

2018-05-01

Streptomyces tsukubaensis stands out among actinomycetes by its ability to produce the immunosuppressant tacrolimus. Discovered about 30 years ago, this macrolide is widely used as immunosuppressant in current clinics. Other potential applications for the treatment of cancer and as neuroprotective agent have been proposed in the last years. In this review we introduce the discovery of S. tsukubaensis and tacrolimus, its biosynthetic pathway and gene cluster ( fkb ) regulation. We have focused this work on the omic studies performed in this species in order to understand tacrolimus production. Transcriptomics, proteomics and metabolomics have improved our knowledge about the fkb transcriptional regulation and have given important clues about nutritional regulation of tacrolimus production that can be applied to improve production yields. Finally, we address some points of S. tsukubaensis biology that deserve more attention.

Relative bioavailability of single doses of prolonged-release tacrolimus administered as a suspension, orally or via a nasogastric tube, compared with intact capsules: a phase 1 study in healthy participants.

PubMed

Undre, Nasrullah; Dickinson, James

2017-04-04

Tacrolimus, an immunosuppressant widely used in solid organ transplantation, is available as a prolonged-release capsule for once-daily oral administration. In the immediate postsurgical period, if patients cannot take intact capsules orally, tacrolimus therapy is often initiated as a suspension of the capsule contents, delivered orally or via a nasogastric tube. This study evaluated the relative bioavailability of prolonged-release tacrolimus suspension versus intact capsules in healthy participants. A phase 1, open-label, single-dose, cross-over study. A single clinical research unit. In total, 20 male participants, 18-55 years old, entered and completed the study. All participants received nasogastric administration of tacrolimus 10 mg suspension in treatment period 1, with randomisation to oral administration of suspension or intact capsules in periods 2 and 3. Blood concentration-time profile over 144 hours was used to estimate pharmacokinetic parameters. Primary end point: relative bioavailability of prolonged-release intact capsule versus oral or nasogastric administration of prolonged-release tacrolimus suspension (area under the concentration-time curve (AUC) from time 0 to infinity post-tacrolimus dose (AUC 0-∞ ); AUC measured until the last quantifiable concentration (AUC 0-tz ); maximum observed concentration (C max ); time to C max (T max )). Tolerability was assessed throughout the study. Relative bioavailability of prolonged-release tacrolimus suspension administered orally was similar to intact capsules, with a ratio of least-square means for AUC 0-tz and AUC 0-∞ of 1.05 (90% CI 0.96 to 1.14). Bioavailability was lower with suspension administered via a nasogastric tube versus intact capsules (17%; ratio 0.83; CI 0.76 to 0.92). C max was higher for oral and nasogastric suspension (30% and 28%, respectively), and median T max was shorter (difference 1.0 and 1.5 hours postdose, respectively) versus intact capsules (2.0 hours). Single 10�

Effects of Tacrolimus or Sirolimus on the adhesion of vascular wall cells: Controlled in-vitro comparison study.

PubMed

Krüger-Genge, A; Hiebl, B; Franke, R P; Lendlein, A; Jung, F

2017-01-01

In drug eluting stents the cytostatic drugs Sirolimus or Tacrolimus are used to inhibit blood vessel restenosis by limiting the proliferation of smooth muscle cells. However, the cytostatic activity of both drugs was shown to be not cell specific and could also affect the stent endothelialisation, respectively. Currently, only limited in vitro data are available about the impact of Sirolimus and Tacrolimus on endothelial cell proliferation over a broad concentration range. To answer this question the following study was performed.Commercially obtained HUVEC were expanded with DMEM cell culture medium (GIBCO, Germany) supplemented with 5 vol% fetal calf serum on non-coated regular polystyrene-based 24-multiwell plates. For drug testings 2×104 cells/cm2 were seeded and grown for 24 h until 30-40% of the multiwell surfaces were covered and then exposed to Sirolimus (1.0×10-11 - 1.0×10-5 mol/l) or Tacrolimus (2.0×10-8 - 6.2×10-5 mol/l), both dissolved in DMSO. 12, 24 and 48 h after adding the drugs cell numbers per area were quantified by counting the cells in six wells with four fields of view per well, representing 0.6 mm2, using a confocal laser microscope.After 48 h of cell growth in the drug-free cell culture medium, the HUVEC number increased from 2.0×104 to 3.55×104 cells/cm2 (mean cell doubling time: 53.6 h, n = 6). At lower concentrations (≤2.0×10-6 mol/l) Tacrolimus reduced the number of adherent HUVEC significantly less than Sirolimus (p < 0.05). However, at higher concentrations (≥2.07×10-5 mol/l) the effect of Tacrolimus on the number of adherent endothelial cells was significantly greater than that of Sirolimus (p < 0.05). At the highest concentration applied (6.22×10-5 mol/l), Tacrolimus induced detachment of all HUVECs within 12 h after drug application. The number of adherent HUVEC decreased only slightly (about 9%) after Sirolimus application at the highest concentration (1.09×10-5 mol/l).These data

Successful treatment with tacrolimus in TAFRO syndrome: two case reports and literature review

PubMed Central

Shirai, Taiichiro; Onishi, Akira; Waki, Daisuke; Saegusa, Jun; Morinobu, Akio

2018-01-01

Abstract Rationale: TAFRO syndrome is a systemic inflammatory disorder characterized by thrombocytopenia, anasarca, fever, reticulin fibrosis, renal dysfunction, and organomegaly. In contrast to that in multicentric Castleman disease, interleukin-6 targeting strategies seem ineffective in some TAFRO syndrome cases; however, the optimal treatment remains unclear. Here, we report 2 cases of TAFRO syndrome, where 1 with cardiomyopathy, successfully treated with tacrolimus. This is the first case report of successful treatment with tacrolimus in TAFRO syndrome. Patient concerns: Both patients (cases 1 and 2) developed fever, anasarca, thrombocytopenia, renal dysfunction, and mild hepatosplenomegaly. Diagnoses: In both patients, lymph node pathology revealed mixed type Castleman disease-like features, and bone marrow showed reticulin myelofibrosis. TAFRO syndrome was diagnosed based on the patients’ laboratory, clinical, and pathologic findings. In case 2, we observed a rare complication of cardiomyopathy with no evidence of takotsubo cardiomyopathy or viral myocarditis. Interventions and outcomes: In case 1, tocilizumab combined with glucocorticoids was ineffective and caused septic shock; additionally, cyclosporine A was discontinued because of hepatotoxicity. However, tacrolimus was effective in resolving TAFRO syndrome without any adverse events. In case 2, tacrolimus completely reversed TAFRO syndrome and was also effective in cardiomyopathy. Lessons: This report suggests that tacrolimus is potentially effective and safe as an initial treatment and a glucocorticoid-sparing agent. Our literature review shows that calcineurin inhibitors, including tacrolimus, may be effective in TAFRO syndrome. Since previous studies indicate a role of Th1 inflammation in TAFRO syndrome pathogenesis, tacrolimus may, therefore, be effective in treating TAFRO syndrome. PMID:29879072

A rare but important adverse effect of tacrolimus in a heart transplant recipient: diabetic ketoacidosis.

PubMed

Öztürk, Zeynelabidin; Gönç, E Nazlı; Akcan, Leman; Kesici, Selman; Ertuğrul, İlker; Bayrakçı, Benan

2015-01-01

Heart transplantation indications in pediatric population include congenital heart diseases, cardiomyopathies and retransplants. Cardiomyopathy is the primary indication for 11 to 17 years of age. The surveillance after transplantation is a very important issue because of both the rejection risk and the adverse effects due to medications after transplantation. Immunosuppressive agents that are commonly used after heart transplantations have several toxicities. Here we present an adolescent patient diagnosed with dilated cardiomyopathy, performed heart transplantation, treated with tacrolimus and suffered from diabetic ketoacidosis due to tacrolimus. After the diagnosis was made the appropriate fluid and insulin therapy was started immediately and ketoacidosis resolved in the first 24 hours of the therapy. The diagnosis revised as new onset diabetes mellitus after transplantation and the tacrolimus dosage titrated to therapeutic level. After glycemic control the patient discharged with rapid acting insulin, three times daily, before meals; and long acting insulin once daily at night. In ten month follow up time the insulin dosages were progressively reduced.

The carcinogenic potential of tacrolimus ointment beyond immune suppression: a hypothesis creating case report.

PubMed

Becker, Jürgen C; Houben, Roland; Vetter, Claudia S; Bröcker, Eva B

2006-01-11

Since tacrolimus ointment was approved by the U.S. Food and Drug Administration (FDA) as a promising treatment for atopic dermatitis, it has been approved in more than 30 additional countries, including numerous European Union member nations. Moreover, in the current clinical routine the use of this drug is no longer restricted to the approved indication, but has been extended to a wide variety of inflammatory skin diseases including some with the potential of malignant transformation. So far, the side-effects reported from the topical use of tacrolimus have been relatively minor (e.g. burning, pruritus, erythema). Recently, however, the FDA reviewed the safety of topical tacrolimus, which resulted in a warning that the use of calcineurin inhibitors may be associated with an increased risk of cancer. Oral lichen planus (OLP) was diagnosed in a 56-year-old women in February 1999. After several ineffective local and systemic therapeutic measures an off-label treatment of this recalcitrant condition using Tacrolimus 0.1% ointment was initiated in May 2002. After a few weeks of treatment most of the lesions ameliorated, with the exception of the plaques on the sides of the tongue. Nevertheless, the patient became free of symptoms which, however, reoccurred once tacrolimus was weaned, as a consequence treatment was maintained. In April 2005, the plaques on the left side of the tongue appeared increasingly compact and a biopsy specimen confirmed the suspected diagnosis of an oral squamous cell carcinoma. The suspected causal relationship between topical use of tacrolimus and the development of a squamous cell carcinoma prompted us to test the notion that the carcinogenicity of tacrolimus may go beyond mere immune suppression. To this end, tacrolimus has been shown to have an impact on cancer signalling pathways such as the MAPK and the p53 pathway. In the given case, we were able to demonstrate that these pathways had also been altered subsequent to tacrolimus therapy.

The Pittsburgh Randomized Trial of Tacrolimus Compared to Cyclosporine for Hepatic Transplantation

PubMed Central

Fung, John J.; Eliasziw, Michael; Todo, Satoru; Jain, Ashok; Demetris, Anthony J.; McMichael, John P.; Starzl, Thomas E.; Meier, Paul; Donner, Allan

2009-01-01

Background Tacrolimus (formerly FK 506) was first used clinically in 1989 to successfully replace cyclosporine in hepatic transplant recipients who were experiencing intractable rejection or as the baseline drug from the time of operation. After extensive pilot experience, an institutional review board-mandated clinical trial comparing cyclosporine with tacrolimus was performed. Study Design From February 16, 1990 to December 26, 1991, 154 patients were recruited. The competing drugs were combined with equal induction doses of prednisone in both arms of the study for the first 81 patients and with subsequently higher doses of prednisone in the remaining 35 patients who received cyclosporine and were entered into the trial. Drug crossover was permitted for lack of efficacy or adverse events. End points were rejection confirmed by biopsy and treatment failure leading to retransplantation or death. Results Seventy-nine patients were randomized to the tacrolimus arm and 75 to the cyclosporine arm during 1990 and 1991. All patients were available for follow-up throughout the trial, which terminated on May 30, 1995. The mean duration of follow-up was four years. Patients randomized to the tacrolimus arm were less likely to experience acute rejection than were those receiving cyclosporine, with 36.2 percent of the patients receiving tacrolimus and 16.8 percent of the patients receiving cyclosporine showing freedom from rejection at one year (p=0.003, likelihood ratio test). Survival of patients over the course of the study was virtually the same in the two groups. Conclusions Tacrolimus was more effective than cyclosporine in preventing acute rejection. PMID:8696542

Cyclosporine versus tacrolimus: cost-effectiveness analysis for renal transplantation in Brazil

PubMed Central

Guerra, Augusto Afonso; Silva, Grazielle Dias; Andrade, Eli Iola Gurgel; Cherchiglia, Mariângela Leal; Costa, Juliana de Oliveira; Almeida, Alessandra Maciel; Acurcio, Francisco de Assis

2015-01-01

OBJECTIVE To analyze the cost-effectiveness of treatment regimens with cyclosporine or tacrolimus, five years after renal transplantation. METHODS This cost-effectiveness analysis was based on historical cohort data obtained between 2000 and 2004 and involved 2,022 patients treated with cyclosporine or tacrolimus, matched 1:1 for gender, age, and type and year of transplantation. Graft survival and the direct costs of medical care obtained from the National Health System (SUS) databases were used as outcome results. RESULTS Most of the patients were women, with a mean age of 36.6 years. The most frequent diagnosis of chronic renal failure was glomerulonephritis/nephritis (27.7%). In five years, the tacrolimus group had an average life expectancy gain of 3.96 years at an annual cost of R$78,360.57 compared with the cyclosporine group with a gain of 4.05 years and an annual cost of R$61,350.44. CONCLUSIONS After matching, the study indicated better survival of patients treated with regimens using tacrolimus. However, regimens containing cyclosporine were more cost-effective. PMID:25741648

Cyclosporine versus tacrolimus: cost-effectiveness analysis for renal transplantation in Brazil.

PubMed

Guerra Júnior, Augusto Afonso; Silva, Grazielle Dias; Andrade, Eli Iola Gurgel; Cherchiglia, Mariângela Leal; Costa, Juliana de Oliveira; Almeida, Alessandra Maciel; Acurcio, Francisco de Assis

2015-01-01

OBJECTIVE To analyze the cost-effectiveness of treatment regimens with cyclosporine or tacrolimus, five years after renal transplantation. METHODS This cost-effectiveness analysis was based on historical cohort data obtained between 2000 and 2004 and involved 2,022 patients treated with cyclosporine or tacrolimus, matched 1:1 for gender, age, and type and year of transplantation. Graft survival and the direct costs of medical care obtained from the National Health System (SUS) databases were used as outcome results. RESULTS Most of the patients were women, with a mean age of 36.6 years. The most frequent diagnosis of chronic renal failure was glomerulonephritis/nephritis (27.7%). In five years, the tacrolimus group had an average life expectancy gain of 3.96 years at an annual cost of R$78,360.57 compared with the cyclosporine group with a gain of 4.05 years and an annual cost of R$61,350.44. CONCLUSIONS After matching, the study indicated better survival of patients treated with regimens using tacrolimus. Moreover, regimens containing cyclosporine were more cost-effective [corrected].

Use of Topical Tacrolimus and Topical Pimecrolimus in Four European Countries: A Multicentre Database Cohort Study.

PubMed

Kuiper, Josephina G; van Herk-Sukel, Myrthe P P; Castellsague, Jordi; Pottegård, Anton; Berglind, Ingegärd Anveden; Dedman, Daniel; Gutierrez, Lia; Calingaert, Brian; Hallas, Jesper; Sundström, Anders; Gallagher, Arlene M; Kaye, James A; Pardo, Carolina; Rothman, Kenneth J; Perez-Gutthann, Susana

2018-05-07

Despite the concerns about a potential increased risk of skin cancer and lymphoma with the use of topical tacrolimus and pimecrolimus, no population-based studies have given an overview of the use of these drugs in Europe. To assess the use of topical tacrolimus and pimecrolimus in children and adults in Europe. Multicentre database cohort study comprising data from the Netherlands, Denmark, Sweden and the UK. We analysed users of topical tacrolimus and pimecrolimus starting from the date of first availability (between 2002 and 2003) or start establishment of the prescription database in Sweden (2006) through 2011. Use was assessed separately for children (≤ 18 years) and adults. 32,052 children and 104,902 adults were treated with topical tacrolimus, and 32,125 children and 58,280 adults were treated with topical pimecrolimus. The number of users increased rapidly after first availability, especially for topical tacrolimus. Topical tacrolimus was more frequently used in all countries except Denmark. For both drugs, there was a decrease in users after 2004 in the Netherlands and Denmark and after 2005 in the UK, especially among children. This decrease was largest in Denmark. The decrease in the number of users was temporary for topical tacrolimus, while use remained relatively low for topical pimecrolimus. The number of topical tacrolimus and pimecrolimus users increased rapidly after regulatory approval. A transient reduction in topical tacrolimus use and a persistent reduction in topical pimecrolimus use was seen after 2004 in the Netherlands and Denmark and after 2005 in the UK.

Topical tacrolimus in alopecia areata.

PubMed

Price, Vera H; Willey, Andrea; Chen, Bryan K

2005-01-01

Eleven patients with alopecia areata affecting 10% to 75% of the scalp, average duration 6 years, had no terminal hair growth in response to tacrolimus ointment 0.1% applied twice daily for 24 weeks. Treatment failure may reflect insufficient depth of penetration of the ointment formulation and less than optimal patient selection.

Conversion from tacrolimus-mycophenolate mofetil to tacrolimus-mTOR immunosuppression after kidney-pancreas transplantation reduces the incidence of both BK and CMV viremia.

PubMed

Knight, Richard J; Graviss, Edward A; Nguyen, Duc T; Kuten, Samantha A; Patel, Samir J; Gaber, Lillian; Gaber, A Osama

2018-04-19

We sought to determine whether conversion from tacrolimus/mycophenolate mofetil (TAC-MMF) into tacrolimus/mTOR inhibitor (TAC-mTOR) immunosuppression would reduce the incidences of BK and CMV viremia after kidney/pancreas (KP) transplantation. In this single-center review, the TAC-mTOR cohort (n = 39) was converted at 1 month post-transplant to an mTOR inhibitor and reduced-dose tacrolimus. Outcomes were compared to a cohort of KP recipients (n = 40) maintained on TAC-MMF. At 3 years post-transplant, KP survivals and incidences of kidney/pancreas rejection were equivalent between mTOR and MMF-treated cohorts. (P = ns). BK viremia-free survival was better for the mTOR vs MMF-treated group (P = .004). In multivariate analysis, MMF vs mTOR immunosuppression was an independent risk factor for BK viremia (hazard ratio 12.27, P = .02). Similarly, mTOR-treated recipients displayed better CMV infection-free survival compared to the MMF-treated cohort (P = .01). MMF vs mTOR immunosuppression (hazard ratio 18.77, P = .001) and older recipient age (hazard ratio 1.13 per year, P = .006) were independent risk factors for CMV viremia. Mean estimated GFR and HgbA1c levels were equivalent between groups at 1, 2, and 3 years post-transplantation. Conversion from TAC/MMF into TAC/mTOR immunosuppression after KP transplantation reduced the incidences of BK and CMV viremia with an equivalent risk of acute rejection and similar renal/pancreas function. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Sirolimus Versus Tacrolimus as Primary Immunosuppressant After Renal Transplantation: A Meta-Analysis and Economics Evaluation.

PubMed

Liu, Jin-Yu; Song, Ming; Guo, Min; Huang, Feng; Ma, Bing-Jun; Zhu, Lan; Xu, Gang; Li, Juan; You, Ru-Xu

Sirolimus and tacrolimus are the major immunosuppressants for renal transplantation. Several studies have compared these 2 drugs, but the outcomes were not consistent. The aim of this study was to evaluate the efficacy, safety, and pharmacoeconomics of sirolimus and tacrolimus in the treatment of renal transplantation and provide evidence for the selection of essential drugs. Trials were identified through a computerized literature search of PubMed, EMBASE, Cochrane controlled trials register, Cochrane Renal Group Specialized Register of randomized controlled trials, and Chinese Biomedical database. Two independent reviewers assessed trials for eligibility and quality and then extracted data. Data were extracted for patient and graft mortality, acute rejection (AR), and adverse events. Dichotomous outcomes were reported as relative risk with 95% confidence intervals. A decision tree model was populated with data from a literature review and used to estimate costs and QALYs gained and incremental cost-effectiveness. Altogether, 1189 patients from 8 randomized controlled trials were included. The results of our analysis were that tacrolimus reduced the risks after renal transplantation of AR and patient withdrawn. Nevertheless, tacrolimus increased the risk of infection. Pharmacoeconomic analysis showed that tacrolimus represented a more cost-effective treatment than does cyclosporine for the prevention of adverse events after renal transplant. Tacrolimus is an effective and safe immunosuppressive agent, and it may be more cost-effective than cyclosporine for the primary prevention of AR in renal transplant recipients. However, it should be noted that such superiority was reversal when the cost of sirolimus and tacrolimus changed.

Tacrolimus concentration to dose ratio in solid organ transplant patients treated with fecal microbiota transplantation for recurrent Clostridium difficile infection.

PubMed

Woodworth, Michael H; Kraft, Colleen S; Meredith, Erika J; Mehta, Aneesh K; Wang, Tiffany; Mamo, Yafet T; Dhere, Tanvi; Sitchenko, Kaitlin L; Patzer, Rachel E; Friedman-Moraco, Rachel J

2018-04-01

Fecal microbiota transplantation (FMT) is increasingly being performed for Clostridium difficile infection in solid organ transplant (SOT) patients; however, little is known about the potential pharmacokinetic or pharmacomicrobial effects this may have on tacrolimus levels. We reviewed the medical records of 10 SOT patients from September 2012-December 2016 who were taking tacrolimus at time of FMT for recurrent C. difficile infection. We compared the differences in tacrolimus concentration/dose ratio (C/D ratio) 3 months prior to FMT vs 3 months after FMT. The mean of the differences in C/D ratio calculated as (ng/mL)/(mg/kg/d) was -17.65 (95% CI -1.25 to 0.58) (ng/mL)/(mg/kg/d), P-value .43 by Wilcoxon signed-rank test. The mean of the differences in C/D ratio calculated as (ng/mL)/(mg/d) was -0.33 (95% CI -1.25 to 0.58) (ng/mL)/(mg/d), P-value .28 by Wilcoxon signed-rank test. Of these patients, 2/10 underwent allograft biopsy for allograft dysfunction in the year after FMT, with no evidence of allograft rejection on pathology. These preliminary data suggest that FMT may not predictably alter tacrolimus levels and support its safety for SOT patients however further study in randomized trials is needed. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Impact of intrapatient variability (IPV) in tacrolimus trough levels on long-term renal transplant function: multicentre collaborative retrospective cohort study protocol

PubMed Central

Goldsmith, Petra M; Bottomley, Matthew J; Okechukwu, Okidi; Ross, Victoria C; Ghita, Ryan; Wandless, David; Falconer, Stuart J; Papachristos, Stavros; Nash, Philip; Androshchuk, Vitaliy; Clancy, Marc

2017-01-01

Introduction High intrapatient variability (IPV) in tacrolimus trough levels has been shown to be associated with higher rates of renal transplant failure. There is no consensus on what level of IPV constitutes a risk of graft loss. The establishment of such a threshold could help to guide clinicians in identifying at-risk patients to receive targeted interventions to improve IPV and thus outcomes. Methods and analysis A multicentre Transplant Audit Collaborative has been established to conduct a retrospective study examining tacrolimus IPV and renal transplant outcomes. Patients in receipt of a renal transplant at participating centres between 2009 and 2014 and fulfilling the inclusion criteria will be included in the study. The aim is to recruit a minimum of 1600 patients with follow-up spanning at least 2 years in order to determine a threshold IPV above which a renal transplant recipient would be considered at increased risk of graft loss. The study also aims to determine any national or regional trends in IPV and any demographic associations. Ethics and dissemination Consent will not be sought from patients whose data are used in this study as no additional procedures or information will be required from participants beyond that which would normally take place as part of clinical care. The study will be registered locally in each participating centre in line with local research and development protocols. It is anticipated that the results of this audit will be disseminated locally, in participating NHS Trusts, through national and international meetings and publications in peer-reviewed journals. PMID:28756385

Tacrolimus treatment of atopic eczema/dermatitis syndrome.

PubMed

Thestrup-Pedersen, Kristian

2003-10-01

Atopic dermatitis is today the most common chronic disease of children in Europe, the US and Japan. The 'golden standard' of therapy is topical glucocorticosteroids and emollients. The steroids have been on the market for four decades, are efficacious, but only advised for short-term treatment due to their risks of side effects. More than 16,000 persons suffering from atopic dermatitis have been enrolled in clinical studies of tacrolimus. One third of patients with moderate to severe atopic dermatitis experience over 90% improvement in their disease over a 12-week treatment period and up to 70% of patients have over 50% improvement. A 1-year treatment leads to more than 90% improvement in 75% of patients. The most pronounced side effect is a burning sensation occurring in up to 60% of patients. Atopic dermatitis is a chronic skin disease leading to a demand for long-term treatment control. Such treatment options have not previously been available--except for emollients which are not efficacious for controlling skin inflammation. Tacrolimus and pimecrolimus are new treatment options, free from the potential side effects of topical steroids, which are known for their efficacy in short-term treatment. The new treatment modalities prevent the eczema from relapsing and at the same time they control active eczema. The future will see a shift towards the long-term use of tacrolimus which is able to control the skin inflammation and, hopefully, shorten the course of the eczema.

Clinical Validation of Simultaneous Analysis of Tacrolimus, Cyclosporine A, and Creatinine in Dried Blood Spots in Kidney Transplant Patients.

PubMed

Veenhof, Herman; Koster, Remco A; Alffenaar, Jan-Willem C; Berger, Stefan P; Bakker, Stephan J L; Touw, Daan J

2017-07-01

Monitoring of creatinine and immunosuppressive drug concentrations, such as tacrolimus (TaC) and cyclosporin A (CsA), is important in the outpatient follow-up of kidney transplant recipients. Monitoring by dried blood spot (DBS) provides patients the opportunity to sample a drop of blood from a fingerprick at home, which can be sent to the laboratory by mail. We performed a clinical validation in which we compared measurements from whole-blood samples obtained by venapuncture with measurements from DBS samples simultaneously obtained by fingerprick. After exclusion of 10 DBS for poor quality, and 2 for other reasons, 199, 104, and 58 samples from a total of 172 patients were available for validation of creatinine, TaC and CsA, respectively. Validation was performed by means of Passing & Bablok regression, and bias was assessed by Bland-Altman analysis. For creatinine, we found y = 0.73x - 1.55 (95% confidence interval [95% CI] slope, 0.71-0.76), giving the conversion formula: (creatinine plasma concentration in μmol/L) = (creatinine concentration in DBS in μmol/L)/0.73, with a nonclinically relevant bias of -2.1 μmol/L (95% CI, -3.7 to -0.5 μmol/L). For TaC, we found y = 1.00x - 0.23 (95% CI slope, 0.91-1.08), with a nonclinically relevant bias of -0.28 μg/L (95% CI, -0.45 to -0.12 μg/L). For CsA, we found y = 0.99x - 1.86 (95% CI slope, 0.91-1.08) and no significant bias. Therefore, for neither TaC nor CsA, a conversion formula is required. DBS sampling for the simultaneous analysis of immunosuppressants and creatinine can replace conventional venous sampling in daily routine.

The onset risk of carcinoma in patients continuing tacrolimus topical treatment for oral lichen planus: a case report.

PubMed

Morita, Mayu; Asoda, Seiji; Tsunoda, Kazuyuki; Soma, Tomoya; Nakagawa, Taneaki; Shirakawa, Masayori; Shoji, Hirofumi; Yagishita, Hisao; Nishikawa, Takeji; Kawana, Hiromasa

2017-04-01

Oral lichen planus is a chronic inflammatory mucocutaneous disease. Topical use of steroids and other immuno-modulating therapies have been tried for this intractable condition. Nowadays, tacrolimus ointment is used more commonly as a choice for treatment. However, a number of discussions have taken place after tacrolimus was reported to be carcinogenic. This report describes a patient who applied tacrolimus ointment to the lower lip after being diagnosed with oral lichen planus in 2008, and whose lesion developed squamous cell carcinoma in 2010. Since the relationship between tacrolimus and cancer development has been reported in only a few cases, including this case report, the clinician must be careful selecting tacrolimus as a second-line treatment for oral lichen planus.

Open-Label, Randomized Study of Transition From Tacrolimus to Sirolimus Immunosuppression in Renal Allograft Recipients

PubMed Central

Tedesco-Silva, Helio; Peddi, V. Ram; Sánchez-Fructuoso, Ana; Marder, Brad A.; Russ, Graeme R.; Diekmann, Fritz; Flynn, Alison; Hahn, Carolyn M.; Li, Huihua; Tortorici, Michael A.; Schulman, Seth L.

2016-01-01

Background Calcineurin inhibitor–associated nephrotoxicity and other adverse events have prompted efforts to minimize/eliminate calcineurin inhibitor use in kidney transplant recipients. Methods This open-label, randomized, multinational study evaluated the effect of planned transition from tacrolimus to sirolimus on kidney function in renal allograft recipients. Patients received tacrolimus-based immunosuppression and then were randomized 3 to 5 months posttransplantation to transition to sirolimus or continue tacrolimus. The primary end point was percentage of patients with 5 mL/min per 1.73 m2 or greater improvement in estimated glomerular filtration rate from randomization to month 24. Results The on-therapy population included 195 patients (sirolimus, 86; tacrolimus, 109). No between-group difference was noted in percentage of patients with 5 mL/min per 1.73 m2 or greater estimated glomerular filtration rate improvement (sirolimus, 34%; tacrolimus, 42%; P = 0.239) at month 24. Sirolimus patients had higher rates of biopsy-confirmed acute rejection (8% vs 2%; P = 0.02), treatment discontinuation attributed to adverse events (21% vs 3%; P < 0.001), and lower rates of squamous cell carcinoma of the skin (0% vs 5%; P = 0.012). Conclusions Our findings suggest that renal function improvement at 24 months is similar for patients with early conversion to sirolimus after kidney transplantation versus those remaining on tacrolimus. PMID:27500260

Personalized tacrolimus doses determined by CYP3A5 genotype for induction and maintenance phases of kidney transplantation.

PubMed

Vannaprasaht, Suda; Reungjui, Sirirat; Supanya, Darika; Sirivongs, Dhavee; Pongskul, Cholatip; Avihingsanon, Yingyos; Tassaneeyakul, Wichittra

2013-11-01

Cytochrome P450 (CYP) 3A4 and 3A5 are major isoforms involved in the metabolism of tacrolimus, with the CYP3A5 gene being more polymorphic. It is hypothesized that individual variation in the metabolism of tacrolimus drug may result from genetic polymorphism of CYP3A5. It has been reported that the clearance of tacrolimus in patients with the CYP3A5*1 allele was ~2.5-fold greater than that in those with the CYP3A5*3/*3 genotype. Recent data have also shown that polymorphism in exon 26 (C3435T) of the multidrug resistance gene (MDR1) was correlated with the expression level and function of P-glycoprotein in the lower duodenum, making the relationship between polymorphism of MDR1 and the effective dose of tacrolimus a source of controversy. This study investigated the influence of genetic polymorphisms of CYP3A5 and MDR1 on the dose requirements for the induction and maintenance phases of tacrolimus therapy in kidney transplant recipients. Sixty-eight kidney transplant recipients were enrolled, and their clinical and laboratory data were retrospectively reviewed after 6 months of tacrolimus administration. Genotypes of CYP3A5*1 and CYP3A5*3 and exon 26 of MDR1 (C3435T) were determined by the single-nucleotide polymorphism genotyping method. The frequencies of CYP3A5*3/*3, CYP3A5*1/*3, and CYP3A5*1/*1 were 44.1%, 35.3%, and 20.6%, respectively. The mean dose of tacrolimus required for the induction phase was significantly greater in the CYP3A5*1/*1 group (0.142 [0.050] mg/kg/d) than that required in the CYP3A5*1/*3 group (0.097 [0.040] mg/kg/d; P = 0.072) and in the CYP3A5*3/*3 group (0.077 [0.020] mg/kg/d; P = 0.005). The maintenance dose of tacrolimus required in the CYP3A5*1/*1 group (0.12 [0.03] mg/kg/d) was 1.3-fold higher than that in the CYP3A5*1/*3 group (0.09 [0.03] mg/kg/d; P = 0.018) and 2.4-fold higher than in the CYP3A5*3/*3 group (0.05 [0.02] mg/kg/d; P < 0.0001). No statistically significant relationship was observed between the doses of tacrolimus

Pharmacogenetic considerations for optimizing tacrolimus dosing in liver and kidney transplant patients

PubMed Central

Provenzani, Alessio; Santeusanio, Andrew; Mathis, Erin; Notarbartolo, Monica; Labbozzetta, Manuela; Poma, Paola; Provenzani, Ambra; Polidori, Carlo; Vizzini, Giovanni; Polidori, Piera; D’Alessandro, Natale

2013-01-01

The introduction of tacrolimus in clinical practice has improved patient survival after organ transplant. However, despite the long use of tacrolimus in clinical practice, the best way to use this agent is still a matter of intense debate. The start of the genomic era has generated new research areas, such as pharmacogenetics, which studies the variability of drug response in relation to the genetic factors involved in the processes responsible for the pharmacokinetics and/or the action mechanism of a drug in the body. This variability seems to be correlated with the presence of genetic polymorphisms. Genotyping is an attractive option especially for the initiation of the dosing of tacrolimus; also, unlike phenotypic tests, the genotype is a stable characteristic that needs to be determined only once for any given gene. However, prospective clinical studies must show that genotype determination before transplantation allows for better use of a given drug and improves the safety and clinical efficacy of that medication. At present, research has been able to reliably show that the CYP3A5 genotype, but not the CYP3A4 or ABCB1 ones, can modify the pharmacokinetics of tacrolimus. However, it has not been possible to incontrovertibly show that the corresponding changes in the pharmacokinetic profile are linked with different patient outcomes regarding tacrolimus efficacy and toxicity. For these reasons, pharmacogenetics and individualized medicine remain a fascinating area for further study and may ultimately become the face of future medical practice and drug dosing. PMID:24409044

A randomized, crossover pharmacokinetic study comparing generic tacrolimus vs. the reference formulation in subpopulations of kidney transplant patients.

PubMed

Bloom, R D; Trofe-Clark, J; Wiland, A; Alloway, R R

2013-01-01

An exploratory, post hoc analysis was performed using data from a prospective, multicenter, open-label, randomized, two-period (14 d per period), two-sequence, crossover, steady-state pharmacokinetic study comparing generic tacrolimus (Sandoz) vs. reference tacrolimus in stable renal transplant patients receiving their pre-study twice-daily dose. Pharmacokinetic parameters were compared in 68 patients according to gender, African American ethnicity, the presence or absence of diabetes, and use of steroids. The ratios of tacrolimus AUC0-12 h , Cmax , and C12 with generic vs. reference tacrolimus were calculated using the geometric mean (GM) of dose-normalized values at days 14 and 28. Mean (SD) tacrolimus dose at baseline was 5.7 (4.2) mg/d. There were no consistent differences in dose-normalized AUC0-12 h , C12 , Cmax, or tmax between the generic and reference preparations within subpopulations. The 90% confidence intervals (CI) for the ratios of dose-normalized AUC0-12 h and C12 with generic vs. reference tacrolimus were within 80-125% for all subpopulations, as were 90% CIs for Cmax other than for females, African Americans, and non-diabetics, which is not unexpected given the wide variability of tacrolimus Cmax and the small subpopulation sizes. These exploratory results suggest that this generic tacrolimus preparation would be expected to offer comparable bioavailability to the reference drug in these patient subpopulations. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Tacrolimus hydrate ointment inhibits skin plasma extravasation in rats induced by topical m-xylene but not capsaicin.

PubMed

Goto, Shiho; Kondo, Fumio; Ikai, Yoshitomo; Miyake, Mio; Futamura, Masaki; Ito, Komei; Sakamoto, Tatsuo

2009-04-17

Tacrolimus ointment is used to treat various chronic inflammatory skin diseases. However, the effect of this ointment on acute neurogenic inflammation in the skin remains to be fully elucidated. Topical capsaicin and m-xylene produce tachykinin release from sensory nerves in the skin, resulting in skin plasma leakage. We investigated the effect of tacrolimus ointment (0.1%) on skin microvascular leakage induced by topical capsaicin (10 mM) and m-xylene (neat), and intracutaneous compound 48/80 (c48/80) (10 microg/ml, 50 microl/site) in two groups of rats pretreated with excessive capsaicin or its vehicle. The amount of leaked Evans blue dye reflected skin plasma leakage. Capsaicin, m-xylene or c48/80 was applied to the shaved abdomens of rats 8 h after topical application of tacrolimus ointment or its base. Desensitization with capsaicin reduced the skin response to capsaicin and m-xylene by 100% and 65%, respectively, but not to c48/80. Tacrolimus ointment significantly inhibited the skin response induced by m-xylene and c48/80, regardless of pretreatment with capsaicin. However, topical tacrolimus did not influence the skin response induced by capsaicin. We also evaluated whether topical capsaicin and m-xylene, and intracutaneous c48/80 cause mast cell degranulation in skin treated with tacrolimus. Mast cell degranulation was microscopically assessed. Topical tacrolimus only significantly suppressed degranulation induced by m-xylene and c48/80. Our data shows that tacrolimus ointment partially inhibits plasma leakage and mast cell degranulation in rat skin induced by m-xylene and c48/80 but not capsaicin, suggesting that the inhibitory effect is not associated with a reduction in neurogenic-mediated mechanisms.

Evaluation of the Ocular Tolerance of Three Tacrolimus Topical Pharmaceutical Preparations by Bovine Corneal Opacity and Permeability Test.

PubMed

Pastor-Clerigues, Alfonso; Serrano, Adela; Milara, Javier; Marti-Bonmati, Ezequiel; Lopez-Perez, Francisco J; Garcia-Montanes, Sara; Sanfeliu, Joan; Saval-Victoria, Ana C; Cortijo, Julio

2016-07-01

Tacrolimus ocular preparations are commonly employed in autoimmune or inflammatory ocular disorders. However, currently there are not yet approved ocular formulations. Tacrolimus ocular side effects have been reported in clinical use, so the evaluation of different pharmaceutical preparations is mandatory. In this study, the local corneal tolerance and safety profile of three common tacrolimus 0.03% pharmaceutical preparations were evaluated. Corneal irritation and permeability of tacrolimus preparations were evaluated with the bovine corneal opacity and permeability (BCOP) test. Complementary corneal hematoxylin/eosin and immunohistochemistry staining for tight junctions and adherent junctions E-cadherin, VE-cadherin and zonula occludens-1 were examined and scored to evaluate and to confirm corneal disruption and irritation scores obtained with the BCOP method. Commercial brand ointment (Protopic®), topical compounded eye ointment (pharmacy elaboration) and tacrolimus suspension eye drops (elaborated from parenteral prograf®) were tested as potential ocular preparations to be used in clinics. Tacrolimus preparations hereby studied do not alter the opacity and permeability of the bovine cornea by more than three units, measured by the In Vitro Irritancy Score, neither affected the immunohistochemical parameters, composite score or transepithelial electrical resistance. Tacrolimus preparations studied can be safely applied as a topical ocular treatment.

Population pharmacokinetics of tacrolimus in paediatric systemic lupus erythematosus based on real-world study.

PubMed

Wang, D-D; Lu, J-M; Li, Q; Li, Z-P

2018-05-15

Different population pharmacokinetics (PPK) models of tacrolimus have been established in various populations. However, the tacrolimus PPK model in paediatric systemic lupus erythematosus (PSLE) is still undefined. This study aimed to establish the tacrolimus PPK model in Chinese PSLE. A total of nineteen Chinese patients with PSLE from real-world study were characterized with nonlinear mixed-effects modelling (NONMEM). The impact of demographic features, biological characteristics, and concomitant medications was evaluated. Model validation was assessed by bootstrap and prediction-corrected visual predictive check (VPC). A one-compartment model with first-order absorption and elimination was determined to be the most suitable model in PSLE. The typical values of apparent oral clearance (CL/F) and the apparent volume of distribution (V/F) in the final model were 2.05 L/h and 309 L, respectively. Methylprednisolone and simvastatin were included as significant. The first validated tacrolimus PPK model in patients with PSLE is presented. © 2018 John Wiley & Sons Ltd.

The Tacrolimus Metabolism Rate Influences Renal Function after Kidney Transplantation

PubMed Central

Thölking, Gerold; Fortmann, Christian; Koch, Raphael; Gerth, Hans Ulrich; Pabst, Dirk; Pavenstädt, Hermann; Kabar, Iyad; Hüsing, Anna; Wolters, Heiner

2014-01-01

The effective calcineurin inhibitor (CNI) tacrolimus (Tac) is an integral part of the standard immunosuppressive regimen after renal transplantation (RTx). However, as a potent CNI it has nephrotoxic potential leading to impaired renal function in some cases. Therefore, it is of high clinical impact to identify factors which can predict who is endangered to develop CNI toxicity. We hypothesized that the Tac metabolism rate expressed as the blood concentration normalized by the dose (C/D ratio) is such a simple predictor. Therefore, we analyzed the impact of the C/D ratio on kidney function after RTx. Renal function was analyzed 1, 2, 3, 6, 12 and 24 months after RTx in 248 patients with an immunosuppressive regimen including basiliximab, tacrolimus, mycophenolate mofetil and prednisolone. According to keep the approach simple, patients were split into three C/D groups: fast, intermediate and slow metabolizers. Notably, compared with slow metabolizers fast metabolizers of Tac showed significantly lower estimated glomerular filtration rate (eGFR) values at all the time points analyzed. Moreover, fast metabolizers underwent more indication renal biopsies (p = 0.006) which revealed a higher incidence of CNI nephrotoxicity (p = 0.015) and BK nephropathy (p = 0.024) in this group. We herein identified the C/D ratio as an easy calculable risk factor for the development of CNI nephrotoxicity and BK nephropathy after RTx. We propose that the simple C/D ratio should be taken into account early in patient’s risk management strategies. PMID:25340655

Nano-liposomal dry powder inhaler of tacrolimus: preparation, characterization, and pulmonary pharmacokinetics.

PubMed

Chougule, Mahavir; Padhi, Bijay; Misra, Ambikanandan

2007-01-01

The studies were undertaken to evaluate feasibility of pulmonary delivery of liposomaly encapsulated tacrolimus dry powder inhaler for prolonged drug retention in lungs as rescue therapy to prevent refractory rejection of lungs after transplantation. Tacrolimus encapsulated liposomes were prepared by thin film evaporation technique and liposomal dispersion was passed through high pressure homogenizer. Tacrolimus nano-liposomes (NLs) were separated by centrifugation and characterized. NLs were dispersed in phosphate buffer saline (PBS) pH 7.4 containing different additives like lactose, sucrose, and trehalose, and L-leucine as antiadherent. The dispersion was spray dried and spray dried powders were characterized. In vitro and in vivo pulmonary deposition was performed using Andersen Cascade Impactor and intratracheal instillation in rats respectively. NLs were found to have average size of 140 nm, 96% +/- 1.5% drug entrapment, and zeta potential of 1.107 mV. Trehalose based formulation was found to have low density, good flowability, particle size of 9.46 +/- 0.8 microm, maximum fine particle fraction (FPF) of 71.1 +/- 2.5%, mean mass aerodynamic diameter (MMAD) 2.2 +/- 0.1 microm, and geometric standard deviation (GSD) 1.7 +/- 0.2. Developed formulations were found to have in vitro prolonged drug release up to 18 hours, following Higuchi's Controlled Release model. In vivo studies revealed maximal residence of tacrolimus within lungs of 24 hours, suggesting slow clearance from the lungs. The investigation provides a practical approach for direct delivery of tacrolimus encapsulated in NLs for controlled and prolonged retention at the site of action. It may play a promising role as rescue therapy in reducing the risk of acute rejection and chronic rejection.

CYP3A5*3 and ABCB1 61A>G Significantly Influence Dose-adjusted Trough Blood Tacrolimus Concentrations in the First Three Months Post-Kidney Transplantation.

PubMed

Hu, Rong; Barratt, Daniel T; Coller, Janet K; Sallustio, Benedetta C; Somogyi, Andrew A

2018-03-30

Tacrolimus (TAC) is a first-line immunosuppressant used to prevent organ rejection after kidney transplantation. There is large inter-individual variability in its pharmacokinetics. Single nucleotide polymorphisms (SNPs) in genes encoding TAC metabolizing enzymes cytochromes P450 3A4/5 (CYP3A4/5), P-glycoprotein efflux transporter (ABCB1), their expression regulator pregnane X receptor (NR1I2) and CYP3A co-factor cytochrome P450 reductase (POR) have been studied for their effects on tacrolimus disposition. However, except for CYP3A5*3, controversies remain about their roles in predicting dose-adjusted trough blood TAC concentrations (C 0 /D). This study aimed to investigate the effects of ABCB1 (61A>G, 1199G>A, 1236C>T, 2677G>T and 3435C>T), CYP3A4*22, CYP3A5*3, NR1I2 (8055C>T, 63396C>T and -25385C>T) and POR*28 SNPs on TAC C 0 /D. In total, 165 kidney transplant recipients were included in this study. SNPs were genotyped by probe-based real-time polymerase chain reaction. Associations between log-transformed whole blood TAC C 0 /D (measured at 1 and 3 months post-transplant) and genotypes/haplotypes were assessed by linear mixed effects analysis, controlling for age, sex and haematocrit. It was observed that CYP3A5 expressors (*1/*1 + *1/*3) (p = 5.5 × 10 -16 ) and ABCB1 61G allele carriers (p = 0.001) had lower log-transformed TAC C 0 /D (56% and 26% lower geometric mean TAC C 0 /D, respectively) and accounted for approximately 30% and 4%, respectively, of log-transformed TAC C 0 /D variability in the first 3 months post-transplant. In conclusion, CYP3A5*3 is a major, and ABCB1 61A>G is a novel, although minor, genetic factor affecting TAC C 0 /D in kidney transplant recipients. © 2018 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Medium-Term Renal Function in a Large Cohort of Stable Kidney Transplant Recipients Converted From Twice-Daily to Once-Daily Tacrolimus.

PubMed

Guirado, Lluís; Burgos, Dolores; Cantarell, Carme; Fernández, Ana; Franco, Antonio; Gentil, Miguel Ángel; Mazuecos, Auxiliadora; Torregrosa, Josep Vicenç; Huertas, Ernesto Gómez; Ruiz, Juan Carlos; Plumed, Jaime Sánchez; Paul, Javier; Lauzurica, Ricardo; Zárraga, Sofía; Osuna, Antonio; Jiménez, Carlos; Alonso, Ángel; Rodríguez, Alberto; Bardají, Beatriz; Hernández, Domingo

2015-08-01

There is some evidence pointing toward better renal function in kidney transplant recipients (KTR) treated with once-daily tacrolimus (QD-TAC) vs. twice-daily tacrolimus (BID-TAC). This is an extension study of a 1-year, single arm prospective study of stable KTR who were converted from BID-TAC to QD-TAC (4.9 ± 4.0 years after transplantation) in Spanish routine clinical practice. Patient and graft survival, renal function, acute rejection episodes, and other analytic parameters were assessed at 24 and 36 months after conversion. A total of 1798 KTR were included in the extension study. Tacrolimus doses at 36 months were significantly lower compared to those at time of conversion (-0.2 mg/day; P = 0.023). Blood levels were lower than baseline during all the study (P < 0.001). Graft and patient survival at 3 years after conversion were 93.9% and 95.1%, respectively. Compared with baseline, the mean estimated glomerular filtration rate (eGFR) remained very stable at all timepoints (56.7 ± 19.8 vs 58.1 ± 24.6 mL/min per 1.73 m(2) at month 36; P = 0.623). Even when patients reinitiating dialysis were counted as eGFR = 0, the mean eGFR was very stable. In fact, a small but significant increase was observed at 36 months versus baseline (+0.1 mL/min per 1.73 m(2); P = 0.025). An increase in proteinuria was observed at 36 months versus baseline (+0.11 g/24 h; P < 0.001). Acute rejection rates were low during the study. Conversion from BID-TAC to QD-TAC in a large cohort of stable KTR was safe and associated with a very stable renal function after 3 years. Comparative studies are warranted to assess the feasibility of such conversion.

Medium-Term Renal Function in a Large Cohort of Stable Kidney Transplant Recipients Converted From Twice-Daily to Once-Daily Tacrolimus

PubMed Central

Guirado, Lluís; Burgos, Dolores; Cantarell, Carme; Fernández, Ana; Franco, Antonio; Gentil, Miguel Ángel; Mazuecos, Auxiliadora; Torregrosa, Josep Vicenç; Huertas, Ernesto Gómez; Ruiz, Juan Carlos; Plumed, Jaime Sánchez; Paul, Javier; Lauzurica, Ricardo; Zárraga, Sofía; Osuna, Antonio; Jiménez, Carlos; Alonso, Ángel; Rodríguez, Alberto; Bardají, Beatriz; Hernández, Domingo

2015-01-01

Background There is some evidence pointing toward better renal function in kidney transplant recipients (KTR) treated with once-daily tacrolimus (QD-TAC) vs. twice-daily tacrolimus (BID-TAC). Methods This is an extension study of a 1-year, single arm prospective study of stable KTR who were converted from BID-TAC to QD-TAC (4.9 ± 4.0 years after transplantation) in Spanish routine clinical practice. Patient and graft survival, renal function, acute rejection episodes, and other analytic parameters were assessed at 24 and 36 months after conversion. Results A total of 1798 KTR were included in the extension study. Tacrolimus doses at 36 months were significantly lower compared to those at time of conversion (−0.2 mg/day; P = 0.023). Blood levels were lower than baseline during all the study (P < 0.001). Graft and patient survival at 3 years after conversion were 93.9% and 95.1%, respectively. Compared with baseline, the mean estimated glomerular filtration rate (eGFR) remained very stable at all timepoints (56.7 ± 19.8 vs 58.1 ± 24.6 mL/min per 1.73 m2 at month 36; P = 0.623). Even when patients reinitiating dialysis were counted as eGFR = 0, the mean eGFR was very stable. In fact, a small but significant increase was observed at 36 months versus baseline (+0.1 mL/min per 1.73 m2; P = 0.025). An increase in proteinuria was observed at 36 months versus baseline (+0.11 g/24 h; P < 0.001). Acute rejection rates were low during the study. Conclusions Conversion from BID-TAC to QD-TAC in a large cohort of stable KTR was safe and associated with a very stable renal function after 3 years. Comparative studies are warranted to assess the feasibility of such conversion. PMID:27500226

The cost effectiveness of tacrolimus versus microemulsified cyclosporin: a 10-year model of renal transplantation outcomes.

PubMed

Orme, Michelle E; Jurewicz, Wieslaw A; Kumar, Nagappan; McKechnie, Tracy L

2003-01-01

In 1983, the launch of cyclosporin was a significant clinical advance for organ transplant recipients. Subsequent drug research led to further advances with the introduction of cyclosporin microemulsion (cyclosporin ME) and tacrolimus. This paper presents the results from a long-term model comparing the clinical and economic outcomes associated with cyclosporin ME and tacrolimus immunosuppression for the prevention of graft rejection following renal transplantation. A model was developed to project the costs and outcomes over a 10-year period following transplantation. The model was based on the results of a prospective, randomised study of 179 renal transplantation recipients receiving either cyclosporin ME or tacrolimus, which was conducted by the Welsh Transplantation Research Group (median follow-up: 2.7 years). The short-term costs and outcomes were the averages from the actual head-to-head trial data. From this, the long-term costs and outcomes were extrapolated based on the rate of change in patient and graft survival at 3, 5 and 10 years post transplant, as reported in the 1995 United Kingdom Transplant Support Service Authority Renal Transplant Audit. PERSPECTIVE AND YEAR OF COST DATA: The analysis was conducted from the perspective of a UK transplant unit. Costs were at 1999 prices (pounds sterling 1 = dollars US 1.42 = Euro 1.5) and costs and outcomes were discounted at 6% and 1.5%, respectively. The model estimated that 10 years after transplantation, the proportion of patients surviving was 56% of the cyclosporin ME cohort and 64% of the tacrolimus cohort. The cumulative cost of maintenance therapy at 10 years was pounds sterling 23204 per patient maintained on cyclosporin ME versus pounds sterling 23803 per patient on tacrolimus. The cost per survivor at 10 years was pounds sterling 37000 (tacrolimus) versus pounds sterling 41000 (cyclosporin ME) and the cost per patient with a functioning graft was pounds sterling 39000 versus pounds sterling 45000

Outcome of tacrolimus and vedolizumab after corticosteroid and anti-TNF failure in paediatric severe colitis.

PubMed

Hamel, Blaise; Wu, May; Hamel, Elizabeth O; Bass, Dorsey M; Park, K T

2018-01-01

Severe colitis flare from ulcerative colitis (UC) or Crohn's disease (CD) may be refractory to corticosteroids and antitumour necrosis factor (TNF) agents resulting in high colectomy rates. We aimed to describe the utility of tacrolimus to prevent colectomy during second-line vedolizumab initiation after corticosteroid and anti-TNF treatment failure in paediatric severe colitis. A retrospective cohort analysis was performed between 1 October 2014 and 31 October 2016 at a single tertiary care centre. Inclusion criteria were patients with severe colitis who received tacrolimus before or during vedolizumab induction and previous exposure to anti-TNF therapy with or without corticosteroids. The initiation of tacrolimus was clinician dependent based on an institutional protocol. Twelve patients (10 UC, two CD; median age 16 years; three female) received at least one dose of vedolizumab 10 mg/kg (max of 300 mg) due to anti-TNF therapy failure and persistent flare not responsive to corticosteroids. Of the 12 patients, eight (67%) and four (33%) had failed one or two anti-TNF agents, respectively. Tacrolimus was initiated for acute disease severity during hospitalisation (58%) or ongoing flare during outpatient care (42%). 9 (75%) of 12 patients avoided colectomy or inflammatory bowel disease-related surgery at 24 weeks and eight (68%) continued on vedolizumab maintenance with no adverse events out to 80 weeks. We report real-world data on the outcome of tacrolimus around vedolizumab initiation in paediatric UC or CD after corticosteroid and anti-TNF therapy treatment failure. Our pilot experience indicates a potential benefit of concomitant tacrolimus when initiating vedolizumab therapy.

Tacrolimus Versus Cyclosporine as Primary Immunosuppressant After Renal Transplantation: A Meta-Analysis and Economics Evaluation.

PubMed

Liu, Jin-Yu; You, Ru-Xu; Guo, Min; Zeng, Lu; Zhou, Pu; Zhu, Lan; Xu, Gang; Li, Juan; Liu, Dong

2016-01-01

Tacrolimus and cyclosporine are the major immunosuppressants for renal transplantation. Several studies have compared these 2 drugs, but the outcomes were not consistent. The aim of this study was to evaluate the efficacy, safety, and pharmacoeconomics of cyclosporine and tacrolimus in the treatment of renal transplantation and provide evidence for the selection of essential drugs. Trials were identified through a computerized literature search of PubMed, EMBASE, Cochrane Controlled Trials Register, Cochrane Renal Group Specialized Register of randomized controlled trials, and Chinese Biomedical database. Two independent reviewers assessed trials for eligibility and quality and then extracted data. Data were extracted for patient and graft mortality, acute rejection, and adverse events. Dichotomous outcomes were reported as relative risk with 95% confidence intervals. A decision tree model was populated with data from a literature review and used to estimate costs and quality-adjusted life years gained and incremental cost-effectiveness. Altogether, 6137 patients from 27 randomized controlled trials were included. The results of our analysis were that tacrolimus reduced the risks after renal transplantation of patient mortality, graft loss, acute rejection, and hypercholesterolemia. Nevertheless, tacrolimus increased the risk of new-onset diabetes. Pharmacoeconomic analysis showed that tacrolimus represented a more cost-effective treatment than does cyclosporine for the prevention of adverse events following renal transplant. Tacrolimus is an effective and safe immunosuppressive agent and it may be more cost-effective than cyclosporine for the primary prevention of graft rejection in renal transplant recipients. However, new-onset diabetes should be closely monitored during the medication period.

Comparison between the efficacy of microneedling combined with 5-fluorouracil vs microneedling with tacrolimus in the treatment of vitiligo.

PubMed

Mina, Mary; Elgarhy, Lamia; Al-Saeid, Hanan; Ibrahim, Zeinab

2018-03-12

Several treatment modalities had been used for the treatment of vitiligo, but the optimal treatment has not yet been identified. To study the efficacy of microneedling with 5-flurouracil vs its efficacy with tacrolimus in the treatment of vitiligo. Twenty-five patients with vitiligo were subjected to microneedling of 2 patches of vitiligo with dermapen, then application of 5-fluorouracil to 1 patch and tacrolimus on the other patch. This procedure was repeated every 2 weeks for every patient for maximum 6 months (12 sessions). The patients were followed up for 3 months after the last session. The overall repigmentation was significantly higher in 5-fluorouracil-treated patches compared with tacrolimus. Excellent improvement occurred in 48% of 5- flurouracil-treated patches while only in 16% of tacrolimus-treated patches. In the acral parts, 40% of the patches treated with 5-fluorouracil achieved excellent improvement (repigmentation >75%), while no patch in the acral parts achieved excellent improvement with tacrolimus. However, there was significant difference between the 2 drugs,regarding inflammation, ulceration, and hyperpigmentation which occurred with 5-fluorouracil. Microneedling combined with 5-fluorouracil or tacrolimus is safe and effective treatment of vitiligo. However, 5-fluorouracil achieved a greater percentage of repigmentation than tacrolimus particularly in the acral parts. © 2018 Wiley Periodicals, Inc.

Novel gastroretentive sustained-release tablet of tacrolimus based on self-microemulsifying mixture: in vitro evaluation and in vivo bioavailability test.

PubMed

Wang, Yan-ping; Gan, Yong; Zhang, Xin-xin

2011-10-01

To develop a novel gastroretentive drug delivery system based on a self-microemulsifying (SME) lipid mixture for improving the oral absorption of the immunosuppressant tacrolimus. Liquid SME mixture, composed of Cremophor RH40 and monocaprylin glycerate, was blended with polyethylene oxide, chitosan, polyvinylpyrrolidone and mannitol, and then transformed into tablets via granulation, with ethanol as the wetting agent. The tablets were characterized in respect of swelling, bioadhesive and SME properties. In vitro dissolution was conducted using an HCl buffer at pH 1.2. Oral bioavailability of the tablets was examined in fasted beagle dogs. The tablet could expand to 13.5 mm in diameter and 15 mm in thickness during the initial 20 min of contact with the HCl buffer at pH 1.2. The bioadhesive strength was as high as 0.98±0.06 N/cm(2). The SME gastroretentive sustained-release tablets preserved the SME capability of the liquid SME formations under transmission electron microscope. The drug-release curve was fit to the zero-order release model, which was helpful in reducing fluctuations in blood concentration. Compared with the commercially available capsules of tacrolimus, the relative bioavailability of the SME gastroretentive sustained-release tablets was 553.4%±353.8%. SME gastroretentive sustained-release tablets can enhance the oral bioavailability of tacrolimus with poor solubility and a narrow absorption window.

Pharmacogenetics of tacrolimus and sirolimus in renal transplant patients: from retrospective analyses to prospective studies.

PubMed

Anglicheau, D; Legendre, C; Thervet, E

2007-09-01

The promises of pharmacogenetics are to elucidate the inherited basis of differences between individual responses to drugs in order to identify the right drug and dose for each patient. The recent identification of genetic polymorphisms in drug-metabolizing enzymes and drug transporters led to the hypothesis that genetic factors may be implicated in the interindividual variability of the pharmacokinetic or pharmacodynamic characteristics of immunosuppressive drugs, major side effects, and efficacy. The purpose of this study was to provide a short overview of recent results obtained in the field of pharmacogenetics of tacrolimus and sirolimus, both substrates of the cytochrome P450 3A (CYP3A) enzymes and of the efflux pump P-glycoprotein, the product of the Multidrug Resistance-1 (MDR1) genes. A number of retrospective studies that demonstrated a link between the polymorphisms governing the CYP3A5 protein expression, with more conflicting results with the MDR1 gene polymorphisms, related to the daily dose necessary to achieve adequate blood tacrolimus levels. The CYP3A5 polymorphisms have also been associated with sirolimus pharmacokinetics. One challenge is to investigate the combined effect of a number of different polymorphisms in various genes to define genetic backgrounds with different pharmacokinetic profiles using high throughput technologies. Another challenge is to move toward prospective randomized studies to explore whether a pharmacogenetic approach, taking into account a limited number of polymorphisms prior to drug treatment, could be used on an individual basis to guide initial dosing of a given drug. The last challenge is based on "target" pharmacogenetics to investigate the role of the polymorphisms of other genes implicated in the efficacy and/or safety of the drug.

Topical tacrolimus for parastomal pyoderma gangrenosum: a report of two cases.

PubMed

Altieri, Maria; Vaziri, Khashayar; Orkin, Bruce A

2010-09-01

Pyoderma gangrenosum (PG) is an idiopathic, ulcerative, inflammatory dermatologic condition that occurs in patients with systemic diseases such as inflammatory bowel disease (IBD). This inflammatory skin disorder is presumably caused by an autoimmune mechanism and the diagnosis is one of exclusion. PG is not a common condition but it is thought to account for approximately 50% of chronic parastomal ulcers. Refractory parastomal PG (PPG) occurs in patients with inactive disease or after bowel resection. Multiple medical treatments, ranging from topical agents for mild disease to systemic immunosuppressive therapy for severe disease, have been used with varying rates of success. Using topical tacrolimus, an immunosuppressant that inhibits T-lymphocyte proliferation, and meticulous stoma care can result in successful treatment. Two women (ages 59 and 62 years) with a history of ulcerative colitis and colon resection presented with parastomal ulcers consistent with PPG. The 59-year patient presented with a painful 2 cm x 2 cm parastomal ulcer that improved following daily application of topical tacrolimus 0.1%. The 62-year old woman first was prescribed daily appliance changes and application of topical triamcinolone 0.5% to her 3-cm ulcer. The ulcer increased in size and treatment was changed to daily application of tacrolimus 0.1%. After 2 months and a reduction in ulcer size and severity, the dosage was changed to daily application of tacrolimus 0.03%. Both patients reported resolution of pain and itching, the most common symptoms of PPG, and no adverse effects were observed. The encouraging results observed in these two cases confirm that tacrolimus helps resolve PPG lesions even at concentrations previously thought to be ineffective. Additional studies to help clinicians optimize care of these painful lesions are needed.

Nano-liposomal dry powder inhaler of tacrolimus: Preparation, characterization, and pulmonary pharmacokinetics

PubMed Central

Chougule, Mahavir; Padhi, Bijay; Misra, Ambikanandan

2007-01-01

The studies were undertaken to evaluate feasibility of pulmonary delivery of liposomaly encapsulated tacrolimus dry powder inhaler for prolonged drug retention in lungs as rescue therapy to prevent refractory rejection of lungs after transplantation. Tacrolimus encapsulated liposomes were prepared by thin film evaporation technique and liposomal dispersion was passed through high pressure homogenizer. Tacrolimus nano-liposomes (NLs) were separated by centrifugation and characterized. NLs were dispersed in phosphate buffer saline (PBS) pH 7.4 containing different additives like lactose, sucrose, and trehalose, and L-leucine as antiadherent. The dispersion was spray dried and spray dried powders were characterized. In vitro and in vivo pulmonary deposition was performed using Andersen Cascade Impactor and intratracheal instillation in rats respectively. NLs were found to have average size of 140 nm, 96% ± 1.5% drug entrapment, and zeta potential of 1.107 mV. Trehalose based formulation was found to have low density, good flowability, particle size of 9.46 ± 0.8 μm, maximum fine particle fraction (FPF) of 71.1 ± 2.5%, mean mass aerodynamic diameter (MMAD) 2.2 ± 0.1 μm, and geometric standard deviation (GSD) 1.7 ± 0.2. Developed formulations were found to have in vitro prolonged drug release up to 18 hours, following Higuchi’s Controlled Release model. In vivo studies revealed maximal residence of tacrolimus within lungs of 24 hours, suggesting slow clearance from the lungs. The investigation provides a practical approach for direct delivery of tacrolimus encapsulated in NLs for controlled and prolonged retention at the site of action. It may play a promising role as rescue therapy in reducing the risk of acute rejection and chronic rejection. PMID:18203434

Sirolimus Associated with Tacrolimus at Low Doses in Elderly Kidney Transplant Patients: A Prospective Randomized Controlled Trial.

PubMed

Kojima, Cristiane Akemi; Nga, Hong Si; Takase, Henrique Mochida; Bravin, Ariane Moyses; Martinez Garcia, Márcia de Fátima Faraldo; Garcia, Paula Dalsoglio; Contti, Mariana Moraes; de Andrade, Luis Gustavo Modelli

2018-06-01

There is no consensus on the best immunosuppressive regimen for elderly renal transplant recipients. The objective of this study was to assess cytomegalovirus infection incidence and kidney transplant outcomes in elderly recipients treated with mammalian target of rapamycin inhibitors sirolimus/ tacrolimus at low doses compared with those receiving tacrolimus/mycophenolate sodium. In this single-center prospective randomized study (Trial Registration No. NCT02683291), kidney transplant recipients over 60 years of age were randomly allocated into 2 groups: tacrolimus-sirolimus (21 patients) and tacrolimus-mycophenolate (23 patients). Cytomegalovirus infection rate and patient survival, biopsy-proven acute rejection, and renal function at 12 months were assessed. Cytomegalovirus infection rate was higher in the mycophenolate group (60.9%) than in the sirolimus group (16.7%; P = .004). The rates of biopsy-proven acute rejection, patient survival, graft survival, and estimated glomerular filtration rate over 12 months did not significantly differ between groups. The incidence of cytomegalovirus infection was significantly lower in the sirolimus group. The use of tacrolimus combined with sirolimus in elderly kidney transplant recipients is safe.

Automated processing of whole blood samples for the determination of immunosuppressants by liquid chromatography tandem-mass spectrometry.

PubMed

Vogeser, Michael; Spöhrer, Ute

2006-01-01

Liquid chromatography tandem-mass spectrometry (LC-MS/MS) is an efficient technology for routine determination of immunosuppressants in whole blood; however, time-consuming manual sample preparation remains a significant limitation of this technique. Using a commercially available robotic pipetting system (Tecan Freedom EVO), we developed an automated sample-preparation protocol for quantification of tacrolimus in whole blood by LC-MS/MS. Barcode reading, sample resuspension, transfer of whole blood aliquots into a deep-well plate, addition of internal standard solution, mixing, and protein precipitation by addition of an organic solvent is performed by the robotic system. After centrifugation of the plate, the deproteinized supernatants are submitted to on-line solid phase extraction, using column switching prior to LC-MS/MS analysis. The only manual actions within the entire process are decapping of the tubes, and transfer of the deep-well plate from the robotic system to a centrifuge and finally to the HPLC autosampler. Whole blood pools were used to assess the reproducibility of the entire analytical system for measuring tacrolimus concentrations. A total coefficient of variation of 1.7% was found for the entire automated analytical process (n=40; mean tacrolimus concentration, 5.3 microg/L). Close agreement between tacrolimus results obtained after manual and automated sample preparation was observed. The analytical system described here, comprising automated protein precipitation, on-line solid phase extraction and LC-MS/MS analysis, is convenient and precise, and minimizes hands-on time and the risk of mistakes in the quantification of whole blood immunosuppressant concentrations compared to conventional methods.

Using Supercritical Fluid Technology (SFT) in Preparation of Tacrolimus Solid Dispersions.

PubMed

Obaidat, Rana M; Tashtoush, Bassam M; Awad, Alaa Abu; Al Bustami, Rana T

2017-02-01

Tacrolimus is an immunosuppressant agent that suffers from poor and variable bioavailability. This can be related to limited solubility and dissolution. The main objective of this study is to use SFT to prepare solid dispersions of tacrolimus in order to enhance its dissolution. SFT was selected since it offers several advantages over conventional techniques such as efficiency and stability. Several solid dispersions of tacrolimus were prepared using SFT to enhance its dissolution. The selected polymers included soluplus, PVP, HPMC, and porous chitosan. TPGS was used as a surfactant additive with chitosan, HPMC, and PVP. Soluplus dispersions were used to study the effect of processing parameters (time, temperature, and pressure) on loading efficiency (LE) and dissolution of the preparation. Physicochemical characterization was performed using DSC, X-ray diffraction, FTIR analysis, SEM, and in vitro drug release. Stability testing was evaluated after 3 months for selected dispersions. Significant improvement for the release profile was achieved for the prepared dispersions. Better release achieved in the soluplus dispersions which reached maximum cumulative release equal to 98.76% after 24 h. Drug precipitated in its amorphous form in all prepared dispersions except those prepared from chitosan. All dispersions were physically stable except for PVP preparations that contained TPGS which started to re-crystallize after one month. Prepared dispersions were proved to be affected by supercritical processing parameters. In conclusion, SFT was successfully used to prepare dispersions of tacrolimus that exhibited higher dissolution than raw drug. Dissolution rate and stability are affected by the type of the polymer.

No-load sirolimus with tacrolimus and steroids is safe and effective in renal transplantation.

PubMed

Tellis, V; Schechner, R; Mallis, M; Rosegreen, S; Glicklich, D; Moore, N; Greenstein, S

2005-03-01

Basiliximab (BX) induction, tacrolimus (TAC), and steroids have sharply reduced acute cellular rejection at our institution. However, late graft loss has continued, for which sirolimus (SL) was introduced into the protocol. From July 1, 2001 to December 31, 2003, 152 live donor (LD) renal transplant recipients received TAC (level 15 to 20 ng/mL) and steroids, with BX induction. One hundred twenty-two patients (Group 1) received SL (3 mg/d African-americans; 2 mg/d for others) starting on days 2 and 3. The SL level was adjusted to 8 to 10 ng/d, usually by weeks 3 to 4 posttransplant. The TAC doses were then progressively reduced. Records were reviewed for demographics, immunosuppressive drug levels, serum cholesterol and blood pressure, and complications. Graft and patient survival rates were calculated. Comparison was made to 53 LD recipients transplanted from July 1, 1998, to June 30, 2001 (Group 2) receiving BX, steroids and TAC, without SL. Recipients of deceased donor kidneys were excluded because of variability in kidney quality, ischemic time, and patient management. Demographics were similar between groups: African Americans, 25% to 35%; mean age 36 years; mean HLA mismatch 3.7. Wound problems and infection were minimal in both groups. Mean serum creatinine and cholesterol and systolic and diastolic blood pressure measured periodically up to 1 year were similar, as was the incidence of rejection. In 25% of patients, SL was discontinued. Gradual introduction of SL appears to be associated with minimal wound problems. With more aggressive reduction in TAC, better renal function, and better long-term graft survival may be attainable. We currently lower TAC levels to 5 ng/mL by 3 months.

Immunophenotype of infiltrating cells in protocol renal allograft biopsies from tacrolimus-versus cyclosporine-treated patients.

PubMed

Serón, Daniel; O'Valle, Francisco; Moreso, Francesc; Gomà, Montse; Hueso, Miguel; Grinyó, Josep M; Garcia del Moral, Raimundo

2007-03-15

The prevalence of subclinical rejection is lower in patients receiving tacrolimus than in patients treated with cyclosporine. However, it is not known whether this difference is related to the modulation of a specific cell immunophenotype. We perform a two case-one control study in patients treated with tacrolimus (n=44) or cyclosporine (n=22) with a protocol biopsy performed at 4 to 6 months. Immunophenotype of infiltrating cells was evaluated with monoclonal antibodies directed against CD45 (all leukocytes), CD3 (T lymphocytes), CD68 (monocytes/macrophages), and CD20 (B lymphocytes) and expressed as interstitial positive cells/mm(2). The number of interstitial CD45 (290+/-209 vs. 696+/-560; P<0.01), CD3 (121+/-84 vs. 208+/-104; P<0.01), and CD68 (155+/-232 vs. 242+/-280; P<0.05) but not CD20 (137+/-119 vs. 197+/-154) positive cells was lower in tacrolimus-treated patients. T lymphocytes and macrophages interstitial infiltration was reduced in tacrolimus treated patients evaluated with protocol biopsies in comparison to cyclosporine-treated patients.

Novel gastroretentive sustained-release tablet of tacrolimus based on self-microemulsifying mixture: in vitro evaluation and in vivo bioavailability test

PubMed Central

Wang, Yan-ping; Gan, Yong; Zhang, Xin-xin

2011-01-01

Aim: To develop a novel gastroretentive drug delivery system based on a self-microemulsifying (SME) lipid mixture for improving the oral absorption of the immunosuppressant tacrolimus. Methods: Liquid SME mixture, composed of Cremophor RH40 and monocaprylin glycerate, was blended with polyethylene oxide, chitosan, polyvinylpyrrolidone and mannitol, and then transformed into tablets via granulation, with ethanol as the wetting agent. The tablets were characterized in respect of swelling, bioadhesive and SME properties. In vitro dissolution was conducted using an HCl buffer at pH 1.2. Oral bioavailability of the tablets was examined in fasted beagle dogs. Results: The tablet could expand to 13.5 mm in diameter and 15 mm in thickness during the initial 20 min of contact with the HCl buffer at pH 1.2. The bioadhesive strength was as high as 0.98±0.06 N/cm2. The SME gastroretentive sustained-release tablets preserved the SME capability of the liquid SME formations under transmission electron microscope. The drug-release curve was fit to the zero-order release model, which was helpful in reducing fluctuations in blood concentration. Compared with the commercially available capsules of tacrolimus, the relative bioavailability of the SME gastroretentive sustained-release tablets was 553.4%±353.8%. Conclusion: SME gastroretentive sustained-release tablets can enhance the oral bioavailability of tacrolimus with poor solubility and a narrow absorption window. PMID:21927013

Tacrolimus potently inhibits human osteoclastogenesis induced by IL-17 from human monocytes alone and suppresses human Th17 differentiation.

PubMed

Yago, Toru; Nanke, Yuki; Kawamoto, Manabu; Yamanaka, Hisashi; Kotake, Shigeru

2012-08-01

Tacrolimus (FK506, Prograf®) is an orally available, T cell specific and anti-inflammatory agent that has been proposed as a therapeutic drug in rheumatoid arthritis (RA) patients. It has been known that T cells have a critical role in the pathogenesis of RA. Recent studies suggest that Th17 cells, which mainly produce IL-17, are involved in many autoimmune inflammatory disease including RA. The present study was undertaken to assess the effect of tacrolimus on IL-17-induced human osteoclastogenesis and human Th17 differentiation. Human CD14(+) monocytes were cultured in the presence of macrophage-colony stimulating factor (M-CSF) and IL-17. From day 4, tacrolimus was added to these cultures. Osteoclasts were immunohistologically stained for vitronectin receptor 10days later. IL-17 production from activated T cells stimulated with IL-23 was measured by enzyme-linked immunosorbent assay (ELISA). Th17 differentiation from naïve T cells was assayed by flow cytometry. Tacrolimus potently inhibited IL-17-induced osteoclastogenesis from human monocytes and osteoclast activation. Addition of tacrolimus also reduced production of IL-17 in human activated T cells stimulated with IL-23. Interestingly, the population of human IL-17(+)IFN-γ(-) CD4 T cells or IL-17(+)TNF-α(+) CD4 T cells were decreased by adding of tacrolimus. The present study demonstrates that the inhibitory effect of tacrolimus on IL-17-induced osteoclastogenesis from human monocytes. Tacrolimus also inhibited expression of IL-17 or TNF-α by reducing the proportion of Th17, suggesting that therapeutic effect on Th17-associated disease such as RA, inflammatory bowel disease, multiple sclerosis, psoriasis, or allograft rejection. Copyright © 2012 Elsevier Ltd. All rights reserved.

Stability of tacrolimus injection diluted in 0.9% sodium chloride injection and stored in Excel bags.

PubMed

Myers, Alan L; Zhang, Yanping; Kawedia, Jitesh D; Shank, Brandon R; Deaver, Melissa A; Kramer, Mark A

2016-12-15

The chemical stability and physical compatibility of tacrolimus i.v. infusion solutions prepared in Excel bags and stored at 23 or 4 °C for up to nine days were studied. Tacrolimus admixtures (2, 4, and 8 μg/mL) were prepared in Excel bags using 0.9% sodium chloride injection and stored at 23 °C without protection from light or at 4 °C in the dark. Test samples were withdrawn from triplicate bag solutions immediately after preparation and at predetermined time intervals (1, 3, 5, 7, and 9 days). Chemical stability was assessed by measuring tacrolimus concentrations using a validated stability-indicating high-performance liquid chromatography assay. The physical stability of the admixtures was assessed by visual examination and by measuring turbidity, particle size, and drug content. All test solutions stored at 23 or 4 °C had a no greater than 6% loss of the initial tacrolimus concentration throughout the nine-day study period. All test samples of tacrolimus admixtures, under both storage conditions, were without precipitation and remained clear initially and throughout the nine-day observation period. Changes in turbidities were minor; measured particulates remained few in number in all samples throughout the study. Extemporaneously prepared infusion solutions of tacrolimus 2, 4, and 8 μg/mL in 0.9% sodium chloride injection in Excel bags were chemically and physically stable for at least nine days when stored at room temperature (23 °C) without protection from light and when stored in a refrigerator (4 °C) in the dark. Copyright © 2016 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

Tacrolimus and mycophenolate mofetil after nonmyeloablative matched-sibling donor allogeneic stem-cell transplantations conditioned with fludarabine and low-dose total body irradiation.

PubMed

Nieto, Yago; Patton, Nigel; Hawkins, Timothy; Spearing, Ruth; Bearman, Scott I; Jones, Roy B; Shpall, Elizabeth J; Rabinovitch, Rachel; Zeng, Chan; Barón, Anna; McSweeney, Peter A

2006-02-01

We evaluated tacrolimus/mycophenolate mofetil (MMF) for graft-versus-host disease (GVHD) prophylaxis after a nonmyeloablative stem cell transplantation (NST) from a matched sibling donor (MSD). Thirty-two patients (median age, 57 years) with advanced hematologic malignancies, who were poor candidates for a conventional myeloablative transplantation, received fludarabine (30 mg/m(2), day -4 to day -2), total-body irradiation (TBI) (200 cGy, day 0), infusion of donor peripheral blood progenitor cells (day 0), oral tacrolimus 0.06 mg/kg twice daily (from day 3), and oral MMF at 15 mg/kg twice daily (days 0-+27). Tacrolimus was tapered from day +100 to day +180 in those patients with indolent malignancies (n = 25), and from day +35 to day +56 in those with aggressive tumors (n = 7). Regimen toxicities and myelosuppression were mild, allowing 75% of patients to have entirely outpatient transplantations. One patient (3%) experienced a nonfatal graft rejection. Rates of grades II-IV and III-IV acute GVHD were 15.6% and 3%, respectively. Acute GVHD was diagnosed at median day +78 (range, days +31-+84). Extensive chronic GVHD was observed in 10 of 24 evaluable patients (41.6%) at a median onset of day +198 (range, days +128-+277), either spontaneously (n = 5) or elicited after tumor progression (n = 5). Five patients experienced transplantation-related mortality (TRM) (15.6%) from either acute GVHD-related multiorgan failure (MOF) (n = 3) or infectious complications (n = 2). At median follow-up of 19 months (range, 2-41 months), the overall survival, progression-free survival, and disease-free survival rates are 62.5%, 50%, and 40%, respectively. In conclusion, the use of tacrolimus/MMF after MSD NST is associated with encouraging rates of GVHD control.

Albuminuria after renal transplantation: maintenance with sirolimus/low-dose tacrolimus vs. mycophenolate mofetil/high-dose tacrolimus.

PubMed

Miles, Clifford D; Skorupa, Jill Y; Sandoz, John P; Rigley, Theodore H; Nielsen, Kathleen J; Stevens, R Brian

2011-01-01

Maintenance immunosuppression with sirolimus (SRL) in renal transplantation has been associated with proteinuria. We report long-term outcomes of kidney transplant recipients maintained on steroid-free regimens, either SRL with low-dose tacrolimus (SRL/L-Tac) or mycophenolate mofetil (MMF) with high-dose tacrolimus (MMF/H-Tac). We conducted a case-matched study of 50 patients receiving MMF/H-Tac, matched 1:2 with 100 patients maintained on SRL/L-Tac. All patients were induced with rabbit antithymocyte globulin followed by early steroid withdrawal. Comparisons were made of patient and graft survival, graft function, acute rejection, and albuminuria. There were no significant differences between the SRL/L-Tac and MMF/H-Tac groups for patient survival, graft survival, occurrence of acute rejection, or graft function. There was no difference in the proportion of patients with albumin/creatinine ratio (ACR) ≥300 μg/mg (19% vs. 20%), but more patients in the SRL group were receiving renin-angiotensin system blocking agents (72% vs. 53%, p = 0.04). Only flushing the donor kidney with histidine-tryptophan-ketoglutarate solution (vs. UW solution) was predictive of albuminuria. Long-term outcomes are similar at our center for kidney transplant patients receiving either SRL/L-Tac or MMF/H-Tac. Although the occurrence of albuminuria was not different, significantly more SRL-treated patients were receiving antiproteinuric medications. © 2010 John Wiley & Sons A/S.

Evaluating the efficacy, safety and evolution of renal function with early initiation of everolimus-facilitated tacrolimus reduction in de novo liver transplant recipients: Study protocol for a randomized controlled trial.

PubMed

Nashan, Bjorn; Schemmer, Peter; Braun, Felix; Dworak, Markus; Wimmer, Peter; Schlitt, Hans

2015-03-26

Introduction of calcineurin inhibitors had led to improved survival rates in liver transplant recipients. However, long-term use of calcineurin inhibitors is associated with a higher risk of chronic renal failure, neurotoxicity, de novo malignancies, recurrence of hepatitis C viral (HCV) infection and hepatocellular carcinoma. Several studies have shown that everolimus has the potential to provide protection against viral replication, malignancy, and progression of fibrosis, as well as preventing nephrotoxicity by facilitating calcineurin inhibitor reduction without compromising efficacy. The Hephaistos study evaluates the beneficial effects of early initiation of everolimus in de novo liver transplant recipients. Hephaistos is an ongoing 12-month, multi-center, open-label, controlled study aiming to enroll 330 de novo liver transplant recipients from 15 centers across Germany. Patients are randomized in a 1:1 ratio (7-21 days post-transplantation) to receive everolimus (trough levels 3-8 ng/mL) with reduced tacrolimus (trough levels <5 ng/mL), or standard tacrolimus (trough levels 6-10 ng/mL) after entering a run-in period (3-5 days post-transplantation). In the run-in period, patients are treated with induction therapy, mycophenolate mofetil, tacrolimus, and corticosteroids according to local practice. Randomization is stratified by HCV status and model of end-stage liver disease scores at transplantation. The primary objective of the study is to exhibit superior renal function (estimated glomerular filtration rate assessed by the Modification of Diet in Renal Disease (MDRD)-4 formula) with everolimus plus reduced tacrolimus compared to standard tacrolimus at Month 12. Other objectives are: to assess the incidence of treated biopsy-proven acute rejection, graft loss, or death; the incidences of components of the composite efficacy endpoint; renal function via estimated glomerular filtration rate using various formulae (MDRD-4, Nankivell, Cockcroft

Lead levels - blood

MedlinePlus

Blood lead levels ... A blood sample is needed. Most of the time blood is drawn from a vein located on the inside ... may be used to puncture the skin. The blood collects in a small glass tube called a ...

Artificial neural network model for predicting the bioavailability of tacrolimus in patients with renal transplantation

PubMed Central

Thishya, Kalluri; Vattam, Kiran Kumar; Naushad, Shaik Mohammad; Raju, Shree Bhushan

2018-01-01

The objective of the current study was to explore the role of ABCB1 and CYP3A5 genetic polymorphisms in predicting the bioavailability of tacrolimus and the risk for post-transplant diabetes. Artificial neural network (ANN) and logistic regression (LR) models were used to predict the bioavailability of tacrolimus and risk for post-transplant diabetes, respectively. The five-fold cross-validation of ANN model showed good correlation with the experimental data of bioavailability (r2 = 0.93–0.96). Younger age, male gender, optimal body mass index were shown to exhibit lower bioavailability of tacrolimus. ABCB1 1236 C>T and 2677G>T/A showed inverse association while CYP3A5*3 showed a positive association with the bioavailability of tacrolimus. Gender bias was observed in the association with ABCB1 3435 C>T polymorphism. CYP3A5*3 was shown to interact synergistically in increasing the bioavailability in combination with ABCB1 1236 TT or 2677GG genotypes. LR model showed an independent association of ABCB1 2677 G>T/A with post transplant diabetes (OR: 4.83, 95% CI: 1.22–19.03). Multifactor dimensionality reduction analysis (MDR) revealed that synergistic interactions between CYP3A5*3 and ABCB1 2677 G>T/A as the determinants of risk for post-transplant diabetes. To conclude, the ANN and MDR models explore both individual and synergistic effects of variables in modulating the bioavailability of tacrolimus and risk for post-transplant diabetes. PMID:29621269

Distinct deleterious effects of cyclosporine and tacrolimus and combined tacrolimus-sirolimus on endothelial cells: protective effect of defibrotide.

PubMed

Carmona, Alba; Díaz-Ricart, Maribel; Palomo, Marta; Molina, Patricia; Pino, Marc; Rovira, Montserrat; Escolar, Ginés; Carreras, Enric

2013-10-01

Endothelial dysfunction seems to be a key factor in the development of several complications observed early after hematopoietic stem cell transplantation (HSCT). The conditioning regimen and many other factors associated with the procedure are responsible for this endothelial damage. The effects of immunosuppressive agents on endothelial function have not been explored in detail. We evaluated the effects of 3 drugs commonly used in HSCT: 2 calcineurin inhibitors, cyclosporine A (CSA) and tacrolimus (TAC), and an inhibitor of mTOR, sirolimus (SIR). We also evaluated the effect of the combination of TAC and SIR (TAC+SIR), which is used increasingly in clinical practice. Microvascular endothelial cells (HMEC-1) were exposed to these drugs to evaluate changes in (1) intercellular adhesion molecule (ICAM)-1 expression on the cell surface, assessed by immunofluorescence labeling and expressed as the mean gray value (MGV); (2) reactivity of the extracellular matrix (ECM) toward platelets, upon exposure of the ECM to circulating blood; and (3) whole-blood clot formation, assessed by thromboelastometry. Studies were conducted in the absence and presence of defibrotide (DF) to assess its possible protective effect. The exposure of HMEC-1 to CSA and TAC+SIR significantly increased the expression of ICAM-1 (157.5 ± 11.6 and 153.4 ± 9.5 MGV, respectively, versus 105.7 ± 6.5 MGV in controls [both P < .05]). TAC applied alone increased ICAM-1 slightly (120.3 ± 8.2 MGV), and SIR had no effect (108.9 ± 7.4 MGV). ECM reactivity increased significantly only in response to CSA (surface covered by platelets of 41.2% ± 5.4% versus 30.1% ± 2.0%, P < .05). DF attenuated all these changes. No significant changes in the viscoelastic properties of clot formation were observed in any condition with blood samples incubated in vitro. In conclusion, CSA and TAC+SIR had a proinflammatory effect, but only CSA exhibited an additional prothrombotic effect. Interestingly, DF exerted clear

Adult Heart Transplantation Under Tacrolimus (FK506) Immunosuppression: Histopathologic Observations and Comparison to a Cyclosporine-based Regimen with Lympholytic (ATG) Induction

PubMed Central

Tsamandas, Athanassios C.; Pham, Si M.; Seaberg, Eric C.; Pappo, Orit; Kormos, Robert L.; Kawai, Akihiko; Griffith, Bartley P.; Zeevi, Adriana; Duquesnoy, Rene; Fung, John J.; Starzl, Thomas E.; Demetris, Anthony J.

2011-01-01

Background Tacrolimus (FK506) is an effective immunosuppressant for human heart transplantation, but information about its effects on cardiac allograft and nonallograft kidney and liver histopathologic study is limited. Methods We therefore reviewed 1145 endomyocardial biopsy specimens and eight autopsy results from 80 heart transplant recipients who received tacrolimus as baseline immunosuppression. These were compared with 619 endomyocardial biopsy specimens and four autopsy results from 51 patients treated with cyclosporine-based immunosuppression with lympholytic induction (CLI) by use of rabbit anti-thymocyte globulin. Twenty-one histologic features including the International Society for Heart and Lung Transplantation histopathologic grade were retrospectively assessed without knowledge of the treatment regimen. The lymphocyte growth index on biopsy specimens obtained from these patients was also compared. Results In general, there were no qualitative differences in the histopathologic appearance of various allograft syndromes between tacrolimus- and CLI-treated patients. Thus histopathologic criteria used to diagnose various graft syndromes are applicable under tacrolimus immunosuppression. However, early (between 10 and 30 days) after transplantation, biopsy specimens from patients treated with tacrolimus showed a significantly higher percentage of inflamed fragments (p = 0.02), the inflammation tended to be more severe (p = 0.09), and the rejection grade tended to be slightly higher (p = 0.08). In contrast, during the late transplantation period (275 to 548 days), biopsy specimens from patients treated with CLI showed a significantly higher percentage of inflamed fragments (p = 0.03), more severe inflammation (p = 0.03), higher rejection grades (p = 0.01), and a higher frequency of Quilty lesions (p = 0.05). Although overall freedom from any grade 3A or higher rejection was greater in the CLI-treated arm, tacrolimus was successfully used to treat

Successful treatment of eosinophilic pustular folliculitis with topical tacrolimus 0.1 percent ointment.

PubMed

Ng, Shanna Shan-Yi; Tay, Yong-Kwang

2012-02-15

Classic eosinophilic pustular folliculitis (EPF), otherwise known as Ofugi disease, is a rare condition commonly treated with topical glucocorticosteroids. If this fails, oral indomethacin is frequently the next line. Because the condition is recurrent, the use of long term steroids may cause side effects such as skin atrophy, hypertrichosis, and dyspigmentation. Topical tacrolimus is an immunosuppressant that is generally used as a steroid-sparing agent in atopic dermatitis. We report a case of classic EPF, which was recurrent over 5 years that had failed topical glucocorticosteroids but was successfully treated with topical tacrolimus 0.1 percent ointment.

Effects of topical corticosteroid and tacrolimus on ceramides and irritancy to sodium lauryl sulphate in healthy skin.

PubMed

Jungersted, Jakob Mutanu; Høgh, Julie K; Hellegren, Lars I; Jemec, Gregor B E; Agner, Tove

2011-05-01

The skin barrier, located in the stratum corneum, is influenced mainly by the lipid and protein composition of this layer. In eczematous diseases impairment of the skin barrier is thought to be of prime importance. Topical anti-inflammatory drugs and emollients are the most widely used eczema treatments. The aim of this study was to examine the effects of topically applied corticosteroid, tacrolimus and emollient on stratum corneum lipids and barrier parameters. Nineteen healthy volunteers participated in the study. Both forearms of the subjects were divided into four areas, which were treated twice daily for one week with betamethasone, tacrolimus, emollient, or left untreated, respectively. After one week each area was challenged with a 24 h sodium lauryl sulphate patch test. The lipids were collected using the cyanoacrylate method and evaluated by high performance thin layer chromatography. For evaluation of the skin barrier, transepidermal water loss, erythema and electrical capacitance were measured. The ceramide/cholesterol ratio was increased in betamethasone- (p = 0.008) and tacrolimus-treated (p = 0.025) skin compared with emollient-treated skin. No differences in ceramide subgroups were found between treatment regimes. Pretreatment with betamethasone (p = 0.01) or with tacrolimus (p = 0.001) causes a decreased inflammatory response to sodium lauryl sulphate compared with emollient. In conclusion, treatment with betamethasone and tacrolimus has a positive effect on the ceramide/cholesterol ratio and susceptibility to irritant reaction compared with an emollient.

Safety and efficacy of the switch to generic mycophenolate mofetil and tacrolimus in heart transplant patients.

PubMed

Söderlund, Carl; Rådegran, Göran

2015-07-01

Generic immunosuppressants may offer economic advantages, but their use is still controversial. At our center, 55 heart transplant patients were switched from CellCept(®) to Myfenax Teva(®) (MT) (n = 51, 18% female, 8.1 ± 6.6 yr post-transplantation) and/or Prograf(®) to Tacrolimus Sandoz(®) (TS) (n = 17, 41% female, 6.6 ± 5.8 yr post-transplantation). We conducted an acute monitoring and a retrospective follow-up with regard to safety and efficacy. Acute cellular rejections (ACRs) on endomyocardial biopsies (EMBs) four wk after the MT switch were specifically compared to a matched retrospective control group. Tacrolimus C0 levels (TS switch) as well as hemoglobin, leukocytes, and thrombocytes (MT switch) did not change (p = NS) during the three wk after each respective switch (8.7 ± 2.9 vs. 8.4 ± 1.9 μg/L, 129.1 ± 12.6 vs. 130.1 ± 12.8 g/L, 6.3 vs. 6.2 × 10(9) /L, and 217.4 ± 56.6 vs. 219.3 ± 61.8 × 10(9) /L, respectively). 0% of the EMBs in the MT switch vs. 3% of the EMBs in the control group showed ACR>grade 1R (p = NS). After six months, survival was 96% (MT switch) and 100% (TS switch), and the frequency of severe ACR was low. Safety parameters measured at the next annual follow-up were also stable following each switch. Switching to MT and/or TS several years after heart transplantation appeared safe in the short-term perspective, showing no detectable changes in tacrolimus C0 levels, safety or efficacy, during an average follow-up of six months. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Conservation of small-airway function by tacrolimus/cyclosporine conversion in the management of bronchiolitis obliterans following lung transplantation.

PubMed

Revell, M P; Lewis, M E; Llewellyn-Jones, C G; Wilson, I C; Bonser, R S

2000-12-01

We studied serial lung function in 11 patients with bronchiolitis obliterans syndrome who were treated with tacrolimus conversion following lung or heart-lung transplantation. Our results show that tacrolimus conversion slows the decline of lung function in bronchiolitis obliterans syndrome. The attenuation continues for at least 1 year following conversion.

Solid state compatibility study and characterization of a novel degradation product of tacrolimus in formulation.

PubMed

Rozman Peterka, Tanja; Grahek, Rok; Hren, Jure; Bastarda, Andrej; Bergles, Jure; Urleb, Uroš

2015-06-10

Tacrolimus is macrolide drug that is widely used as a potent immunosuppressant. In the present work compatibility testing was conducted on physical mixtures of tacrolimus with excipients and on compatibility mixtures prepared by the simulation of manufacturing process used for the final drug product preparation. Increase in one major degradation product was detected in the presence of magnesium stearate based upon UHPLC analysis. The degradation product was isolated by preparative HPLC and its structure was elucidated by NMR and MS studies. Mechanism of the formation of this degradation product is proposed based on complementary degradation studies in a solution and structural elucidation data. The structure was proven to be alpha-hydroxy acid which is formed from the parent tacrolimus molecule through a benzilic acid type rearrangement reaction in the presence of divalent metallic cations. Degradation is facilitated at higher pH values. Copyright © 2015 Elsevier B.V. All rights reserved.

Preliminary study on the treatment of vitiligo with carbon dioxide fractional laser together with tacrolimus.

PubMed

Chen, Wei; Zhou, Yuan; Huang, Fei-Ran; Luo, Dan; Wang, Da-Guang

2018-04-10

Tacrolimus is a conventional medication for the treatment of vitiligo, but the effect of a single medication is limited. This paper aims at observing the effects, adverse responses, and repigmentation results of the joint treatment of vitiligo by Carbon dioxide (CO 2 ) fractional laser together with tacrolimus. Forty-five patients with vitiligo were randomly divided into two groups: treatment (T) group and control (C) group, and each group was further divided into three subgroups (face, torso and limbs, and hand and foot) according to the location of the skin defect. Both groups used topical 0.1% tacrolimus cream, but the T group was given one CO 2 fractional laser treatment each month. We observed the clinical efficacy, adverse responses, and repigmentation results after 6 months. Compared to the C group, the T group showed better improvement in both objective and subjective assessments. When the treatment time was increased, the efficacy was also improved, and the repigmentation in the T group occured in three ways: perifollicular repigmentation, marginal repigmentation and diffuse repigmentation. There were three cases of isomorphic responses (2 cases in the rapid progression stage, one case in the progression stage), and 1 case formed scarring on the neck in the T group. The treatment of vitiligo by CO 2 fractional laser together with tacrolimus is significantly effective and is most suitable for patients in the progression stage. Patients in the rapid progression stage should use this approach with caution, and its efficacy was limited for patients in the stable stage. An extended course of treatment is helpful for the repigmentation of white patches. All three forms of repigmentation can occur in the joint treatment of vitiligo by CO 2 fractional laser together with tacrolimus. Lasers Surg. Med. © 2018 Wiley Periodicals, Inc. © 2018 Wiley Periodicals, Inc.

Central pontine myelinolysis (CPM) associated with tacrolimus (FK506) after liver transplantation.

PubMed

Fukazawa, Kyota; Nishida, Seigo; Aguina, Luz; Pretto, Ernesto

2011-01-01

Central pontine myelinolysis (CPM) is the most detrimental neurologic complication after liver transplantation. The incidence of CPM after liver transplantation ascends to 17%. Although the precise etiology and pathogenesis of CPM is largely unknown, a growing literature implicates a possible role of immunosuppressive agents, such as Cyclosporine (incidence 30%) on its development. Other immunosuppressive agents also can cause CPM but the frequency of these cases is less compared to Cyclosporine. There is only one case report for Tacrolimus (FK506)-associated speech disorder, which might be an atypical presentation of CPM, and no case reports for Rapamycin. We present a case of Tacrolimus induced CPM. A 62-year-old woman who underwent liver transplantation developed clinical symptoms with radiologic evidence consistent with CPM 7 days after liver transplant. Since the electrolytes in this patient remained normal from her admission, the hypothesis of inmunossupressor neurotoxicity was established and the therapy was switched, resulting in an evident clinical and radiological improvement of her condition in the following days. Five months later, the patient's only neurological deficit was slight dysarthria and a follow-up MRI showed no abnormalities. This case provides evidence of Tacrolimus-associated CPM after transplantation, which presented with a classic "lock-in syndrome" with radiographic confirmation.

Novel Once-Daily Extended-Release Tacrolimus Versus Twice-Daily Tacrolimus in De Novo Kidney Transplant Recipients: Two-Year Results of Phase 3, Double-Blind, Randomized Trial.

PubMed

Rostaing, Lionel; Bunnapradist, Suphamai; Grinyó, Josep M; Ciechanowski, Kazimierz; Denny, Jason E; Silva, Helio Tedesco; Budde, Klemens

2016-04-01

1-year data from this trial showed the noninferiority of a novel once-daily extended-release tacrolimus (LCPT; Envarsus XR) to immediate-release tacrolimus (IR-Tac) twice daily after kidney transplantation. Final 24-month analysis of a 2-armed, parallel-group, randomized, double-blind, double-dummy, multicenter, phase 3 trial. 543 de novo kidney recipients randomly assigned to LCPT (n=268) or IR-Tac (n=275); 507 (93.4%) completed the 24-month study. LCPT tablets once daily at 0.17 mg/kg/d or IR-Tac twice daily at 0.1 mg/kg/d; subsequent doses were adjusted to maintain target trough ranges (first 30 days, 6-11 ng/mL; thereafter, 4-11 ng/mL). The intervention was 24 months; the study was double blinded for the entirety. Treatment failure (death, transplant failure, biopsy-proven acute rejection, or loss to follow up) within 24 months. Safety end points included adverse events, serious adverse events, new-onset diabetes, kidney function, opportunistic infections, and malignancies. Pharmacokinetic measures included total daily dose (TDD) of study drugs and tacrolimus trough levels. 24-month treatment failure was LCPT, 23.1%; IR-Tac, 27.3% (treatment difference, -4.14% [95% CI, -11.38% to +3.17%], well below the +10% noninferiority criterion defined for the primary 12-month end point). Subgroup analyses showed fewer treatment failures for LCPT versus IR-Tac among black, older, and female recipients. Safety was similar between groups. From month 1, TDD was lower for LCPT; the difference increased over time. At month 24, mean TDD for LCPT was 24% lower than for the IR-Tac group (P<0.001), but troughs were similar (means at 24 months: LCPT, 5.47 ± 0.17 ng/mL; IR-Tac, 5.8 ± 0.30 ng/mL; P=0.4). Trial participant eligibility criteria may limit the generalizability of results to the global population of de novo kidney transplant recipients. Results suggest that once-daily LCPT in de novo kidney transplantation has comparable efficacy and safety profile to that of IR

Influence of ABCB1 polymorphisms and haplotypes on tacrolimus nephrotoxicity and dosage requirements in children with liver transplant

PubMed Central

Hawwa, Ahmed F; McKiernan, Patrick J; Shields, Michael; Millership, Jeff S; Collier, Paul S; McElnay, James C

2009-01-01

AIMS The aim of this study was to investigate the influence of genetic polymorphisms in ABCB1 on the incidence of nephrotoxicity and tacrolimus dosage-requirements in paediatric patients following liver transplantation. METHODS Fifty-one paediatric liver transplant recipients receiving tacrolimus were genotyped for ABCB1 C1236>T, G2677>T and C3435>T polymorphisms. Dose-adjusted tacrolimus trough concentrations and estimated glomerular filtration rates (EGFR) indicative of renal toxicity were determined and correlated with the corresponding genotypes. RESULTS The present study revealed a higher incidence of the ABCB1 variant-alleles examined among patients with renal dysfunction (≥30% reduction in EGFR) at 6 months post-transplantation (1236T allele: 63.3% vs 37.5% in controls, P= 0.019; 2677T allele: 63.3% vs. 35.9%, p = 0.012; 3435T allele: 60% vs. 39.1%, P= 0.057). Carriers of the G2677->T variant allele also had a significant reduction (%) in EGFR at 12 months post-transplant (mean difference = 22.6%; P= 0.031). Haplotype analysis showed a significant association between T-T-T haplotypes and an increased incidence of nephrotoxicity at 6 months post-transplantation (haplotype-frequency = 52.9% in nephrotoxic patients vs 29.4% in controls; P= 0.029). Furthermore, G2677->T and C3435->T polymorphisms and T-T-T haplotypes were significantly correlated with higher tacrolimus dose-adjusted pre-dose concentrations at various time points examined long after drug initiation. CONCLUSIONS These findings suggest that ABCB1 polymorphisms in the native intestine significantly influence tacrolimus dosage-requirement in the stable phase after transplantation. In addition, ABCB1 polymorphisms in paediatric liver transplant recipients may predispose them to nephrotoxicity over the first year post-transplantation. Genotyping future transplant recipients for ABCB1 polymorphisms, therefore, could have the potential to individualize better tacrolimus immunosuppressive therapy and

Progressive necrotic encephalopathy following tacrolimus therapy for liver transplantation.

PubMed

Aridon, Paolo; Ragonese, Paolo; Di Benedetto, Norma; Grasso, Giovanni; Conaldi, Pier Giulio; D'Amelio, Marco; Savettieri, Giovanni

2009-12-01

Previously described neurologic damage induced by immunosuppressive treatments includes transient or reversible central nervous system involvement. We describe a 57-year-old man who underwent liver transplantation and was started on immunosuppressive therapy with tacrolimus (FK506). Six months later, he started complaining of a progressive motor and sensory impairment of the left side, together with cognitive impairment. Brain MRI showed an enlarging lesion of the white matter with peripheral contrast enhancement. PET study indicated severe hypometabolism in the right hemisphere and spectroscopic MRI showed a peak of choline and relative reduction of other metabolites. Findings of CSF examinations and cultures, serology, and molecular techniques were normal. Tacrolimus treatment was stopped. A cerebral biopsy of the lesion showed a sub acute necrotizing process. In the following months, cognitive status of the patient tended to improve although he remained hemiplegic, while serial MRI confirmed the tendency to the recovery of the lesion that was still present 1 year after. The present observation describes a progressive encephalopathy associated with immune suppression with an unusual feature and permanent brain damage.

Tacrolimus loaded biocompatible lecithin-based microemulsions with improved skin penetration: Structure characterization and in vitro/in vivo performances.

PubMed

Savić, Vedrana; Todosijević, Marija; Ilić, Tanja; Lukić, Milica; Mitsou, Evgenia; Papadimitriou, Vassiliki; Avramiotis, Spyridon; Marković, Bojan; Cekić, Nebojša; Savić, Snežana

2017-08-30

In order to improve skin penetration of tacrolimus we aimed to develop potentially non-irritant, lecithin-based microemulsions containing ethanol, isopropanol and/or propylene glycol as cosurfactants, varying caprylic/capric triglycerides and propylene glycol monocaprylate as oil phase. The influence of excipients on the size of microemulsion region in pseudo-ternary phase diagrams and their ability to form different types of microemulsions was evaluated. The comprehensive physicochemical characterization of microemulsions and the evaluation of their structure was performed, while the localization of tacrolimus in microemulsions was further investigated using electron paramagnetic resonance spectroscopy. Moreover, stability studies proved no change in tacrolimus content during one year of storage at room temperature. In addition, in vivo skin performance indicated no skin irritation potential of blank microemulsions, whereas in vitro release testing using Franz diffusion cells showed superior release rate of tacrolimus from microemulsions (0.98±0.10 and 0.92±0.11μg/cm 2 /h for two bicontinuous and 1.00±0.24μg/cm 2 /h for oil-in-water microemulsion) compared to referent Protopic ointment (0.15±0.08μg/cm 2 /h). Furthermore, ex vivo penetration assessed through porcine ear skin using tape stripping, confirmed superiority of two microemulsions related to the reference, implying developed microemulsions as promising carriers for dermal delivery of tacrolimus. Copyright © 2017 Elsevier B.V. All rights reserved.

MDR1 haplotypes derived from exons 21 and 26 do not affect the steady-state pharmacokinetics of tacrolimus in renal transplant patients.

PubMed

Mai, Ingrid; Perloff, Elke S; Bauer, Steffen; Goldammer, Mark; Johne, Andreas; Filler, Guido; Budde, Klemens; Roots, Ivar

2004-11-01

This retrospective study investigated the influence of MDR1 haplotypes derived from the polymorphisms 2677G > T (exon 21) and 3435C > T (exon 26) on the pharmacokinetics of the immunosuppressant drug tacrolimus in 73 renal transplant patients. Based on both variants of SNPs 2677 and 3435, four different haplotypes and eight different genotypes were identified in the study sample. Tacrolimus trough concentrations (C(0)) were compared between different SNP variants and genotypes, as well as between carriers and noncarriers of each haplotype. Additionally, CYP3A5 genotype (6956G > A) was determined. No significant differences were observed between groups. Differences in mean tacrolimus C(0) values between carriers and noncarriers of each haplotype ranged from -0.04 microg/litre (95% confidence interval: -0.53 to 0.60) to -23 microg/litre (-1.07 to 1.53). No association was found between CYP3A5*1/*3 genotype and tacrolimus Co concentractions. MDR1 haplotypes derived from the SNPs 2677G > T (exon 21) and 3435C > T (exon 26) do not influence the pharmacokinetics of tacrolimus in renal transplant patients.

EFFICACY OF TACROLIMUS FOR INDUCTION OF REMISSION IN PATIENTS WITH MODERATE-TO-SEVERE ULCERATIVE COLITIS: A SYSTEMATIC REVIEW AND META-ANALYSIS.

PubMed

Lasa, Juan; Olivera, Pablo

2017-01-01

There is evidence that shows that calcineurin inhibitors may be useful for the treatment of severe ulcerative colitis. However, evidence regarding the efficacy of tacrolimus for remission induction in this setting is scarce. To develop a systematic review on the existing evidence regarding the clinical efficacy of tacrolimus for the induction of remission in patients with moderate-to-severe ulcerative colitis. A literature search was undertaken from 1966 to August 2016 using MEDLINE, Embase, LILACS and the Cochrane Library. The following MeSH terms were used: "Inflammatory Bowel Diseases" or "Ulcerative Colitis" and "Calcineurin Inhibitors" or "Tacrolimus" or "FK506". Studies performed in adult ulcerative colitis patients that evaluated the clinical efficacy of tacrolimus for the induction of remission were considered for revision. A meta-analysis was performed with those included studies that were also placebo-controlled and randomized. Clinical response as well as clinical remission and mucosal healing were evaluated. Overall, 755 references were identified, from which 22 studies were finally included. Only two of them were randomized, placebo-controlled trials. A total of 172 patients were evaluated. A significantly lower risk of failure in clinical response was found for tacrolimus versus placebo [RR 0.58 (0.45-0.73)]; moreover, a lower risk of failure in the induction of remission was also found versus placebo [RR 0.91 (0.82-1)]. Tacrolimus seems to be a valid therapeutic alternative for the induction of remission in patients with moderate-to-severe ulcerative colitis.

High-performance liquid chromatography-tandem mass spectrometry as a reference for analysis of tacrolimus to assess two immunoassays in patients with liver and renal transplants.

PubMed

Salm, P; Taylor, P J; Clark, A; Balderson, G A; Grygotis, A; Norris, R L; Lynch, S V; Shaw, L M; Pond, S M

1997-12-01

The accuracy and imprecision of three assays used for therapeutic monitoring of tacrolimus were tested using blood-containing weighed-in amounts of the drug, an enzyme-linked immunosorbent assay (ELISA), a microparticle enzyme immunoassay (MEIA I), and a high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS2) assay. Accuracy was acceptable for the HPLC-MS2 assay at all concentrations tested (< 10% deviation) and for the ELISA at 1.0 and 4.0 microg/l. Accuracy was not acceptable for the ELISA at 15.0 and 50.0 microg/l or for the MEIA I at all concentrations tested. Imprecision was acceptable for the HPLC-MS2 assay at all concentrations tested (coefficient of variation < 10%), for the ELISA at 15.0 and 50.0 microg/l, and for the MEIA I at 15.0 and 50.0 microg/l. Imprecision was not acceptable for the ELISA at 1.0 and 4.0 microg/l or for the MEIA I at 1.0 and 4.0 microg/l. This assessment with weighed-in amounts of tacrolimus verified the HPLC-MS2 assay as a reference method. The performance of the two immunoassays with HPLC-MS2 was then compared in the clinical setting using blood from patients with liver (n = 30) and renal (n = 37) transplants. In the liver transplant group (127 samples), the range of tacrolimus concentrations measured by HPLC-MS2, ELISA, and MEIA I was 1.9 to 31.8, 2.1 to 35.0, and less than 0.1 to 36.5 mg/l, respectively. In the renal transplant group (129 samples), the ranges were 1.7 to 26.1, 1.9 to 24.4, and 0.9 to 28.5 microg/l, respectively. Compared with the HPLC-MS2, the ELISA had minimal bias (0.1 to 0.2 microg/l) but unacceptable variability in values (SD > 13%). The MEIA I had unacceptable bias (1.7-1.8 microg/l) and variability (SD > 23%). These data indicated that neither the ELISA nor MEIA I is interchangeable with HPLC-MS2. Moreover, in view of the current trend to reduce the therapeutic dose of tacrolimus, quantitative results using the MEIA I would not be obtainable during therapeutic drug monitoring in some

Successful Cord Blood Stem Cell Transplantation for an Adult Case of Chronic Active Epstein-Barr Virus Infection

PubMed Central

Saburi, Masuho; Ogata, Masao; Satou, Takako; Yoshida, Natsumi; Nagamatsu, Kentaro; Nashimoto, Yuko; Moroga, Yui; Takano, Kuniko; Kohno, Kazuhiro; Shirao, Kuniaki

2016-01-01

A 41-year-old man was referred to our hospital for treatment of anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma. Chronic active Epstein-Barr virus (CAEBV) was diagnosed based on the findings of elevated EBV antibody titers and positive EBV-DNA in the peripheral blood, and cord blood stem cell transplantation (CBT) was performed. The EBV-DNA levels in the blood fell below the limit of detection. His lymphoma relapsed on Day 165 with the appearance of eruptions, which disappeared after the withdrawal of tacrolimus. One year after transplantation, there were no signs of recurrence. This encouraging result suggests that CBT should be considered for adult cases of CAEBV with aggressive clinical manifestations. PMID:27904117

Successful Cord Blood Stem Cell Transplantation for an Adult Case of Chronic Active Epstein-Barr Virus Infection.

PubMed

Saburi, Masuho; Ogata, Masao; Satou, Takako; Yoshida, Natsumi; Nagamatsu, Kentaro; Nashimoto, Yuko; Moroga, Yui; Takano, Kuniko; Kohno, Kazuhiro; Shirao, Kuniaki

A 41-year-old man was referred to our hospital for treatment of anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma. Chronic active Epstein-Barr virus (CAEBV) was diagnosed based on the findings of elevated EBV antibody titers and positive EBV-DNA in the peripheral blood, and cord blood stem cell transplantation (CBT) was performed. The EBV-DNA levels in the blood fell below the limit of detection. His lymphoma relapsed on Day 165 with the appearance of eruptions, which disappeared after the withdrawal of tacrolimus. One year after transplantation, there were no signs of recurrence. This encouraging result suggests that CBT should be considered for adult cases of CAEBV with aggressive clinical manifestations.

Regulatory effect of calcineurin inhibitor, tacrolimus, on IL-6/sIL-6R-mediated RANKL expression through JAK2-STAT3-SOCS3 signaling pathway in fibroblast-like synoviocytes

PubMed Central

2013-01-01

Introduction This study investigated whether the calcineurin inhibitor, tacrolimus, suppresses receptor activator of NF-κB ligand (RANKL) expression in fibroblast-like synoviocytes (FLS) through regulation of IL-6/Janus activated kinase (JAK2)/signal transducer and activator of transcription-3 (STAT3) and suppressor of cytokine signaling (SOCS3) signaling. Methods The expression of RANKL, JAK2, STAT3, and SOCS3 proteins was assessed by western blot analysis, real-time PCR and ELISA in IL-6 combined with soluble IL-6 receptor (sIL-6R)-stimulated rheumatoid arthritis (RA)-FLS with or without tacrolimus treatment. The effects of tacrolimus on synovial inflammation and bone erosion were assessed using mice with arthritis induced by K/BxN serum. Immunofluorescent staining was performed to identify the effect of tacrolimus on RANKL and SOCS3. The tartrate-resistant acid phosphatase staining assay was performed to assess the effect of tacrolimus on osteoclast differentiation. Results We found that RANKL expression in RA FLS is regulated by the IL-6/sIL-6R/JAK2/STAT3/SOCS3 pathway. Inhibitory effects of tacrolimus on RANKL expression in a serum-induced arthritis mice model were identified. Tacrolimus inhibits RANKL expression in IL-6/sIL-6R-stimulated FLS by suppressing STAT3. Among negative regulators of the JAK/STAT pathway, such as CIS1, SOCS1, and SOCS3, only SOCS3 is significantly induced by tacrolimus. As compared to dexamethasone and methotrexate, tacrolimus more potently suppresses RANKL expression in FLS. By up-regulating SOCS3, tacrolimus down-regulates activation of the JAK-STAT pathway by IL-6/sIL-6R trans-signaling, thus decreasing RANKL expression in FLS. Conclusions These data suggest that tacrolimus might affect the RANKL expression in IL-6 stimulated FLS through STAT3 suppression, together with up-regulation of SOCS3. PMID:23406906

Application of Machine-Learning Models to Predict Tacrolimus Stable Dose in Renal Transplant Recipients

NASA Astrophysics Data System (ADS)

Tang, Jie; Liu, Rong; Zhang, Yue-Li; Liu, Mou-Ze; Hu, Yong-Fang; Shao, Ming-Jie; Zhu, Li-Jun; Xin, Hua-Wen; Feng, Gui-Wen; Shang, Wen-Jun; Meng, Xiang-Guang; Zhang, Li-Rong; Ming, Ying-Zi; Zhang, Wei

2017-02-01

Tacrolimus has a narrow therapeutic window and considerable variability in clinical use. Our goal was to compare the performance of multiple linear regression (MLR) and eight machine learning techniques in pharmacogenetic algorithm-based prediction of tacrolimus stable dose (TSD) in a large Chinese cohort. A total of 1,045 renal transplant patients were recruited, 80% of which were randomly selected as the “derivation cohort” to develop dose-prediction algorithm, while the remaining 20% constituted the “validation cohort” to test the final selected algorithm. MLR, artificial neural network (ANN), regression tree (RT), multivariate adaptive regression splines (MARS), boosted regression tree (BRT), support vector regression (SVR), random forest regression (RFR), lasso regression (LAR) and Bayesian additive regression trees (BART) were applied and their performances were compared in this work. Among all the machine learning models, RT performed best in both derivation [0.71 (0.67-0.76)] and validation cohorts [0.73 (0.63-0.82)]. In addition, the ideal rate of RT was 4% higher than that of MLR. To our knowledge, this is the first study to use machine learning models to predict TSD, which will further facilitate personalized medicine in tacrolimus administration in the future.

Physicochemical characterization of tacrolimus-loaded solid dispersion with sodium carboxylmethyl cellulose and sodium lauryl sulfate.

PubMed

Park, Young-Joon; Ryu, Dong-Sung; Li, Dong Xun; Quan, Qi Zhe; Oh, Dong Hoon; Kim, Jong Oh; Seo, Youn Gee; Lee, Young-Im; Yong, Chul Soon; Woo, Jong Soo; Choi, Han-Gon

2009-06-01

To develop a novel tacrolimus-loaded solid dispersion with improved solubility, various solid dispersions were prepared with various ratios of water, sodium lauryl sulfate, citric acid and carboxylmethylcellulose-Na using spray drying technique. The physicochemical properties of solid dispersions were investigated using scanning electron microscopy, differential scanning calorimetery and powder X-ray diffraction. Furthermore, their solubility and dissolution were evaluated compared to drug powder. The solid dispersion at the tacrolimus/CMC-Na/sodium lauryl sulfate/citric acid ratio of 3/24/3/0.2 significantly improved the drug solubility and dissolution compared to powder. The scanning electron microscopy result suggested that carriers might be attached to the surface of drug in this solid dispersion. Unlike traditional solid dispersion systems, the crystal form of drug in this solid dispersion could not be converted to amorphous form, which was confirmed by the analysis of DSC and powder X-ray diffraction. Thus, the solid dispersion system with water, sodium lauryl sulfate, citric acid and CMC-Na should be a potential candidate for delivering a poorly water-soluble tacrolimus with enhanced solubility and no convertible crystalline.

Simultaneous LC-MS-MS determination of cyclosporine A, tacrolimus, and sirolimus in whole blood as well as mycophenolic acid in plasma using common pretreatment procedure.

PubMed

Bogusz, Maciej J; Enazi, Eid Al; Hassan, Huda; Abdel-Jawaad, Jamil; Ruwaily, Jamal Al; Tufail, Mohammed Al

2007-05-01

The purpose of the study was to develop rapid and simple procedure for simultaneous determination of cyclosporine A (CsA), tacrolimus (TCR), and sirolimus (SIR) in whole blood and mycophenolic acid (MPA) in plasma. Ascomycin (ASCO), cyclosporine D (CsD), and desmethoxysirolimus (DMSIR) were used as internal standards (IS) for TCR, CsA and MPA, and SIR, respectively. In the method development, six-level blood calibrators were used for CsA (range 47-1725 ng/ml), TCR (range 2.1-38.8 ng/ml), and SIR (range 2.4-39.6 ng/ml). Four-level calibrators were used for MPA (range 0.15-5.48 microg/ml). Four levels of quality control (QC) standards were used for blood samples, together with two levels of QC standards in plasma. All QC standards and calibrators were obtained from commercial sources. Sample preparation based on precipitation of 50 microl of sample in zinc sulfate-methanol-acetonitrile mixture containing IS, followed by centrifugation. HPLC was performed on ChromSpher pi column, 30 mm x 3 mm, in ballistic gradient of ammonium formate buffer-methanol at 0.8 ml flow rate. Following gradient elution profile was applied: 0-1.2 min at 30% methanol (divert valve to waste), 1.21-3.1 min 97% methanol (divert valve to detector), 3.11-3.7 min 30% methanol (divert valve to waste). ESI-MS-MS (MRM) was done on TSQ Quantum instrument with ESI source in positive ion mode. Ammoniated adducts of protonated molecules were used as precursor ions for all analytes but MPA. For this compound sodium adduct was used. Following transitions were monitored: for CsA m/z 1220-1203; for CsD 1234-1217; for SIR 931.6-864.5 and 882.6; for DMSIR 902-834.5; for TCR 821.5-768.5 and 785.5; for ASCO 809.5-756; for MPA 343-211.6; for MPA-glucuronide 514-306 and 211.6. The limits of quantitation were: 1 ng/ml for TCR and SIR, 20 ng/ml for CsA, and 0.1 microg/ml for MPA. Post-column infusion experiments showed that no positive or negative peaks appeared after injection of matrix in the elution range of

Alemtuzumab induction with tacrolimus monotherapy in de novo renal transplantation.

PubMed

Villanueva, M E; Muñoz, A S; Casasola, C C; Africa, J B; Danguilan, R A; Ona, E T

2008-09-01

Alemtuzumab is increasingly being used as induction therapy for kidney transplantation, allowing immunosuppression minimization. This study examined the efficacy of alemtuzumab induction followed by low-dose tacrolimus monotherapy in standard risk primary kidney transplant patients. This retrospective cohort of primary standard risk renal transplant recipients were given alemtuzumab induction and low-dose tacrolimus maintenance immunosuppression (target trough 7 to 10 ng/mL for the first 6 months and 5 to 7 ng/mL thereafter). Serum creatinine values, acute rejection episodes, and graft survival were noted at week 1 as well as months 3, 6, 12, and 18. At the time of analysis, 47 patients were at 6 months, 28 at 12 months, and 6 patients at 18 months from transplant. Mean follow-up was 12.53 months (range, 6 to 23). Mean serum creatinine was 1.47 +/- 0.65 mg/dL at 3 months, 1.56 +/- 0.84 at 6 months, 1.45 +/- 0.37 at 12 months, and 1.74 +/- 0.35 at 18 months. The 1-year clinical acute rejection rate was 21% (6/28), occurring at 0 to 3 months in 2 (33%), 4 to 6 months in 1 (17%), and >6 months in 3 patients (50%). Biopsy-proven acute rejection was 14% (4/28). The episodes were classified as borderline in one, Banff 2A in two, and Banff 3 in one patients. One patient had both acute cellular and acute humoral rejection; half responded to steroid pulse therapy. The 1-year patient survival rate was 90%. The 1-year death-censored graft survival rate was 98%. Alemtuzumab induction with tacrolimus monotherapy is an acceptable option in standard risk patients. BPAR was 14%, but renal function remained satisfactory at 18 months posttransplant.

Increased medication compliance of liver transplant patients switched from a twice-daily to a once-daily tacrolimus-based immunosuppressive regimen.

PubMed

Eberlin, M; Otto, G; Krämer, I

2013-01-01

Compliance with immunosuppressive therapy plays a major role in the long-term success of liver transplantation. Thus, the development of strategies to promote compliance of liver transplant patients and its evaluation over time are of particular interest. The main objective of this study was to compare medication compliance rates among liver transplant patients over time after transplantation where switched from a twice- to once-daily tacrolimus-based regimen. Sixty-five liver transplant patients being administered tacrolimus-based therapy were classified into three subgroups with regard to time posttransplantation. Medication compliance with tacrolimus-based therapy was measured using an electronic medication event monitoring system over a 12-month period: for 6 months tacrolimus was administered twice-daily and for 6 months, once-daily. Dosing, taking, and timing compliance as well as drug holidays were compared intra-individually between twice- and once-daily intake and among the three subgroups. In addition, patient compliance and quality of life were evaluated using questionnaires. A per protocol analysis of electronically obtained data showed 63 patients to be eligible. The resulting dosing, taking, and timing compliance rates of the patients were higher during the once-daily dosing period. No significant differences in compliance rates with tacrolimus therapy were observed among three subgroups independent of the dosing regimen. More patients failed the correct timing of the evening compared to the morning dose. Missing doses occurred particularly during weekends. Compliance variables measured by questionnaires (Morisky score, self-report, Medication Experience Scale for Immunosuppressants (MESI) score) and the Hospital Anxiety and Depression Scale score were similar in the two dosing periods. The short-form health survey (SF-36) score was higher with once-daily intake. The high measured compliance rates did not vary significantly dependent upon the time

Physical and microbiological stability of an extemporaneous tacrolimus suspension for paediatric use.

PubMed

Han, J; Beeton, A; Long, P F; Wong, I; Tuleu, C

2006-04-01

An extemporaneous suspension of tacrolimus for paediatric use has recently been developed but poor bioavailability and erratic plasma concentrations were observed during clinical use. It was not clear whether this was due to changes in the physical properties of the suspension during storage. The aim of this work was to investigate the physical and microbiological stability over the recommended 8-week shelf-life of this extemporaneous tacrolimus suspension. Suspensions (0.5 mg/mL) were custom made by a special manufacturer under Good Manufacturing Practice conditions. The procedure involved mixing tacrolimus capsule contents into Ora Plus and Simple Syrup (1 : 1) using a mortar and pestle followed by an homogenization step. The particle sizes of the suspensions were measured using a MasterSizer. A light microscope equipped with polarizers was used to visualize any particle size changes or crystal growth. Viable bacterial and fungal contamination was assessed using standard colony count techniques on solid media. The suspensions were kept at 22-26 degrees C and evaluated weekly. The volume mean diameter d((4,3)) from laser diffraction did not change significantly. Light microscopy did not reveal any significant change in particle size or crystal growth. Contamination by viable and culturable micro-organisms could not be detected. The suspension was physically (particle size) and microbiologically stable during the 8-week study period suggesting other factors including poor dosing could be responsible for the pharmacokinetic variation observed during clinical use which warrants further investigation.

Treatment of Sjögren's syndrome dry eye using 0.03% tacrolimus eye drop: Prospective double-blind randomized study.

PubMed

Moscovici, Bernardo Kaplan; Holzchuh, Ricardo; Sakassegawa-Naves, Fernando Eiji; Hoshino-Ruiz, Diego Ricardo; Albers, Marcos Bottene Villa; Santo, Ruth Miyuki; Hida, Richard Yudi

2015-10-01

To describe the clinical efficacy of the treatment of Sjögren's syndrome dry eye using 0.03% tacrolimus eye drop. Prospective double-blind randomized study. Institutional outpatient clinic. Forty-eight eyes of twenty-four patients with dry eye related to Sjögren syndrome were enrolled in this study. The patients were randomized in 2 groups: tacrolimus (n=14) and vehicle (n=10) group. The tacrolimus group received a vial containing tacrolimus 0.03% (almond oil as vehicle) and the other group received the almond oil vehicle. All patients were instructed to use the eye drops every 12h in the lower conjunctival sac. Schirmer I test, break-up-time (BUT), corneal fluorescein and Rose Bengal staining scores were evaluated in all patients one day before the treatment (baseline), 7, 14, 28 and 90 days after treatment with the eye drops. The average fluorescein and Rose Bengal scores improved statistically after 7 days of treatment and even more after 90 days. The average Schirmer I and BUT values were unchanged after 7, 14 and 21 days but did show an improvement relative to baseline after 28 days of treatment. Schirmer I, BUT, fluorescein and Rose Bengal did not show any statistical significance in the vehicle group. Topical 0.03% tacrolimus eye drop improved tear stability and ocular surface status in cases of inflammatory or SS-related dry eye. ClinicalTrials.gov Identifier: NCT01850979. Copyright © 2015 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.

The impact of conversion from prograf to generic tacrolimus in liver and kidney transplant recipients with stable graft function.

PubMed

Momper, J D; Ridenour, T A; Schonder, K S; Shapiro, R; Humar, A; Venkataramanan, R

2011-09-01

Bioequivalence of the recently available generic tacrolimus formulation, manufactured by Sandoz, to the reference product (Prograf; Astellas Pharma, Tokyo, Japan) has been demonstrated in healthy subjects. However, the safety and efficacy of substitution with generic tacrolimus in transplant patients have not been evaluated. Tacrolimus trough concentrations and indices of liver and kidney function were recorded before and after generic substitution in 48 liver and 55 kidney transplant recipients. In liver transplant patients, the mean tacrolimus concentration/dose (C/D) ratio (± SD) was 184.1 (± 123.2) ([ng/mL]/[mg/kg/day]) for the reference product and 154.7 (± 87.8) ([ng/mL]/[mg/kg/day]) for the generic product (p < 0.05). The mean C/D-ratios in kidney transplant patients were 125.3 (± 92.7) and 110.4 (± 79.2) ([ng/mL]/[mg/kg/day]) for the reference and generic products, respectively (p < 0.05). Actual trough concentrations declined by an average of 1.98 ng/mL in liver and 0.87 ng/mL in kidney transplant patients following the switch, after accounting for all significant covariates. No change was observed in biochemical indices of liver or kidney function and no cases of acute rejection occurred following the substitution. These results suggest that transplant patients currently taking the reference tacrolimus formulation may be safely switched to the Sandoz-generic product provided trough concentrations are closely monitored following the substitution. © 2011 The Authors Journal compilation © 2011 The American Society of Transplantation and the American Society of Transplant Surgeons.

Blood creatinine level in postmortem cases.

PubMed

Nishida, Atsushi; Funaki, Hironao; Kobayashi, Masaki; Tanaka, Yuka; Akasaka, Yoshihisa; Kubo, Toshikazu; Ikegaya, Hiroshi

2015-05-01

Blood chemical analysis for the diagnosis of diseases in forensic cases should be conducted in the same way as for clinical cases. However, it is sometimes difficult to obtain serum samples in forensic cases because of postmortem changes such as hemolysis and putrefaction. This study aimed to evaluate renal function in postmortem cases by blood creatinine analysis. The blood creatinine level was measured by high performance liquid chromatography (HPLC) using whole blood samples taken from 77 postmortem cases, and the relationships between blood creatinine level, postmortem interval, and cause of death were examined. The median blood creatinine level was found to be 1.15 mg/dL, with no significant differences between blood samples taken from different parts of the body. The blood creatinine level was stable for 3 days after death and gradually increased after that period, in line with a previous study using enzymatic analysis that found the serum creatinine level was stable in the early postmortem period. The blood creatinine level was high in the cases of blunt injury, intoxication, and in deaths caused by fire. This was considered to reflect acute renal dysfunction. However, the postmortem blood creatinine level remained higher than the clinical normal value despite omitting cases with renal dysfunction from the analysis. Therefore, we next investigated the change in postmortem creatinine levels in mice and found that the blood creatinine level increased with the emergence of rigor mortis. Our findings indicate that HPLC is useful in the postmortem evaluation of renal function even in the cases where serum cannot be obtained. However, the presence of rigor mortis should be considered in the evaluation of blood creatinine values. Copyright © 2014 Forensic Science Society. Published by Elsevier Ireland Ltd. All rights reserved.

[Hemolytic anemia caused by graft-versus-host reaction in ABO-nonidentical renal transplants from blood group O donors].

PubMed

Peces, R; Díaz Corte, C; Navascués, R A

2001-01-01

Acute hemolytic anemia is one of the side effects associated with cyclosporin and tacrolimus therapy, and three mechanisms have been described to account for hemolytic anemia in patients receiving these drugs: drug induced hemolysis, autoimmune hemolysis and alloimmune hemolysis resulting from donor lymphocytes derived from the allograft (passenger lymphocyte syndrome). We report four cases of renal transplant recipients who developed alloimmune hemolytic anemia due to minor ABO incompatibility while under treatment with cyclosporin (two) and tacrolimus (two). The anti-erythrocyte antibodies responsible for hemolysis were of the IgG isotype and showed anti-A or anti-B specificity. These findings suggest that the hemolysis could be related to alloantibodies derived from the clonal development of donor B lymphocytes in the recipients (microchimerism). In summary, hemolytic anemia due to ABO-minor incompatibility occurs infrequently after renal transplantation. Risks are higher for patients A, B or AB blood group receiving an O blood group graft under treatment with cyclosporin or tacrolimus. Follow-up of these patients is warranted for the early detection and optimal management may be achieved by reduction of immunosuppression and change to mycophenolate mofetil.

Effects of tacrolimus and erythropoietin in experimental spinal cord lesion in rats: functional and histological evaluation

PubMed Central

de Mesquita Coutinho, P R; Cristante, A F; de Barros Filho, T E P; Ferreira, R; dos Santos, G B

2016-01-01

Study design: Experimental study with rats. Objective: To evaluate functional and histological effects of tacrolimus (FK 506) and erythropoietin (EPO) after experimental spinal cord contusion injury (SCI). Setting: Brazil. Methods: Wistar rats (n=60) were submitted to SCI with the NYU Impactor system. The control group received saline; the EPO group received EPO; the group EPO+FK 506 received EPO associated with tacrolimus and the group FK 506 received tacrolimus only. The Sham group underwent SCI, but did not receive any drug. Locomotor function was evaluated after SCI by BBB (Basso, Beattie and Bresnahan) weekly and by the motor-evoked potential test in 42 days. The spinal cord was histologically evaluated. Results: There was a significant difference between treated and the control groups from the seventh day on for BBB scores, with no difference between the groups EPO and EPO+FK 506 by the end of the study. There were significant differences between groups for necrosis and bleeding, but not for hiperemia, degeneration and cellular infiltrate. Axon neuron count was different between all groups (P=0.001), between EPO+FK 506 and FK 506 (P=0.011) and between EPO+FK 506 and Sham (P=0.002). Amplitude was significantly different between all groups except between control and sham. For latency, there was no difference. Conclusions: This study did not reveal significant differences in the recovery of locomotor function, or in the histological and electrophysiological analysis in animals treated with EPO and tacrolimus after thoracic SCI. PMID:26481712

Blood Glucose Levels and Problem Behavior

ERIC Educational Resources Information Center

Valdovinos, Maria G.; Weyand, David

2006-01-01

The relationship between varying blood glucose levels and problem behavior during daily scheduled activities was examined. The effects that varying blood glucose levels had on problem behavior during daily scheduled activities were examined. Prior research has shown that differing blood glucose levels can affect behavior and mood. Results of this…

Successful treatment of plasma cell cheilitis with topical tacrolimus: report of two cases.

PubMed

Hanami, Yuka; Motoki, Yoshikazu; Yamamoto, Toshiyuki

2011-02-15

Plasma cell cheilitis is an uncommon chronic inflammatory dermatitis that presents with flat to slightly elevated erosive erythematous plaques. It is histologically characterized by plasma cell infiltrates into the mucosa. Other than the lip, genital areas are often involved, which is called plasma cell balanitis or vulvitis. Plasma cell cheilitis is sometimes resistant to conventional topical corticosteroid therapy. Other choices include oral griseofulvin, topical cyclosporine, and intralesional corticosteroid injection, all of which occasionally fail to produce satisfactory results. Recent reports show that topical calcineurin inhibitors are effective for plasma cell cheilitis, balanitis, and vulvitis. However, there are so far only 2 reports of plasma cell cheilitis successfully treated with topical pimecrolimus and tacrolimus. We present herein two cases of plasma cell cheilitis, in which topical tacrolimus showed beneficial effects, suggesting that this immunomodulatory agent is a promising option for plasma cell cheilitis.

De novo kidney transplant recipients need higher doses of Advagraf compared with Prograf to get therapeutic levels.

PubMed

Crespo, M; Mir, M; Marin, M; Hurtado, S; Estadella, C; Gurí, X; Rap, O; Moral, R; Puig, J M; Lloveras, J

2009-01-01

Advagraf is a new modified-release once-daily formulation of tacrolimus with a similar efficacy and safety profile to twice-daily tacrolimus (Prograf) according to clinical trials. Few data are published about its use in clinical practice, outside of sponsored clinical trials. We compared efficacy and basic pharmacokinetics of once-daily and twice-daily tacrolimus in de novo renal transplantation. The Advagraf group included 26 de novo renal cases who had received initial immunosuppression with once-daily tacrolimus (0.2 mg/kg from day 1 posttransplantation) combined with mycophenolic acid, steroids, and anti-CD25 monoclonal antibodies (2 doses). We compared them with a Prograf group of 26 transplants performed immediately before, who received equivalent immunosuppression with twice-daily tacrolimus (0.2 mg/kg from day 1). We did not observe significant differences between groups in demographics, efficacy, and basic pharmacokinetics, namely, tacrolimus trough levels at 7, 15, 30, 60, or 90 days. We found that recipients on Advagraf needed significantly higher tacrolimus doses per kg up to 6 months post-transplantation than those on Prograf: 0.16 vs 0.11; 0.14 vs 0.08; and 0.12 vs 0.08 mg/kg at 1, 3, and 6 months. No patient suffered severe liver dysfunction. There were no differences between groups in the administration of drugs interacting with CYP3A4 or prokinetics, which could alter tacrolimus pharmacokinetics. Among de novo renal cases, the new once-daily formulation of tacrolimus offered a similar short-term efficacy profile as the twice-daily tacrolimus. But it was necessary to use up to a 50% higher dose of Advagraf than Prograf to achieve similar trough levels during the first 6 months.

Age-dependent metabolic and immunosuppressive effects of Tacrolimus

PubMed Central

Krenzien, Felix; Quante, Markus; Heinbokel, Timm; Seyda, Midas; Minami, Koichiro; Uehara, Hirohito; Biefer, Hector Rodriguez Cetina; Schuitenmaker, Jeroen M.; Gabardi, Steven; Splith, Katrin; Schmelzle, Moritz; Petrides, Athena K.; Azuma, Haruhito; Pratschke, Johann; Li, Xian C.; ElKhal, Abdallah; Tullius, Stefan G.

2016-01-01

Immunosuppression in elderly recipients has been underappreciated in clinical trials. Here, we assessed age-specific effects of the calcineurin inhibitor Tacrolimus (TAC) in a murine transplant model and assessed its clinical relevance on human T-cells. Old recipient mice exhibited prolonged skin graft survival when compared to young animals following TAC administration. More importantly, half of the TAC dose was sufficient in old mice to achieve comparable systemic trough levels. TAC administration was able to reduce pro-inflammatory IFN-γ cytokine production and promote IL-10 production in old CD4+ T-cells. In addition, TAC administration decreased IL-2 secretion in old CD4+ T-cells more effectively while inhibiting the proliferation of CD4+ T-cells in old mice. Both, TAC treated murine and human CD4+ T-cells demonstrated an age-specific suppression of intracellular calcineurin levels and Ca2+-influx, two critical pathways in T-cell activation. Of note, depletion of CD8+ T-cells did not alter allograft survival outcome in old TAC treated mice, suggesting that TAC age-specific effects were mainly CD4+ T-cell mediated. Collectively, our study demonstrates age-specific immunosuppressive capacities of TAC that are CD4+ T-cell mediated. The suppression of calcineurin levels and Ca2+-influx in both, old murine and human T-cells emphasizes on the clinical relevance of age-specific effects when utilizing TAC. PMID:27754593

Local Tacrolimus (FK506) Delivery for Prevention of Acute Rejection in the Nonhuman Primate Delayed Mixed Chimerism Vascularized Composite Allograft Tolerance Induction Protocol

DTIC Science & Technology

2016-10-01

Chimerism Vascularized Composite Allograft Tolerance Induction Protocol PRINCIPAL INVESTIGATORS: Dr. Curtis L. Cetrulo CONTRACTING ORGANIZATION...Tacrolimus (FK506) Delivery for Prevention of Acute Rejection in the Nonhuman Primate Delayed Mixed Chimerism Vascularized Composite Allograft Tolerance...tacrolimus, FK506, vascularized composite allografts , immune rejection, preclinical, transplant, nonhuman primate model, degradable polymer, tyrosine

Reduction of serum TARC levels in atopic dermatitis by topical anti-inflammatory treatments.

PubMed

Yasukochi, Yumi; Nakahara, Takeshi; Abe, Takeru; Kido-Nakahara, Makiko; Kohda, Futoshi; Takeuchi, Satoshi; Hagihara, Akihito; Furue, Masutaka

2014-09-01

Serum thymus and activation-regulated chemokine (TARC) levels are associated with the disease activity of patients with atopic dermatitis (AD) and sensitively reflect short-term changes in skin conditions. The main treatment for AD is topical agent application. This study investigated the relationship between serum TARC levels and the dosage of topical agents, including corticosteroids and/or tacrolimus, in patients with AD. The serum TARC levels of 56 AD patients and the amounts of topical agents prescribed to them were investigated retrospectively. The weekly reduction in serum TARC levels and weekly dosage of topical agents among AD patients were compared and their associations were evaluated. The dosage of topical agents was closely related to serum TARC levels. One gram of strong rank steroid or the equivalent amount of steroid/tacrolimus is required to reduce serum TARC levels by 9.94 pg/mL weekly in moderate to severe AD patients. Higher initial TARC levels require more topical agent, which results in a more rapid decrease in TARC levels. The serum TARC levels and eosinophil numbers in peripheral blood are significantly correlated. Serum TARC level improvement and topical agent dosage are strongly correlated. TARC and eosinophil numbers are significantly correlated, but the wider range of TARC levels seems to be clinically more useful for monitoring AD severity. The serum TARC level is a very sensitive biomarker for monitoring the severity and treatment response in AD.

Efficacy and Safety of Tacrolimus Therapy for Active Ulcerative Colitis; A Systematic Review and Meta-analysis

PubMed Central

Komaki, Yuga; Komaki, Fukiko; Ido, Akio

2016-01-01

Background: Approximately 25% of patients with ulcerative colitis [UC] experience a severe flare requiring steroid therapy to avoid colectomy. We performed a systematic review and meta-analysis to assess the efficacy of tacrolimus as a rescue therapy for active UC. Methods: Electronic databases were searched for relevant studies assessing the efficacy of tacrolimus for active UC. Outcomes included short- and long-term clinical response, colectomy free rates, and rate of adverse events in randomised controlled trials [RCTs] and observational studies. Results: Two RCTs comparing high trough concentration [10–15ng/ml] versus placebo [n = 103] and 23 observational studies [n = 831] were identified. Clinical response at 2 weeks was significantly higher with tacrolimus compared with placebo (risk ratio [RR] = 4.61, 95% confidence interval [CI] = 2.09–10.17, p = 0.15 x 10-3] among RCTs. Rates of clinical response at 1 and 3 months were 0.73 [95% CI = 0.64–0.81] and 0.76 [95% CI = 0.59–0.87], and colectomy-free rates remained high at 1, 3, 6, and 12 months [0.86, 0.84, 0.78, and 0.69, respectively] among observational studies. Among RCTs, adverse events were more frequent compared with placebo [RR = 2.01, 95% CI = 1.20–3.37, p = 0.83 x 10-2], but there was no difference in severe adverse events [RR = 3.15, 95% CI = 0.14–72.9, p = 0.47]. Severe adverse events were rare among observational studies [0.11, 95% CI = 0.06–0.20]. Conclusions: In the present meta-analysis, tacrolimus was associated with high clinical response and colectomy-free rates without increased risk of severe adverse events for active UC. PMID:26645641

Efficacy and Safety of Tacrolimus Therapy for Active Ulcerative Colitis; A Systematic Review and Meta-analysis.

PubMed

Komaki, Yuga; Komaki, Fukiko; Ido, Akio; Sakuraba, Atsushi

2016-04-01

Approximately 25% of patients with ulcerative colitis [UC] experience a severe flare requiring steroid therapy to avoid colectomy. We performed a systematic review and meta-analysis to assess the efficacy of tacrolimus as a rescue therapy for active UC. Electronic databases were searched for relevant studies assessing the efficacy of tacrolimus for active UC. Outcomes included short- and long-term clinical response, colectomy free rates, and rate of adverse events in randomised controlled trials [RCTs] and observational studies. Two RCTs comparing high trough concentration [10-15ng/ml] versus placebo [n = 103] and 23 observational studies [n = 831] were identified. Clinical response at 2 weeks was significantly higher with tacrolimus compared with placebo (risk ratio [RR] = 4.61, 95% confidence interval [CI] = 2.09-10.17, p = 0.15 x 10(-3)] among RCTs. Rates of clinical response at 1 and 3 months were 0.73 [95% CI = 0.64-0.81] and 0.76 [95% CI = 0.59-0.87], and colectomy-free rates remained high at 1, 3, 6, and 12 months [0.86, 0.84, 0.78, and 0.69, respectively] among observational studies. Among RCTs, adverse events were more frequent compared with placebo [RR = 2.01, 95% CI = 1.20-3.37, p = 0.83 x 10(-2)], but there was no difference in severe adverse events [RR = 3.15, 95% CI = 0.14-72.9, p = 0.47]. Severe adverse events were rare among observational studies [0.11, 95% CI = 0.06-0.20]. In the present meta-analysis, tacrolimus was associated with high clinical response and colectomy-free rates without increased risk of severe adverse events for active UC. Copyright © 2015 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Clinical study of double dose of valsartan combined with tacrolimus in treatment of diabetic nephropathy.

PubMed

Jin, H; Zhang, H-N; Hou, X-L; Zhang, B; Wu, J; Zhang, H-B

2016-01-01

To investigate the clinical effect of double dose of valsartan combined with tacrolimus in the treatment of diabetic nephropathy (DN). HA total of 86 cases diagnosed with DN were selected from October 2013 to October 2014 in Zaozhuang Municipal Hospital, China. The study was approved by our hospital Ethics Committee and written consent was obtained from patients and their family members. Patients were randomly divided into three groups according to the sequence of admission, group A (conventional dose of valsartan group, n = 28 cases), group B (double dose of valsartan group, n = 29 cases) and group C (double dose of valsartan combined with tacrolimus group, n = 29). Clinical effects were compared by analyzing the renal function tests after 8 weeks. 24h urine protein, serum creatinine level of patients in group B and group C were significantly lower than that of group A. Those in group C was much lower. The glomerular filtration rates were significantly higher for group B and C than that of group A, and those in group C were much higher. The difference is statistically significant (p < 0.05). High-sensitivity C-reactive protein (hs CRP) and adiponectin levels of patients in group B and C of were significantly lower than that of group A and those in group C were much lower. The difference is statistically significant (p < 0.05). The high mobility group protein 1 (HMGB1) and renal tubular and interstitial damage index (TDI) of patients in B and C groups were significantly lower than those in the A group, and those in C group were significantly lower. The difference was statistically significant p < 0.05). The clinical effective rates of patients in group B and C were significantly higher than that in group A, and those of group C were much higher. The difference is statistically significant (p < 0.05). The recurrence rates of patients in group B and group C were significantly lower than those of group A and those in group C were much lower. The difference is

Advantage of Rapamycin Over Mycophenolate Mofetil When Used With Tacrolimus for Simultaneous Pancreas Kidney Transplants: Randomized, Single-Center Trial at 10 Years

PubMed Central

Ciancio, G.; Sageshima, J.; Chen, L.; Gaynor, J. J.; Hanson, L.; Tueros, L.; Montenora-Velarde, E.; Gomez, C.; Kupin, W.; Guerra, G.; Mattiazzi, A.; Fornoni, A.; Pugliese, A.; Roth, D.; Wolf, M.; Burke, G. W.

2015-01-01

Simultaneous pancreas kidney transplantation (SPKT) is the treatment of choice for patients with type 1 diabetes and end-stage renal disease. Rapamycin and mycophenolate mofetil (MMF) have been used for maintenance immunosuppression with tacrolimus in SPKT; however, long-term outcomes are lacking. From September 2000 through December 2009, 170 SPKT recipients were enrolled in a randomized, prospective trial receiving Rapamycin (n = 84) or MMF (n = 86). All patients received dual induction therapy with thymoglobulin and daclizumab, and low-dose maintenance tacrolimus and corticosteroids. Compared to MMF, rates of freedom from first biopsy-proven acute kidney or pancreas rejection were superior for Rapamycin at year 1 (kidney: 100% vs. 88%; P = 0.001; pancreas: 99% vs. 92%; P = 0.04) and at year 10 (kidney: 88% vs. 71%, P = 0.01; pancreas: 99% vs. 89%, P = 0.01). The higher rates of rejection were associated with withholding MMF (vs. Rapamycin, p = 0.009), generally for gastrointestinal or bone marrow toxicity. There was no significant difference in creatinine, proteinuria, c-peptide, viral infections, lymphoproliferative disorders or posttransplant diabetes. HbA1C and lipid levels were normal in both groups, although higher in the Rapamycin arm. There were no significant differences in patient or allograft survival. In this 10-year SPKT study, Rapamycin in combination with tacrolimus was better tolerated and more effective than MMF. Overall, the patient and allograft survival were equivalent. PMID:22946986

Tacrolimus in the treatment of myasthenia gravis in patients with an inadequate response to glucocorticoid therapy: randomized, double-blind, placebo-controlled study conducted in China.

PubMed

Zhou, Lei; Liu, Weibin; Li, Wei; Li, Haifeng; Zhang, Xu; Shang, Huifang; Zhang, Xu; Bu, Bitao; Deng, Hui; Fang, Qi; Li, Jimei; Zhang, Hua; Song, Zhi; Ou, Changyi; Yan, Chuanzhu; Liu, Tao; Zhou, Hongyu; Bao, Jianhong; Lu, Jiahong; Shi, Huawei; Zhao, Chongbo

2017-09-01

To determine the efficacy of low-dose, immediate-release tacrolimus in patients with myasthenia gravis (MG) with inadequate response to glucocorticoid therapy in a randomized, double-blind, placebo-controlled study. Eligible patients had inadequate response to glucocorticoids (GCs) after ⩾6 weeks of treatment with prednisone ⩾0.75 mg/kg/day or 60-100 mg/day. Patients were randomized to receive 3 mg tacrolimus or placebo daily (orally) for 24 weeks. Concomitant glucocorticoids and pyridostigmine were allowed. Patients continued GC therapy from weeks 1-4; from week 5, the dose was decreased at the discretion of the investigator. The primary efficacy outcome measure was a reduction, relative to baseline, in quantitative myasthenia gravis (QMG) score assessed using a generalized linear model; supportive analyses used alternative models. Of 138 patients screened, 83 [tacrolimus ( n = 45); placebo ( n = 38)] were enrolled and treated. The change in adjusted mean QMG score from baseline to week 24 was -4.9 for tacrolimus and -3.3 for placebo (least squares mean difference: -1.7, 95% confidence interval: -3.5, -0.1; p = 0.067). A post-hoc analysis demonstrated a statistically significant difference for QMG score reduction of ⩾4 points in the tacrolimus group (68.2%) versus the placebo group (44.7%; p = 0.044). Adverse event profiles were similar between treatment groups. Tacrolimus 3 mg treatment for patients with MG and inadequate response to GCs did not demonstrate a statistically significant improvement in the primary endpoint versus placebo over 24 weeks; however, a post-hoc analysis demonstrated a statistically significant difference for QMG score reduction of ⩾4 points in the tacrolimus group versus the placebo group. This study was limited by the low number of patients, the absence of testing for acetylcholine receptor antibody and the absence of stratification by disease duration (which led to a disparity between the two groups). Clinical

Age-Dependent Metabolic and Immunosuppressive Effects of Tacrolimus.

PubMed

Krenzien, F; Quante, M; Heinbokel, T; Seyda, M; Minami, K; Uehara, H; Biefer, H R C; Schuitenmaker, J M; Gabardi, S; Splith, K; Schmelzle, M; Petrides, A K; Azuma, H; Pratschke, J; Li, X C; ElKhal, A; Tullius, S G

2017-05-01

Immunosuppression in elderly recipients has been underappreciated in clinical trials. Here, we assessed age-specific effects of the calcineurin inhibitor tacrolimus (TAC) in a murine transplant model and assessed its clinical relevance on human T cells. Old recipient mice exhibited prolonged skin graft survival compared with young animals after TAC administration. More important, half of the TAC dose was sufficient in old mice to achieve comparable systemic trough levels. TAC administration was able to reduce proinflammatory interferon-γ cytokine production and promote interleukin-10 production in old CD4 + T cells. In addition, TAC administration decreased interleukin-2 secretion in old CD4 + T cells more effectively while inhibiting the proliferation of CD4 + T cells in old mice. Both TAC-treated murine and human CD4 + T cells demonstrated an age-specific suppression of intracellular calcineurin levels and Ca 2+ influx, two critical pathways in T cell activation. Of note, depletion of CD8 + T cells did not alter allograft survival outcome in old TAC-treated mice, suggesting that TAC age-specific effects were mainly CD4 + T cell mediated. Collectively, our study demonstrates age-specific immunosuppressive capacities of TAC that are CD4 + T cell mediated. The suppression of calcineurin levels and Ca 2+ influx in both old murine and human T cells emphasizes the clinical relevance of age-specific effects when using TAC. © 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.

A case of vesicular cutaneous lupus erythematosus in a Border collie successfully treated with topical tacrolimus and nicotinamide-tetracycline.

PubMed

Lehner, Georg M; Linek, Monika

2013-12-01

Canine vesicular cutaneous lupus erythematosus (VCLE) is an autoimmune skin disease of the Shetland sheepdog and rough collie, which manifests as an erosive dermatitis of sparsely haired skin of the ventrum and concave pinnae. Reported treatment consists of immunosuppression with glucocorticoids alone or in combination with azathioprine, but successful treatment is unpredictable. To report on the treatment of VCLE in a Border collie dog with topical 0.1% tacrolimus and nicotinamide in combination with tetracycline. An 8-year-old male neutered Border collie was presented with multiple coalescing erosions on the ventral abdomen, groin and axillae and ulceration on the oral commissures. Clinical presentation, routine diagnostics, histology and immunohistochemistry were consistent with VCLE. Remission was achieved with topical 0.1% tacrolimus and combination therapy of nicotinamide and tetracycline. This dog responded well to treatment with topical 0.1% tacrolimus, nicotinamide-tetracycline and sun avoidance. Complete remission was achieved after 2.5 months, and the dog was lesion free during a 1 year follow-up period. © 2013 ESVD and ACVD.

Alarming levels of carboxyhemoglobin in banked blood.

PubMed

Ehlers, Melissa; Labaze, Georges; Hanakova, Marcela; McCloskey, David; Wilner, George

2009-06-01

To determine the level of carboxyhemoglobin found in banked blood in the Albany, NY region. A retrospective descriptive analysis of carboxyhemoglobin (COHb) levels in a series of packed red blood cell (PRBC) units. The blood bank of a university tertiary care hospital in Albany, NY. All PRBC units considered for possible use in pediatric cardiac surgery were first analyzed for levels of COHb. Only those units with COHb levels of <1.5% were deemed acceptable for use during pediatric cardiac surgery. A sample of blood drawn from the sample side arm of each PRBC unit was analyzed on a Chiron 855 Blood Gas Analyzer (Chiron Inc, Emeryville, CA, now Siemens/Bayer RapidLab 865) to determine the level of COHb. The average COHb level was 0.78% (standard deviation +/- 1.48%), and out of the 468 units tested, 48 (10.3%) had COHb levels of 1.5% or greater. The highest recorded COHb level was 12%. The transfusion of PRBC units may artificially elevate readings of COHb and cause confusion over possible causes. Certain high-risk populations (eg, cyanotic neonates undergoing cardiopulmonary bypass) may be especially at risk. Although levels of COHb in the US blood supply are dropping, institutions may want to consider analyzing COHb levels in their PRBC units before transfusion in these high-risk populations.

Simultaneous assessment of blood coagulation and hematocrit levels in dielectric blood coagulometry.

PubMed

Hayashi, Yoshihito; Brun, Marc-Aurèle; Machida, Kenzo; Lee, Seungmin; Murata, Aya; Omori, Shinji; Uchiyama, Hidetoshi; Inoue, Yoshinori; Kudo, Toshifumi; Toyofuku, Takahiro; Nagasawa, Masayuki; Uchimura, Isao; Nakamura, Tomomasa; Muneta, Takeshi

2017-01-01

In a whole blood coagulation test, the concentration of any in vitro diagnostic agent in plasma is dependent on the hematocrit level but its impact on the test result is unknown. The aim of this work was to clarify the effects of reagent concentration, particularly Ca2+, and to find a method for hematocrit estimation compatible with the coagulation test. Whole blood coagulation tests by dielectric blood coagulometry (DBCM) and rotational thromboelastometry were performed with various concentrations of Ca2+ or on samples with different hematocrit levels. DBCM data from a previous clinical study of patients who underwent total knee arthroplasty were re-analyzed. Clear Ca2+ concentration and hematocrit level dependences of the characteristic times of blood coagulation were observed. Rouleau formation made hematocrit estimation difficult in DBCM, but use of permittivity at around 3 MHz made it possible. The re-analyzed clinical data showed a good correlation between permittivity at 3 MHz and hematocrit level (R2=0.83). Changes in the hematocrit level may affect whole blood coagulation tests. DBCM has the potential to overcome this effect with some automated correction using results from simultaneous evaluations of the hematocrit level and blood coagulability.

Bioequivalence between innovator and generic tacrolimus in liver and kidney transplant recipients: A randomized, crossover clinical trial

PubMed Central

Vinks, Alexander A.; Fukuda, Tsuyoshi; King, Eileen C.; Zou, Yuanshu; Jiang, Wenlei; Klawitter, Jelena; Christians, Uwe

2017-01-01

Background Although the generic drug approval process has a long-term successful track record, concerns remain for approval of narrow therapeutic index generic immunosuppressants, such as tacrolimus, in transplant recipients. Several professional transplant societies and publications have generated skepticism of the generic approval process. Three major areas of concern are that the pharmacokinetic properties of generic products and the innovator (that is, “brand”) product in healthy volunteers may not reflect those in transplant recipients, bioequivalence between generic and innovator may not ensure bioequivalence between generics, and high-risk patients may have specific bioequivalence concerns. Such concerns have been fueled by anecdotal observations and retrospective and uncontrolled published studies, while well-designed, controlled prospective studies testing the validity of the regulatory bioequivalence testing approach for narrow therapeutic index immunosuppressants in transplant recipients have been lacking. Thus, the present study prospectively assesses bioequivalence between innovator tacrolimus and 2 generics in individuals with a kidney or liver transplant. Methods and findings From December 2013 through October 2014, a prospective, replicate dosing, partially blinded, randomized, 3-treatment, 6-period crossover bioequivalence study was conducted at the University of Cincinnati in individuals with a kidney (n = 35) or liver transplant (n = 36). Abbreviated New Drug Applications (ANDA) data that included manufacturing and healthy individual pharmacokinetic data for all generics were evaluated to select the 2 most disparate generics from innovator, and these were named Generic Hi and Generic Lo. During the 8-week study period, pharmacokinetic studies assessed the bioequivalence of Generic Hi and Generic Lo with the Innovator tacrolimus and with each other. Bioequivalence of the major tacrolimus metabolite was also assessed. All products fell within

Bioequivalence between innovator and generic tacrolimus in liver and kidney transplant recipients: A randomized, crossover clinical trial.

PubMed

Alloway, Rita R; Vinks, Alexander A; Fukuda, Tsuyoshi; Mizuno, Tomoyuki; King, Eileen C; Zou, Yuanshu; Jiang, Wenlei; Woodle, E Steve; Tremblay, Simon; Klawitter, Jelena; Klawitter, Jost; Christians, Uwe

2017-11-01

Although the generic drug approval process has a long-term successful track record, concerns remain for approval of narrow therapeutic index generic immunosuppressants, such as tacrolimus, in transplant recipients. Several professional transplant societies and publications have generated skepticism of the generic approval process. Three major areas of concern are that the pharmacokinetic properties of generic products and the innovator (that is, "brand") product in healthy volunteers may not reflect those in transplant recipients, bioequivalence between generic and innovator may not ensure bioequivalence between generics, and high-risk patients may have specific bioequivalence concerns. Such concerns have been fueled by anecdotal observations and retrospective and uncontrolled published studies, while well-designed, controlled prospective studies testing the validity of the regulatory bioequivalence testing approach for narrow therapeutic index immunosuppressants in transplant recipients have been lacking. Thus, the present study prospectively assesses bioequivalence between innovator tacrolimus and 2 generics in individuals with a kidney or liver transplant. From December 2013 through October 2014, a prospective, replicate dosing, partially blinded, randomized, 3-treatment, 6-period crossover bioequivalence study was conducted at the University of Cincinnati in individuals with a kidney (n = 35) or liver transplant (n = 36). Abbreviated New Drug Applications (ANDA) data that included manufacturing and healthy individual pharmacokinetic data for all generics were evaluated to select the 2 most disparate generics from innovator, and these were named Generic Hi and Generic Lo. During the 8-week study period, pharmacokinetic studies assessed the bioequivalence of Generic Hi and Generic Lo with the Innovator tacrolimus and with each other. Bioequivalence of the major tacrolimus metabolite was also assessed. All products fell within the US Food and Drug Administration

Effects of blood lead and cadmium levels on homocysteine level in plasma.

PubMed

Cai, R; Zheng, Y-F; Bu, J-G; Zhang, Y-Y; Fu, S-L; Wang, X-G; Guo, L-L; Zhang, J-R

2017-01-01

We studied the effect of non-occupational exposure to lead and cadmium on homocysteine level in plasma. Homocysteine is a marker for plasma folate folic acid metabolism in urban populations. 159 individuals from Beijing, Guangzhou, Shenzhen and Shanghai with no history of close exposure to heavy metals and no history of metabolic diseases were enrolled to participate in this study. Blood lead and cadmium levels were detected using ICP-MS method and the level of homocysteine was also measured using enzyme method. Our results showed that blood lead and cadmium levels in males were significantly higher than those in females. Also, blood lead and cadmium levels in smokers were higher than those in non-smokers; homocysteine level was significantly higher in smokers as well. According to blood lead and cadmium levels, cases were divided into four groups. Our results showed that a surge in blood lead and cadmium levels could result in an increase in homocysteine level. We concluded that in the Chinese population, smoking and gender might be the risk factors for elevated levels of lead and cadmium. Meanwhile, blood lead and cadmium levels may influence the homocysteine levels in the body. It is possible to speculate that non-occupational exposure to lead and cadmium, by increasing the homocysteine levels, negatively affect the cardiovascular and nervous system.

Characteristic features of tacrolimus-induced lung disease in rheumatoid arthritis patients.

PubMed

Sasaki, Takanori; Nakamura, Wataru; Inokuma, Shigeko; Matsubara, Erika

2016-02-01

This paper aims to study the background and clinical characteristics of tacrolimus (TAC)-induced lung disease. A case of a rheumatoid arthritis (RA) patient who developed TAC-induced interstitial lung disease (TAC-ILD) is reported. The Japanese Pharmaceuticals and Medical Devices Agency (PMDA) website was searched for cases of TAC-ILD and its prevalence among all cases of TAC-related adverse events. As for cases of TAC-ILD, its underlying disease, preexisting lung diseases, and fatal outcome were also searched. Literature review of TAC-ILD cases was added. A 65-year-old female RA patient with preexisting bronchiectasis developed near-fatal TAC-ILD. Amelioration of RA, ground-glass opacities in the upper, anterior, and central lung fields, and decrease in peripheral blood lymphocyte count were the major findings in this patient. A search of the PMDA website revealed the following: the prevalence of TAC-ILD was 3 % of all cases of TAC-related adverse events, 56 out of 85 RA cases (66 %), and one out of 15 other cases had a preexisting lung disease; the prevalences of fatal outcome in RA and other cases were 24 and 38 %, respectively. A few cases in the literature had preexisting ILD and developed diffuse alveolar damage. In our case, preexisting bronchiectasis, arthritis remission, newly developed ground-glass opacities (GGOs) in the upper, anterior, and central lung fields, and decrease in peripheral blood lymphocyte count were the major findings. From the search of the PMDA website, about one fourth of the cases with TAC-related lung injury had a fatal outcome, and among RA patients, two thirds had preexisting lung diseases.

Simultaneous assessment of blood coagulation and hematocrit levels in dielectric blood coagulometry

PubMed Central

Hayashi, Yoshihito; Brun, Marc-Aurèle; Machida, Kenzo; Lee, Seungmin; Murata, Aya; Omori, Shinji; Uchiyama, Hidetoshi; Inoue, Yoshinori; Kudo, Toshifumi; Toyofuku, Takahiro; Nagasawa, Masayuki; Uchimura, Isao; Nakamura, Tomomasa; Muneta, Takeshi

2017-01-01

Background: In a whole blood coagulation test, the concentration of any in vitro diagnostic agent in plasma is dependent on the hematocrit level but its impact on the test result is unknown. Objective: The aim of this work was to clarify the effects of reagent concentration, particularly Ca2+, and to find a method for hematocrit estimation compatible with the coagulation test. Methods: Whole blood coagulation tests by dielectric blood coagulometry (DBCM) and rotational thromboelastometry were performed with various concentrations of Ca2+ or on samples with different hematocrit levels. DBCM data from a previous clinical study of patients who underwent total knee arthroplasty were re-analyzed. Results: Clear Ca2+ concentration and hematocrit level dependences of the characteristic times of blood coagulation were observed. Rouleau formation made hematocrit estimation difficult in DBCM, but use of permittivity at around 3 MHz made it possible. The re-analyzed clinical data showed a good correlation between permittivity at 3 MHz and hematocrit level (R2=0.83). Conclusions: Changes in the hematocrit level may affect whole blood coagulation tests. DBCM has the potential to overcome this effect with some automated correction using results from simultaneous evaluations of the hematocrit level and blood coagulability. PMID:28800301

De novo use of a generic formulation of tacrolimus versus reference tacrolimus in kidney transplantation: evaluation of the clinical results, histology in protocol biopsies, and immunological monitoring.

PubMed

Melilli, Edoardo; Crespo, Elena; Sandoval, Diego; Manonelles, Anna; Sala, Neus; Mast, Richard; Padulles, Ariadna; Grinyo, Josep M; Bestard, Oriol; Cruzado, Josep Maria

2015-11-01

The use of generic formulations of immunosuppressive drugs in renal transplantation has been and still is a controversial subject. The lack of clinical studies about safety and efficacy in transplant patients is one of the factors restricting the diffusion of generic drugs in the renal transplant field. Since March 2013, our transplant unit has incorporated generic tacrolimus (Adoport(®) ; Sandoz), replacing the one we were currently using (Prograf(®) ; Astellas). When carrying out our retrospective analysis comparing the two different formulations, we evaluated several clinical results: tacrolimus trough concentrations (C0) at 5-7 days; 1, 3, and 6 months post-transplantation; concentration/dose ratio at 6 months; acute rejection incidence; delayed graft function (DGF); renal function (as CKD-EPI); and proteinuria at 6 months in 120 patients (1:1 ratio of Prograf(®) versus Adoport(®) ), noticing no important differences. We also evaluated the results of protocol biopsies at 6 months in a subgroup of patients, thus verifying the safety and efficacy of this particular generic drug versus the reference product on a histological basis as well. No difference in the development of dnDSA (de novo donor-specific antibody) was found between the two groups. © 2015 Steunstichting ESOT.

Evaluation of blood zinc, calcium and blood lead levels among children aged 1-36 months.

PubMed

Ji, Xiaojun; He, Hong; Ren, Lisheng; Liu, Ji; Han, Chunhua

2014-09-01

Early childhood lead exposure is associated with numerous adverse health effects. Biomonitoring among susceptible populations, such as children, has not been previously conducted. The aim of the study is to evaluate the blood lead (Pb) and total blood calcium (Ca) levels; blood zinc (Zn) levels. A cross-sectional study was designed to collect healthy children age 1- 36 months (Mean ± SD: 1.5 ± 0.6 age, 60% boys) in the study from January 2010 to September 2011. The overall mean blood Pb levels were 42.18 ± 12.13 μg/L, the overall mean blood Zn and total blood Ca concentrations were 62.18 ± 12.33 μmol/L and 1.78 ± 0.13 mmol/L, respectively. The prevalence of elevated blood Pb levels in all children was 1.3%. A significant difference was found between female and male subjects for the blood Pb and Zn. After controlling for gender and age, there was a weak positive correlation between total blood Ca and Zn level. The blood Pb levels had a significant negative correlation with total blood Ca level after adjusting for age and gender, and these findings suggest that Pb had effect on positive blood Zn and total blood Ca levels; parents should pay more attention to the nutrition of girls. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

Sirolimus and tacrolimus rather than cyclosporine A cause bone loss in healthy adult male rats.

PubMed

Rubert, Mercedes; Montero, Mercedes; Guede, David; Caeiro, Jose-Ramón; Martín-Fernández, Marta; Díaz-Curiel, Manuel; de la Piedra, Concepción

2015-06-01

The aim of this work was to study the effects of cyclosporine (CsA), tacrolimus (FK-506), and rapamycin (RAPA) on bone mass, femoral microstructure, femoral biomechanical properties, and bone remodeling in healthy adult male rats. Forty-eight 5-month-old male Wistar rats were used. CsA (2 mg/kg/day), FK-506 (3 mg/kg/day), RAPA (1.25 mg/kg/day), or water (0.5 ml/rat/day, control group) were administered orally for 3 months. After sacrifice, mean values of immunosuppressants in blood were: CsA (670.4 ng/ml), FK-506 (19.2 ng/ml), and RAPA (4.8 ng/ml). Levels of biochemical parameters were normal in all groups. Femoral BMD was decreased in FK-506 and RAPA groups and lumbar BMD in FK-506 group. Trabecular volume fraction (BV/TV) decreased only in FK-506 group. RAPA and CsA affected femoral cortical structure, but FK-506 did not. FK-506 produced an increase in bone remodeling, and CsA a decrease. FK-506 group showed a decrease in biomechanical parameters relative to all groups. RAPA group showed a decrease in ultimate stress vs control group, and CsA group presented an increase in biomechanical parameters versus control group. We found that administration of both RAPA and FK-506 as monotherapy for healthy rats produced osteopenia. CsA treatment only produces slight damages in the cortical zone of the femur.

Successful treatment for ulcerative proctitis with rectal tacrolimus in an 8-year-old girl with intolerance to mesalamine.

PubMed

Navas-López, Víctor Manuel; Blasco-Alonso, Javier; Girón Fernández-Crehuet, Francisco; Serrano Nieto, Maria Juliana; Gallego-Gutiérrez, Silvia; Luque Pérez, Silvia; Sierra Salinas, Carlos

2014-08-01

Ulcerative colitis (UC) is defined as a chronic inflammatory condition causing continuous mucosal inflammation of the colon without granulomas on biopsy. It affects the rectum, and, to a variable extent, the colon in continuity and is characterized by a relapsing and remitting course. Oral 5-aminosalicylic acid (5-ASA) regimens are recommended as first-line induction therapy for mild to moderately active pediatric UC and for maintenance of remission regardless of other initial treatments. In large clinical trials in adults, mesalamine intolerance was found in 2-5 % of the patients. We present a case of an 8-year-old female patient with intolerance to mesalamine and proctitis resistant to conventional therapy who responded to rectal tacrolimus treatment. The patient started with a dose of 2 mg/day at night with an excellent response. She reported feeling better than any of the previously prescribed treatments and without feeling the discomfort of previously administered enemas. After four weeks of treatment, the dose was reduced to 2 mg/week with no relapses. Tacrolimus suppositories were very well tolerated, and no adverse effects have been reported. Although only very little data has been published, rectal tacrolimus seems to be safe and of efficacy in ulcerative proctitis resistant to standard therapy.

Blood Lead Level Among Fuel Station Workers

PubMed Central

Al-Rudainy, Laith Abdulmajeed

2010-01-01

Objectives This study aims to determine the level of lead in blood of fuel station workers and in a group of people not occupationally exposed to lead Methods 53 control subjects with low risk lead exposure and 45 fuel station workers comprising the study group were included in this study in a period from September 2008 to December 2009. Blood samples were collected and analyzed for each subject by Lead Care Blood Testing System. The average blood lead levels of each group were compared using the independent sample (Mann – Whitney U) test. Results The median (range) 14.1 (7.5–56) μg/dl concentration of lead in the blood of fuel stations workers was significantly higher than the median (range) 6.5 (4.0–1.6) μg/dl concentration of lead in the blood of the control group (p< 0.001).The results obtained also showed that the values of blood lead levels in many workers were higher than action and upper limits acceptable for adults. In fuel station workers, the duration of exposure to leaded fuel was significantly correlated with the blood lead level. Conclusions Occupational exposure to lead is prevalent among many fuel station workers in Basrah. A policy action to improve working conditions and to phase out the use of leaded gasoline is recommended. PMID:22043339

Tacrolimus has immunosuppressive effects on heavy/light chain pairs and free light chains in patients after heart transplantation: A relationship with infection.

PubMed

Lavríková, Petra; Sečník, Peter; Kubíček, Zdenek; Jabor, Antonín; Hošková, Lenka; Franeková, Janka

2018-06-15

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. Copyright © 2018 Elsevier B.V. All rights reserved.

HLA phenotypes and cadmium blood level.

PubMed

Gualde, N; Delage, C

1979-10-01

The distribution of HLA phenotypes was studied and the amount of cadmium blood level was determined in a group of 100 healthy subjects. The HLA-A3 phenotype seems associated with high cadmium levels in the blood. The lymphocytes transformation test with PHA and different concentrations of cadmium indicates that A3 cells are more sensitive than others to inhibition by cadmium.

Tacrolimus interaction with nafcillin resulting in significant decreases in tacrolimus concentrations: A case report.

PubMed

Wungwattana, Minkey; Savic, Marizela

2017-04-01

Tacrolimus (TAC) is subject to many drug interactions as a result of its metabolism primarily via CYP450 isoenzyme 3A4. Numerous case reports of TAC and CYP3A4 inducers and inhibitors have been described including antimicrobials, calcium channel antagonists, and antiepileptic drugs. We present the case of a 13-year-old patient with cystic fibrosis and a history of liver transplantation, where subtherapeutic TAC concentrations were suspected to be a result of concomitant TAC and nafcillin (NAF) therapy. The observed drug interaction occurred on two separate hospital admissions, during both of which the patient exhibited therapeutic TAC concentrations prior to exposure to NAF, a CYP3A4 inducer. Upon discontinuation of NAF, TAC concentrations recovered in both instances. This case represents a drug-drug interaction between TAC and NAF that has not previously been reported to our knowledge. Despite the lack of existing reports of interaction between these two agents, this case highlights the importance of therapeutic drug monitoring and assessing for any potential drug-drug or drug-food interactions in patients receiving TAC therapy. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Blood cholinesterase levels in a group of Malaysian blood donors.

PubMed

Chan, L; Balabaskaran, S; Delilkan, A E; Ong, L H

1994-12-01

Data on blood cholinesterase levels in the Malaysian population is lacking. The spectrophotometric method of Ellman was used to determine the red cell, plasma and whole blood cholinesterase (ChE) levels in 407 Malaysian blood donors. The mean+1SD for plasma ChE in females (n = 48) was 2.37 + 0.70 umol/min/ml and 2.76 + 0.75 umol/min/ml in males (n = 359). The mean plasma ChE in males was higher than in females (p < 0.001). The mean+1SD for red cell ChE in females was 9.01 + 1.20 umol/min/ml whereas in males it was 7.69 +1.30 umol/min/ml (the mean red cell ChE in females was higher than in males, p < 0.0001). The mean+1SD for whole blood ChE for females was 4.31+ 0.58 umol/min/ml and for males it was 4.95 + 0.71 umol/min/ml. The mean whole blood ChE in males was higher than in females (p < 0.0001). Sex influenced the plasma, red cell and whole blood ChE. In males the plasma ChE was affected by the race factor. The mean+1SD plasma ChE for the Malay, Chinese and Indian were 2.92 + 0.80, 2.73 + 0.71 and 2.61+ 0.73 respectively (p < 0.002). The age factor in males affected the red cell ChE with 7.88 + 1.32 in the (30-69) age group and 7.47 + 1.23 in the (15-29) age group (p < 0.005). The whole blood ChE in females was affected by blood groups. The mean+1SD whole blood ChE for blood groups A,B and O were 4.19 + 0.42, 3.93 + 0.46 and 4.49 + 0.62 respectively (p < 0.03). The significant difference is between the ChE of group B and O, but the ChE of group A could not be determined to be different from group B or O. These results serve as guidelines for our local population in the evaluation of cholinesterase levels with regard to pesticide poisoning, liver biosynthetic capacity and unusual sensitivity to succinylcholine.

Plasma cell cheilitis, successfully treated with topical 0.03% tacrolimus ointment.

PubMed

Jin, Seon Pil; Cho, Kwang Hyun; Huh, Chang Hun

2010-05-01

Plasma cell cheilitis is a rare, idiopathic mucosal condition. The treatment of plasma cell cheilitis is often disappointing. It is often resistant to various topical treatments. We present a 65-year-old woman who had a painful, eroded area on her lower lip, which responded poorly to various topical treatments. A biopsy revealed a band-like infiltration composed mainly of plasma cells in the dermis. She was diagnosed as having plasma cell cheilitis, and was successfully treated with 0.03% topical tacrolimus ointment.

Prediabetes in patients receiving tacrolimus in the first year after kidney transplantation: a prospective and multicenter study.

PubMed

Porrini, Esteban; Moreno, Jose Manuel; Osuna, Antonio; Benitez, Rocio; Lampreabe, Ildefonso; Diaz, Juan Manuel; Silva, Irene; Domínguez, Rosa; Gonzalez-Cotorruelo, Julio; Bayes, Beatriz; Lauzurica, Ricardo; Ibernon, Meritxell; Moreso, Francisco; Delgado, Patricia; Torres, Armando

2008-04-27

Tacrolimus-based immunosuppression, the most widely used regimen in kidney transplantation, increases the risk of new onset diabetes after transplantation (NODAT). However, the prevalence, evolution and risk factors of different prediabetic alterations: impaired fasting glucose, impaired glucose tolerance, and provisional diabetes, have not been established. In this multicenter and prospective study we evaluated 154 nondiabetic kidney transplant recipients receiving tacrolimus, mycophenolate mofetil and low dose steroids. An oral glucose tolerance test was performed 3 and 12 months after transplantation and prediabetes was defined by American Diabetes Association criteria. Prediabetes was highly prevalent and showed little variation between 3 and 12 months (36% and 33%, respectively). Impaired glucose tolerance was the most frequent abnormality observed (23% and 25%, respectively) observed. In addition, 20% of recipients showed NODAT by 1 year. Multivariate analysis showed that age (odds ratio [OR]: 1.07, 95% confidence interval [CI]: 1.004-1.14), pretransplant body mass index (OR: 1.3, CI: 1.09-1.6) and triglyceride/high density lipoprotein-cholesterol ratio, a marker of insulin resistance, (OR: 1.4, CI: 1.05-1.9) were independent risk factors for prediabetes. One in two recipients with tacrolimus-based immunosuppresion showed prediabetes or NODAT by 1 year posttransplantation when properly investigated. Older age and high pretransplant body mass index and triglyceride/high density lipoprotein-cholesterol ratio were risk factors for prediabetes. These findings may help applying early interventions to prevent the disorder.

Association Between Tacrolimus Pharmacokinetics and Cytochrome P450 3A5 and Multidrug Resistance Protein 1 Exon 21 Polymorphisms.

PubMed

Soda, M; Fujitani, M; Michiuchi, R; Shibayama, A; Kanamori, K; Yoshikuni, S; Ohno, Y; Tsuchiya, T; Suzuki, A; Horie, K; Deguchi, T; Itoh, Y; Kitaichi, K

Individual differences in the pharmacokinetics (PK) of tacrolimus (TAC), an immunosuppressive drug, are reportedly associated with single-nucleotide polymorphisms (SNPs) of cytochrome P450 (CYP) 3A5 and multidrug resistance protein 1 (MDR1). We determined the effect of SNPs in CYP3A5 and MDR1 exons 21 and 26 on TAC PK parameters. Thirty-eight Japanese patients who underwent renal transplantation were genotyped for CYP3A5 and exons 21 and 26 of MDR1 with the use of polymerase chain reaction-restriction fragment length polymorphism analysis. TAC concentrations were determined 3 weeks after renal transplantation and PK parameters calculated. The area under the blood concentration-time curve (AUC) in CYP3A5 expressers was significantly higher than that in CYP3A5 nonexpressers (CYP3A5*3/*3). Patients with the MDR1 exon 21 A allele (G2677A) showed higher dose-adjusted AUC (AUC/D) and lower doses of TAC than those who did not possess that allele. Furthermore, patients with both CYP3A5*3/*3 and MDR1 G2677A showed significantly lower TAC doses and higher dose-adjusted trough levels (C/D) and AUC/D than those without those genotypes. There was no significant association between MDR1 exon 26 polymorphism and the PK of TAC. Patients with both CYP3A5*3/*3 and MDR1 G2677A had higher blood TAC concentrations than those without those genotypes. Japanese patients should be carefully monitored for consideration of lower TAC doses, because 24% of Japanese patients have double mutations. Copyright © 2017 Elsevier Inc. All rights reserved.

Pretransplant Tacrolimus Dose Requirements Predict Early Posttransplant Dose Requirements in Blood Group AB0-Incompatible Kidney Transplant Recipients.

PubMed

Shuker, Nauras; de Man, Femke M; de Weerd, Annelies E; van Agteren, Madelon; Weimar, Willem; Betjes, Michiel G H; van Gelder, Teun; Hesselink, Dennis A

2016-04-01

The aim of this study was to investigate whether pretransplant tacrolimus (Tac) dose requirements of patients scheduled to undergo living donor kidney transplantation correlate with posttransplantation dose requirements. The predictive value of Tac dose requirements (defined as the ratio of the Tac predose concentration, C0, divided by the total daily Tac dose, D) pretransplantation on this same parameter posttransplantation was assessed retrospectively in a cohort of 57 AB0-incompatible kidney transplant recipients. These patients started immunosuppressive therapy 14 days before transplant surgery. All patients were using a stable dose of glucocorticoids and were at steady-state Tac exposure before transplantation. Tac dose requirements immediately before transplantation (C0/Dbefore) explained 63% of the Tac dose requirements on day 3 after transplantation: r = 0.633 [F (1, 44) = 75.97, P < 0.01]. No other clinical and demographic variables predicted Tac dose requirements early after transplantation. Steady-state Tac dose requirement before transplantation largely predicted posttransplantation Tac dose requirements in AB0-incompatible kidney transplant recipients. The importance of this finding is that the posttransplantation Tac dose can be individualized based on a patient's pretransplantation Tac concentration/dose ratio. Pretransplant Tac phenotyping therefore has the potential to improve transplantation outcomes.

Blood lipid levels in a rural male population.

PubMed

Thelin, A; Stiernström, E L; Holmberg, S

2001-06-01

Farmers have a low risk for cardiovascular disease, which may be related to a favourable blood lipid profile. In order to study the blood lipid levels and evaluate the effect of other cardiovascular risk factors on the blood lipid profile, this cross-sectional study was made. A total of 1013 farmers and 769 non-farming rural men in nine different Swedish counties were examined, interviewed, and replied to questionnaires. The inter-relationships between different risk factors were analysed using a multivariate linear regression model. The farmers had a significantly more favourable blood lipid profile than the non-farmers although the total cholesterol levels were almost the same for the two groups. In the total study population there were significant positive relationships between total cholesterol level and body mass index (BMI), diastolic blood pressure and smoking. The high-density lipoprotein (HDL) level was positively related to physical workload and alcohol consumption, and negatively related to BMI, waist/hip ratio and smoking. Triglyceride levels showed a positive relationship to BMI, waist/hip ratio and blood pressure. Differences between farmers and other rural males were seen, especially with respect to the effect of physical activity and psychosocial factors. Among the farmers, a negative correlation between the Karasek-Theorell authority over work index and total cholesterol, the low-density lipoprotein (LDL)/HDL ratio and triglyceride levels was observed. This study indicated that diet is of minor significance for the blood lipid profile, whereas factors such as physical activity, body weight and the waist/hip ratio, smoking, alcohol consumption, and perhaps psychosocial working conditions are major independent factors affecting the blood lipid profile most prominently among farmers, but also among non-farming rural men.

Immunosuppressive Interactions among Calcium Channel Antagonists and Selected Corticosteroids and Macrolides Using Human whole Blood Lymphocytes

PubMed Central

Chow, Fung-Sing; Jusko, William J.

2014-01-01

Summary The immunosuppressive interactions of calcium channel antagonists [diltiazem (Dil), verapamil (Ver) and nifedipine (Nif)], with corticosteroids [methylprednisolone (Mpl), prednisolone (Prd)], and macrolides [tacrolimus (Tac) and sirolnnus (Sir)] were examined in human whole blood lymphocyte cultures. Gender-related differences in responses in the interactions between these drug classes were studied using blood from 6 males and 6 females. The nature and intensity of interactions were determined using an extended Loewe additivity model. All immunosuppressants exhibited higher potency than the calcium channel antagonists with mean IC50 values of: Dil (mM)Ver (mM)Nif (mM)Mpl (nM)Prd (nM)Tac (nM)Sir (nM)Male13541.921312.118.6150327Female11431.847.44.68.8111106 Gender-related differences in responses to Mpl and Prd were observed while the others were not significant. Additive interactions were found among calcium channel antagonists and corticosteroids. Significant synergistic interactions were observed between calcium channel antagonists and tacrolimus and sirolimus, although these are unlikely to be of clinical importance. These studies demonstrate diverse drug interactions in the examination of an important array of immunosuppressant drug combinations. PMID:15681895

Pilot Analysis of Late Conversion to Belatacept in Kidney Transplant Recipients for Biopsy-Proven Chronic Tacrolimus Toxicity

PubMed Central

Rosales, Ivy

2018-01-01

Background Calcineurin inhibitors are associated with chronic nephrotoxicity, manifesting as interstitial fibrosis/tubular atrophy (IF/TA) and arteriolar hyalinosis. Conversion from tacrolimus to belatacept may be one strategy to preserve renal function. Methods We conducted a retrospective review of renal transplant patients followed at our institution who were converted to belatacept and found to have chronic tacrolimus toxicity on biopsy. The primary outcome was eGFR at conversion as compared to eGFR at 3, 6, 12, and 24 months after conversion. We also assessed incidence of infection and rates of allograft survival at 1 year. Results The average time between transplant and conversion was 11.9 years. There was no decrease in eGFR at any postconversion time point as compared with preconversion. The mean eGFR at time of preconversion was 32.9 mL/min, as compared with 35.6 mL/min at 3 months (p = 0.09), 34.1 mL/min at 6 months (p = 0.63), 34.9 mL/min at 12 months (p = 0.57), and 39.6 mL/min at 24 months after conversion (p = 0.92). Four of 7 patients had increases in their eGFR after conversion. All grafts were functioning at 1 year after conversion. Conclusion While this study was limited by a small number of patients, belatacept conversion stabilized eGFR at all time points in patients with late allograft function due to chronic tacrolimus toxicity, with a trend towards increased eGFR at 3 months. PMID:29854421

A single-centre comparison of the clinical outcomes at 6 months of renal transplant recipients administered Adoport® or Prograf® preparations of tacrolimus

PubMed Central

Connor, Andrew; Prowse, Andrew; Newell, Paul; Rowe, Peter A.

2013-01-01

Background The use of generic formulations of immunosuppressive drugs in place of brand name drugs offers considerable cost savings. Brand name tacrolimus (Prograf®) came off patent in April 2008. However, published evidence supporting therapeutic equivalence of generic formulations of tacrolimus in solid organ transplantation is lacking. The South West Transplant Centre switched from administering Prograf® to a generic formulation (Adoport®) for de novo transplant recipients in November 2010. This study sought to compare the clinical outcomes of renal transplant recipients administered Prograf® with those receiving Adoport®. Methods Data regarding patient characteristics and clinical outcomes were collected retrospectively for all patients undergoing renal transplantation at the South West Transplant Centre between 8 November 2009 and 8 November 2011 to whom tacrolimus was prescribed. Results A total of 48 patients received Prograf® and 51 received Adoport®. At 6 months, no statistically significant differences were identified in the rates of patient survival, graft survival, acute allograft rejection, delayed graft function, calcineurin inhibitor toxicity or cytomegalovirus infection occurring within the two groups. Conclusions This is the first study to compare the clinical outcomes of patients receiving Adoport® with those receiving brand name tacrolimus. We report comparable clinical outcomes at 6 months in patients receiving either Prograf® or Adoport® from the time of renal transplantation. These early outcome data therefore support the use of Adoport® in place of Prograf® as a potential cost-saving measure. PMID:27818747

Randomized Comparison of Topical Betamethasone Valerate Foam, Intralesional Triamcinolone Acetonide and Tacrolimus Ointment in Management of Localized Alopecia Areata

PubMed Central

Kuldeep, CM; Singhal, Himanshu; Khare, Ashok Kumar; Mittal, Asit; Gupta, Lalit K; Garg, Anubhav

2011-01-01

Background: Alopecia areata (AA) is a common, non-scarring, patchy loss of hair at scalp and elsewhere. Its pathogenesis is uncertain; however, auto-immunity has been exemplified in various studies. Familial incidence of AA is 10-42%, but in monozygotic twins is 50%. Local steroids (topical / intra-lesional) are very effective in treatment of localized AA. Aim: To compare hair regrowth and side effects of topical betamethasone valerate foam, intralesional triamcinolone acetonide and tacrolimus ointment in management of localized AA. Materials and Methods: 105 patients of localized AA were initially registered but 27 were drop out. So, 78 patients allocated at random in group A (28), B (25) and C (25) were prescribed topical betamethasone valerate foam (0.1%) twice daily, intralesional triamcinolone acetonide (10mg/ml) every 3 weeks and tacrolimus ointment (0.1%) twice daily, respectively, for 12 weeks. They were followed for next12 weeks. Hair re-growth was calculated using “HRG Scale”; scale I- (0-25%), S II-(26-50%), S III - (51-75%) and S IV- (75-100%). Results: Hair re-growth started by 3 weeks in group B (Scale I: P<0.03), turned satisfactory at 6 weeks in group A and B (Scale I: P<0.005, Scale IV: P<0.001)), good at 9 weeks (Scale I: P<0.0005, Scale IV: P<0.00015), and better by 12 weeks of treatment (Scale I: P<0.000021, Scale IV: P<0.000009) in both A and B groups. At the end of 12 weeks follow-up hair re-growth (>75%, HRG IV) was the best in group B (15 of 25, 60%), followed by A (15 of 28, 53.6%) and lastly group-C (Nil of 25, 0%) patients. Few patients reported mild pain and atrophy at injection sites, pruritus and burning with betamethasone valerate foam and tacrolimus. Conclusion: Intralesional triamcinolone acetonide is the best, betamethasone valerate foam is better than tacrolimus in management of localized AA. PMID:21769231

Change in blood glucose level in rats after immobilization

NASA Technical Reports Server (NTRS)

Platonov, R. D.; Baskakova, G. M.; Chepurnov, S. A.

1981-01-01

Experiments were carried out on male white rats divided into four groups. In group one the blood glucose level was determined immediately after immobilization. In the other three groups, two hours following immobilization, the blood glucose level was determined every 20 minutes for 3 hours 40 minutes by the glucose oxidase method. Preliminary immobilization for 2 hours removed the increase in the blood glucose caused by the stress reaction. By the 2nd hour of immobilization in the presence of continuing stress, the blood glucose level stabilized and varied within 42 + or - 5.5 and 47 + or - 8.1 mg %. Within 2 hours after the immobilization, the differences in the blood glucose level of the rats from the control groups were statistically insignificant.

Incidence of Posttransplantation Diabetes Mellitus in De Novo Kidney Transplant Recipients Receiving Prolonged-Release Tacrolimus-Based Immunosuppression With 2 Different Corticosteroid Minimization Strategies: ADVANCE, A Randomized Controlled Trial.

PubMed

Mourad, Georges; Glyda, Maciej; Albano, Laetitia; Viklický, Ondrej; Merville, Pierre; Tydén, Gunnar; Mourad, Michel; Lõhmus, Aleksander; Witzke, Oliver; Christiaans, Maarten H L; Brown, Malcolm W; Undre, Nasrullah; Kazeem, Gbenga; Kuypers, Dirk R J

2017-08-01

ADVANCE (NCT01304836) was a phase 4, multicenter, prospectively randomized, open-label, 24-week study comparing the incidence of posttransplantation diabetes mellitus (PTDM) with 2 prolonged-release tacrolimus corticosteroid minimization regimens. All patients received prolonged-release tacrolimus, basiliximab, mycophenolate mofetil and 1 bolus of intraoperative corticosteroids (0-1000 mg) as per center policy. Patients in arm 1 received tapered corticosteroids, stopped after day 10, whereas patients in arm 2 received no steroids after the intraoperative bolus. The primary efficacy variable was the diagnosis of PTDM as per American Diabetes Association criteria (2010) at any point up to 24 weeks postkidney transplantation. Secondary efficacy variables included incidence of composite efficacy failure (graft loss, biopsy-proven acute rejection or severe graft dysfunction: estimated glomerular filtration rate (Modification of Diet in Renal Disease-4) <30 mL/min per 1.73 m), acute rejection and graft and patient survival. The full-analysis set included 1081 patients (arm 1: n = 528, arm 2: n = 553). Baseline characteristics and mean tacrolimus trough levels were comparable between arms. Week 24 Kaplan-Meier estimates of PTDM were similar for arm 1 versus arm 2 (17.4% vs 16.6%; P = 0.579). Incidence of composite efficacy failure, graft and patient survival, and mean estimated glomerular filtration rate were also comparable between arms. Biopsy-proven acute rejection and acute rejection were significantly higher in arm 2 versus arm 1 (13.6% vs 8.7%, P = 0.006 and 25.9% vs 18.2%, P = 0.001, respectively). Tolerability profiles were comparable between arms. A prolonged-release tacrolimus, basiliximab, and mycophenolate mofetil immunosuppressive regimen is efficacious, with a low incidence of PTDM and a manageable tolerability profile over 24 weeks of treatment. A lower incidence of biopsy-proven acute rejection was seen in patients receiving corticosteroids tapered over 10

Incidence of Posttransplantation Diabetes Mellitus in De Novo Kidney Transplant Recipients Receiving Prolonged-Release Tacrolimus-Based Immunosuppression With 2 Different Corticosteroid Minimization Strategies: ADVANCE, A Randomized Controlled Trial

PubMed Central

Mourad, Georges; Glyda, Maciej; Albano, Laetitia; Viklický, Ondrej; Merville, Pierre; Tydén, Gunnar; Mourad, Michel; Lõhmus, Aleksander; Witzke, Oliver; Christiaans, Maarten H. L.; Brown, Malcolm W.; Undre, Nasrullah; Kazeem, Gbenga; Kuypers, Dirk R. J.

2017-01-01

Background ADVANCE (NCT01304836) was a phase 4, multicenter, prospectively randomized, open-label, 24-week study comparing the incidence of posttransplantation diabetes mellitus (PTDM) with 2 prolonged-release tacrolimus corticosteroid minimization regimens. Methods All patients received prolonged-release tacrolimus, basiliximab, mycophenolate mofetil and 1 bolus of intraoperative corticosteroids (0-1000 mg) as per center policy. Patients in arm 1 received tapered corticosteroids, stopped after day 10, whereas patients in arm 2 received no steroids after the intraoperative bolus. The primary efficacy variable was the diagnosis of PTDM as per American Diabetes Association criteria (2010) at any point up to 24 weeks postkidney transplantation. Secondary efficacy variables included incidence of composite efficacy failure (graft loss, biopsy-proven acute rejection or severe graft dysfunction: estimated glomerular filtration rate (Modification of Diet in Renal Disease-4) <30 mL/min per 1.73 m2), acute rejection and graft and patient survival. Results The full-analysis set included 1081 patients (arm 1: n = 528, arm 2: n = 553). Baseline characteristics and mean tacrolimus trough levels were comparable between arms. Week 24 Kaplan–Meier estimates of PTDM were similar for arm 1 versus arm 2 (17.4% vs 16.6%; P = 0.579). Incidence of composite efficacy failure, graft and patient survival, and mean estimated glomerular filtration rate were also comparable between arms. Biopsy-proven acute rejection and acute rejection were significantly higher in arm 2 versus arm 1 (13.6% vs 8.7%, P = 0.006 and 25.9% vs 18.2%, P = 0.001, respectively). Tolerability profiles were comparable between arms. Conclusions A prolonged-release tacrolimus, basiliximab, and mycophenolate mofetil immunosuppressive regimen is efficacious, with a low incidence of PTDM and a manageable tolerability profile over 24 weeks of treatment. A lower incidence of biopsy-proven acute rejection was seen in patients

Associations between cadmium levels in blood and urine, blood pressure and hypertension among Canadian adults

DOE Office of Scientific and Technical Information (OSTI.GOV)

Garner, Rochelle E., E-mail: rochelle.garner@canad

Background: Cadmium has been inconsistently related to blood pressure and hypertension. The present study seeks to clarify the relationship between cadmium levels found in blood and urine, blood pressure and hypertension in a large sample of adults. Methods: The study sample included participants ages 20 through 79 from multiple cycles of the Canadian Health Measures Survey (2007 through 2013) with measured blood cadmium (n=10,099) and urinary cadmium (n=6988). Linear regression models examined the association between natural logarithm transformed cadmium levels and blood pressure (separate models for systolic and diastolic blood pressure) after controlling for known covariates. Logistic regression models weremore » used to examine the association between cadmium and hypertension. Models were run separately by sex, smoking status, and body mass index category. Results: Men had higher mean systolic (114.8 vs. 110.8 mmHg, p<0.01) and diastolic (74.0 vs. 69.6 mmHg, p<0.01) blood pressure compared to women. Although, geometric mean blood (0.46 vs. 0.38 µg/L, p<0.01) and creatinine-adjusted standardized urinary cadmium levels (0.48 vs. 0.38 µg/L, p<0.01) were higher among those with hypertension, these differences were no longer significant after adjustment for age, sex and smoking status. In overall regression models, increases in blood cadmium were associated with increased systolic (0.70 mmHg, 95% confidence interval [CI]=0.25–1.16, p<0.01) and diastolic blood pressure (0.74 mmHg, 95% CI=0.30–1.19, p<0.01). The associations between urinary cadmium, blood pressure and hypertension were not significant in overall models. Model stratification revealed significant and negative associations between urinary cadmium and hypertension among current smokers (OR=0.61, 95% CI=0.44–0.85, p<0.01), particularly female current smokers (OR=0.52, 95% CI=0.32–0.85, p=0.01). Conclusion: This study provides evidence of a significant association between cadmium levels, blood

Correlation of salivary glucose level with blood glucose level in diabetes mellitus.

PubMed

Gupta, Shreya; Nayak, Meghanand T; Sunitha, J D; Dawar, Geetanshu; Sinha, Nidhi; Rallan, Neelakshi Singh

2017-01-01

Saliva is a unique fluid, which is important for normal functioning of the oral cavity. Diabetes mellitus (DM) is a disease of absolute or relative insulin deficiency characterized by insufficient secretion of insulin by pancreatic beta-cells. The diagnosis of diabetes through blood is difficult in children, older adults, debilitated and chronically ill patients, so diagnosis by analysis of saliva can be potentially valuable as collection of saliva is noninvasive, easier and technically insensitive, unlike blood. The aim of the study was to correlate blood glucose level (BGL) and salivary glucose level (SGL) in DM patients. A cross-sectional study was conducted in 120 patients, who were categorized as 40 controlled diabetics, 40 uncontrolled diabetics and 40 healthy, age- and sex-matched individuals constituted the controls. The blood and unstimulated saliva samples were collected from the patients at the different intervals for fasting, random and postprandial levels. These samples were then subjected for analysis of glucose in blood and saliva using glucose oxidase/peroxidase reagent in HITACHI 902 (R) Automatic analyzer, and the results were recorded. The mean SGLs were higher in uncontrolled and controlled diabetic groups than in nondiabetic group. A highly statistically significant correlation was found between fasting saliva glucose and fasting blood glucose in all the groups. With increase in BGL, increase in SGL was observed in patients with diabetes suggesting that SGL can be used for monitoring glycemic level in DM.

Correlation of salivary glucose level with blood glucose level in diabetes mellitus

PubMed Central

Gupta, Shreya; Nayak, Meghanand T; Sunitha, JD; Dawar, Geetanshu; Sinha, Nidhi; Rallan, Neelakshi Singh

2017-01-01

Background: Saliva is a unique fluid, which is important for normal functioning of the oral cavity. Diabetes mellitus (DM) is a disease of absolute or relative insulin deficiency characterized by insufficient secretion of insulin by pancreatic beta-cells. The diagnosis of diabetes through blood is difficult in children, older adults, debilitated and chronically ill patients, so diagnosis by analysis of saliva can be potentially valuable as collection of saliva is noninvasive, easier and technically insensitive, unlike blood. The aim of the study was to correlate blood glucose level (BGL) and salivary glucose level (SGL) in DM patients. Methodology: A cross-sectional study was conducted in 120 patients, who were categorized as 40 controlled diabetics, 40 uncontrolled diabetics and 40 healthy, age- and sex-matched individuals constituted the controls. The blood and unstimulated saliva samples were collected from the patients at the different intervals for fasting, random and postprandial levels. These samples were then subjected for analysis of glucose in blood and saliva using glucose oxidase/peroxidase reagent in HITACHI 902(R) Automatic analyzer, and the results were recorded. Results: The mean SGLs were higher in uncontrolled and controlled diabetic groups than in nondiabetic group. A highly statistically significant correlation was found between fasting saliva glucose and fasting blood glucose in all the groups. Conclusion: With increase in BGL, increase in SGL was observed in patients with diabetes suggesting that SGL can be used for monitoring glycemic level in DM. PMID:29391704

Blood lead levels in radiator repair workers in Colorado.

PubMed

Dalton, C B; McCammon, J B; Hoffman, R E; Baron, R C

1997-01-01

A laboratory-based blood lead surveillance system in Colorado identified radiator repair workers as having the highest blood lead levels of all worker groups reported. A survey of 42 radiator repair shops in ten locales throughout Colorado was undertaken to estimate the prevalence of workers with elevated blood lead levels > 25 micrograms/dL. The survey was designed to test the sensitivity of the surveillance system and to assess working conditions and practices in the radiator repair industry in Colorado. Of 63 workers, 39 (62%) had blood lead levels > 25 micrograms/dL. The sensitivity of the surveillance system for detecting radiator repair workers with elevated blood lead levels was estimated at 11%. None of the radiator repair shops had adequate local exhaust ventilation. Work practice and engineering modifications are needed to reduce lead exposure in this industry.

Blood glucose level reconstruction as a function of transcapillary glucose transport.

PubMed

Koutny, Tomas

2014-10-01

A diabetic patient occasionally undergoes a detailed monitoring of their glucose levels. Over the course of a few days, a monitoring system provides a detailed track of their interstitial fluid glucose levels measured in their subcutaneous tissue. A discrepancy in the blood and interstitial fluid glucose levels is unimportant because the blood glucose levels are not measured continuously. Approximately five blood glucose level samples are taken per day, and the interstitial fluid glucose level is usually measured every 5min. An increased frequency of blood glucose level sampling would cause discomfort for the patient; thus, there is a need for methods to estimate blood glucose levels from the glucose levels measured in subcutaneous tissue. The Steil-Rebrin model is widely used to describe the relationship between blood and interstitial fluid glucose dynamics. However, we measured glucose level patterns for which the Steil-Rebrin model does not hold. Therefore, we based our research on a different model that relates present blood and interstitial fluid glucose levels to future interstitial fluid glucose levels. Using this model, we derived an improved model for calculating blood glucose levels. In the experiments conducted, this model outperformed the Steil-Rebrin model while introducing no additional requirements for glucose sample collection. In subcutaneous tissue, 26.71% of the calculated blood glucose levels had absolute values of relative differences from smoothed measured blood glucose levels less than or equal to 5% using the Steil-Rebrin model. However, the same difference interval was encountered in 63.01% of the calculated blood glucose levels using the proposed model. In addition, 79.45% of the levels calculated with the Steil-Rebrin model compared with 95.21% of the levels calculated with the proposed model had 20% difference intervals. Copyright © 2014 Elsevier Ltd. All rights reserved.

Relationship of blood lead levels to obstetric outcome

DOE Office of Scientific and Technical Information (OSTI.GOV)

Angell, N.F.; Lavery, J.P.

1982-01-01

Lead represents a significant environmental hazard to pregnant women and their offspring. Exposure to high environmental levels of lead has been associated with spontaneous abortion, premature rupture of fetal membranes (PROM), and preterm delivery. The relationship between lower exposures and obstetric complications is unknown. The concentration of lead in the blood was measured in 635 specimens of umbilical cord blood collected at delivery. No relationship was found between concentrations of lead in cord blood and the incidence of PROM, preterm delivery, preeclampsia, or meconium staining. Maternal and infant capillary blood was collected 24 hours post partum from 154 of thesemore » deliveries. The concentrations of lead in the blood did not vary significantly among cord, infant, and maternal samples, and the three measurements were highly correlated. Levels of zinc protoporphyrin (ZnP) were increased in cord blood as compared with mothers' blood, but no concentration-response relationships between the ratio of cord ZnP to maternal ZnP and lead were found.« less

Topical Tacrolimus and Periodontal Therapy in the Management of a Case of Oral Chronic GVHD Characterized by Specific Gingival Localization

PubMed Central

Conrotto, Davide; Broccoletti, Roberto; Carcieri, Paola; Giaccone, Luisa; Arduino, Paolo G.

2014-01-01

Background. Chronic graft versus host disease (cGVHD) is a complication following bone marrow transplantation. The oral lesions are difficult to control with a systemic pharmacological therapy. Case Description. A 63-year-old female patient, who underwent an allogeniec transplantation for acute myeloid leukemia, developed a chronic oral and cutaneous GVHD. The patient was treated with topical tacrolimus 0.1%, twice daily for two months, and underwent a protocol of oral hygiene characterized by 3 appointments of scaling, root planning, and daily oral hygiene instructions. The patient showed marked resolution of gingival lesions and a significant improvement of related pain and gingival inflammatory indexes. Clinical Implications. This case report suggests that treatment with topical tacrolimus and professional oral hygiene may be helpful in the management of chronic oral GVHD with severe gingival involvement. PMID:24639902

Topical tacrolimus and periodontal therapy in the management of a case of oral chronic GVHD characterized by specific gingival localization.

PubMed

Conrotto, Davide; Broccoletti, Roberto; Carcieri, Paola; Giaccone, Luisa; Arduino, Paolo G

2014-01-01

Background. Chronic graft versus host disease (cGVHD) is a complication following bone marrow transplantation. The oral lesions are difficult to control with a systemic pharmacological therapy. Case Description. A 63-year-old female patient, who underwent an allogeniec transplantation for acute myeloid leukemia, developed a chronic oral and cutaneous GVHD. The patient was treated with topical tacrolimus 0.1%, twice daily for two months, and underwent a protocol of oral hygiene characterized by 3 appointments of scaling, root planning, and daily oral hygiene instructions. The patient showed marked resolution of gingival lesions and a significant improvement of related pain and gingival inflammatory indexes. Clinical Implications. This case report suggests that treatment with topical tacrolimus and professional oral hygiene may be helpful in the management of chronic oral GVHD with severe gingival involvement.

Blood salvage produces higher total blood product costs in single-level lumbar spine surgery.

PubMed

Canan, Chelsea E; Myers, John A; Owens, Roger Kirk; Crawford, Charles H; Djurasovic, Mladen; Burke, Lauren O; Bratcher, Kelly R; McCarthy, Kathryn J; Carreon, Leah Y

2013-04-15

Retrospective review. To determine the incremental cost-effectiveness of cell saver for single-level posterior lumbar decompression and fusion (PLDF). Intraoperative cell salvage is used during surgery to reduce the need for perioperative allogeneic blood transfusion. Although the use of cell saver may be beneficial in certain circumstances, its utility has not been clearly established for the common procedure of an adult single-level PLDF. Randomly selected adult patients treated with a single-level PLDF between July 2010 and June 2011 at a single institution were identified. Patients who had a combined anterior and posterior approach were excluded. The final study sample for analysis consisted of 180 patients. Hospital records were reviewed to determine whether: (1) cell saver was available during surgery, (2) recovered autologous blood was infused, and (3) the patient received intra- or postoperative allogeneic transfusions. Estimated blood loss, levels fused, volume(s) transfused, and all related complications were recorded. Costs included the cost of allogeneic blood transfusion, setting up the cell saver recovery system, and infusing autologous blood from cell saver, whereas effectiveness measures were allogeneic blood transfusions averted and quality adjusted life years. The incremental cost-effectiveness ratio was $55,538 per allogeneic transfusion averted, with a decrease in the transfusion rate from 40.0% to 38.7% associated with the cell saver approach. This translated into an incremental cost-effectiveness ratio of $5,555,380 per quality adjusted life years gained, which is well above the threshold for an intervention to be considered cost-effective ($100,000 per quality adjusted life years gained). The use of cell saver during a single-level PLDF does not significantly reduce the need for allogeneic blood transfusion and is not cost-effective. The high cost of cell saver in combination with the low complication rate of allogeneic blood transfusion

Effect of metronidazole use on tacrolimus concentrations in transplant patients treated for Clostridium difficile.

PubMed

Early, C R; Park, J M; Dorsch, M P; Pogue, K T; Hanigan, S M

2016-10-01

Two case reports suggest that metronidazole treatment for Clostridium difficile infections (CDI) increases tacrolimus (TAC) trough levels. The primary objective of this study was to determine the clinical significance of this potential interaction in transplant patients receiving CDI treatment. Currently, no robust literature exists to estimate a magnitude of pharmacokinetic interaction between metronidazole and TAC. In this retrospective study, the effects of CDI and metronidazole treatment on TAC levels in 52 adult solid organ transplant patients were investigated. The primary outcome was to determine the difference in dose-normalized TAC levels between baseline and symptom resolution in patients treated with metronidazole or vancomycin. The secondary outcome was to determine the difference in dose-normalized TAC levels at baseline and CDI diagnosis. The average change in log-transformed dose-normalized TAC levels from baseline to symptom resolution was 0.99 for metronidazole (n = 35) and 1.04 for vancomycin (n = 17) treatment. The mean difference between the groups was 0.96 (95% confidence interval: 0.74-1.24). No significant difference was found between dose-normalized TAC levels at CDI diagnosis and baseline (P = 0.37). CDI treatment with metronidazole was not associated with a >30% increase in TAC levels compared with vancomycin. Both treatment groups required TAC dose adjustments to maintain goal TAC levels and those treated with metronidazole did not require a significantly greater dose adjustment. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Strangers headed to a strange land? A pilot study of using a transition coordinator to improve transfer from pediatric to adult services.

PubMed

Annunziato, Rachel A; Baisley, Margaret C; Arrato, Nicole; Barton, Codette; Henderling, Fiona; Arnon, Ronen; Kerkar, Nanda

2013-12-01

To compare the impact of a transition coordinator on outcomes for pediatric liver transplant recipients vs a historical comparison group. To examine the utility of a transition coordinator, medication adherence, as measured by SDs of tacrolimus blood levels (Tacrolimus SD), was compared between the "transition coordinator group" (20 transplant recipients transferred between 2007 and 2012) and comparison group for 1 year before and after transfer. Measures of health care management, quality of life, and acceptability were administered to the transition coordinator group as well. A repeated measures ANOVA was used to compare adherence values between the transition coordinator group and the comparison group. During the year before transfer, for the transition coordinator group, Tacrolimus SD was 1.98 (SD = 1.05) vs 3.25 (SD = 1.19) for comparison patients, F(1,25) = 4.77, P = .04. After transfer, levels remained stable for the transition coordinator group, Tacrolimus SD = 1.88 (SD = 1.57), but increased for comparison patients, Tacrolimus SD = 4.36 (SD = 0.99), F(1,25) = 6.99, P = .01. Psychosocial outcomes remained stable during the transfer period and acceptability was high. Our findings, although limited by a small sample size, suggest that a transition coordinator is a promising method to improve this process. Copyright © 2013 Mosby, Inc. All rights reserved.

Feather growth influences blood mercury level of young songbirds.

PubMed

Condon, Anne M; Cristol, Daniel A

2009-02-01

Dynamics of mercury in feathers and blood of free-living songbirds is poorly understood. Nestling eastern bluebirds (Sialia sialis) living along the mercury-contaminated South River (Virginia, USA) had blood mercury levels an order of magnitude lower than their parents (nestling: 0.09 +/- 0.06 mg/kg [mean +/- standard deviation], n = 156; adult: 1.21 +/- 0.57 mg/kg, n = 86). To test whether this low blood mercury was the result of mercury sequestration in rapidly growing feathers, we repeatedly sampled free-living juveniles throughout the period of feather growth and molt. Mean blood mercury concentrations increased to 0.52 +/- 0.36 mg/kg (n = 44) after the completion of feather growth. Some individuals had reached adult blood mercury levels within three months of leaving the nest, but levels dropped to 0.20 +/- 0.09 mg/kg (n = 11) once the autumn molt had begun. Most studies of mercury contamination in juvenile birds have focused on recently hatched young with thousands of rapidly growing feathers. However, the highest risk period for mercury intoxication in young birds may be during the vulnerable period after fledging, when feathers no longer serve as a buffer against dietary mercury. We found that nestling blood mercury levels were not indicative of the extent of contamination because a large portion of the ingested mercury ended up in feathers. The present study demonstrates unequivocally that in songbirds blood mercury level is influenced strongly by the growth and molt of feathers.

Association of low-level blood lead and blood pressure in NHANES 1999-2006

DOE Office of Scientific and Technical Information (OSTI.GOV)

Scinicariello, Franco, E-mail: fes6@cdc.gov; Abadin, Henry G.; Edward Murray, H.

This study investigated whether low blood-lead levels ({<=}10 {mu}g/dL) were associated with blood pressure (BP) outcomes. The authors analyzed data from National Health and Nutrition Examination Survey 1999-2006 and participants aged 20 years or older. Outcome variables were systolic and diastolic BP measurements, pulse pressure, and hypertension status. Multivariable linear and logistic regressions stratified by race/ethnicity and gender were performed. Blood lead levels (BLL) were significantly correlated with higher systolic BP among black men and women, but not white or Mexican-American participants. BLLs were significantly associated with higher diastolic BPs among white men and women and black men, whereas, amore » negative association was observed in Mexican-American men that had, also, a wider pulse pressure. Black men in the 90th percentile of blood lead distribution (BLL{>=}3.50 {mu}g/dL) compared to black men in the 10th percentile of blood lead distribution (BLL{<=}0.7 {mu}g/dL) had a significant increase of risk of having hypertension (adjusted POR=2.69; 95% CI: 1.08-6.72). In addition, blood cadmium was significantly associated with hypertension and systolic and diastolic blood. This study found that, despite the continuous decline in blood lead in the U.S. population, lead exposure disparities among race and gender still exist.« less

Can gingival crevicular blood be relied upon for assessment of blood glucose level?

PubMed

Dwivedi, Shivani; Verma, Sharmila J; Shah, Monali; Jain, Kapil

2014-11-01

Diabetes mellitus (DM) is undiagnosed in approximately half of the patients actually suffering from the disease. In addition, the prevalence of DM is more than twice as high as in patients with periodontitis when compared to periodontally healthy subjects. Thus, a high number of patients with periodontitis may have undiagnosed DM. The purpose of the present study was to evaluate whether blood oozing from a gingival crevice during routine periodontal examination can be used for determining glucose levels. Observational cross-sectional studies were carried out in 75 patients (43 males and 32 females) with chronic periodontitis who were divided into two groups: Group I and Group II, respectively. Blood oozing from the gingival crevices of anterior teeth following periodontal probing was collected with the stick of glucose self-monitoring device, and the blood glucose levels were measured. At the same time, finger-prick blood was taken for glucometric analysis and subsequent readings were recorded. The patient's blood glucose values ranged from 74 to 256 mg/dl. The comparison between gingival crevicular blood and finger-prick blood showed a very strong correlation, with a t value of 3.97 (at P value = 0.001). The data from this study has shown that GCB collected during diagnostic periodontal examination can be an excellent source of blood for glucometric analysis.

A comparison of the extended-release and standard-release formulations of tacrolimus in de novo kidney transplant recipients: a 12-month outcome study.

PubMed

Fanous, Helen; Zheng, Rebecca; Campbell, Carolyn; Huang, Michael; Nash, Michelle M; Rapi, Lindita; Zaltzman, Jeffrey S; Prasad, G V Ramesh

2013-02-01

BACKGROUND: Limited comparative data are available on the outcomes between extended-release and standard-release tacrolimus when used de novo in kidney transplant recipients (KTRs). METHODS: We identified KTRs transplanted at our institution during 2009-10 routinely prescribed extended-release tacrolimus and compared them with those transplanted during 2008-09 prescribed standard-release tacrolimus. Graft function (eGFR by MDRD-7 equation) at 12 months post-transplant (primary outcome); new-onset diabetes and other cardiovascular risk factors, BK viremia incidence, acute rejection, and graft survival to 12 months (secondary outcomes) were compared by intent-to-treat analysis. Time-to-steady-state concentration and number of dose adjustments required to attain steady state were recorded. RESULTS: There were no important demographic differences between the extended-release (N = 106) and standard-release (N = 95) cohorts. The estimated glomerular filtration rate (eGFR) at 12 months was similar (58.8 ± 17 versus 59.2 ± 18 mL/min/1.73 m(2), P = 0.307). There was no difference in new-onset diabetes (17 versus 20%, P = 0.581), BK viremia (10 versus 7%, P = 0.450), acute rejection (7 versus 16%, P = 0.067) or graft survival (97 versus 95%, P = 0.301). Time-to-steady state was similar (9.2 ± 1.1 versus 8.1 ± 4.7 days, P = 0.490) although extended-release patients required fewer adjustments to attain steady state (1.2 ± 1.7 [0-8] versus 1.7 ± 1.5 [0-7], P = 0.030) but a similar dose (7.2 ± 2.4 [2-17] versus 7 ± 2.7 [2-16] mg/day, P = 0.697). CONCLUSION: De novo KTRs prescribed extended-release or standard-release tacrolimus demonstrate similar 12-month outcomes.

Blood lead and carboxyhemoglobin levels in chainsaw operators.

PubMed

van Netten, C; Brubaker, R L; Mackenzie, C J; Godolphin, W J

1987-06-01

Fallers in the British Columbia west coast lumber industry often work in climatic and local conditions where little ventilation in their immediate environment is possible. Under these conditions carbon monoxide (CO) and lead fumes from exhaust gases could build up and become a serious occupational hazard. This study monitored the environmental exposure of six fallers to carbon monoxide, nitrogen oxides, and lead under conditions where buildup of these agents would be expected. At the same time blood samples were taken to correlate these environmental concentrations to carboxyhemoglobin (COHb) and blood lead levels. Although there was a highly significant difference between the fallers and the controls regarding the exposure to CO and lead as well as their corresponding COHb and blood lead levels, the environmental and blood concentration of the agents in question did not exceed the maximum allowable concentrations. Temporary short fluctuations in carboxyhemoglobin levels were not monitored in this study and cannot be ruled out as a potential occupational hazard.

[Factors modifying cord blood IgE levels - a pilot study].

PubMed

Petrovičová, O; Bánovčin, P; Babušíková, E; Jeseňák, M

The complex influence of internal and external environmental factors on the individual and his/her immune system and the lack of suitable markers to assess and reduce the risk of the development of allergies during the lifetime can explain the continuous increase in the number of people affected by some form of allergy. According to the results of some studies, cord blood IgE level could be a useful early marker for assessing the risk of atopic diseases, but the studies showed controversial results. In addition, several authors discuss the origin of these antibodies (synthesis in utero, peripartum contamination from maternal blood or placental transfer). The aim of our pilot study was to investigate the possible influence of modifying factors on cord blood IgE level. Our group of patients consisted of 184 retrospectively selected neonates (98 boys, 53.3% and 86 girls, 46.7%) from whom cord blood was collected and cord blood IgE level was measured 25 years ago (PRIST method). The impact of selected modifying factors (sex, type of delivery or month of birth) on cord blood IgE level was assessed retrospectively. Higher cord blood IgE levels were found in boys than in girls, in neonates born by Caesarean section than in those born by natural delivery, and in those born in the winter months than in other seasons of the year. Our findings are in agreement with those of other authors. Based on our results and those of others, we assume that the selected factors affect the cord blood IgE levels to varying degrees. These facts should be taken into consideration while interpreting the cord blood IgE levels.

Incidence and risk factors for the metabolic syndrome and posttransplant diabetes in renal transplant recipients taking tacrolimus.

PubMed

Pérez-Flores, I; Sánchez-Fructuoso, A; Calvo, N; Valga, E F; Barrientos, A

2010-10-01

We investigated the incidence and risk factors for the metabolic syndrome (MS) and posttransplant diabetes mellitus (PTDM) among renal transplant recipients on tacrolimus-based immunosuppressive regimens during the first year posttransplant. In addition, we studied the relationship between MS and PTDM with transplant renal function at 1 year. We included the 100 patients who received a renal transplant in our unit between January 2007 and June 2008, collecting demographic, clinical and biochemical characteristics at 1, 6, and 12 months posttransplantation. We excluded 15% of patients with pretransplantation diabetes. MS was defined according to the National Cholesterol Education Program criteria and PTDM according to World Health Organization criteria. Insulin resistance at one year posttransplant was measured using the homeostasis model assessment (HOMA) index. Insulin therapy was required in 46% of patients during the first hospitalization and hyperglycemia was present in 65% of the cases. The incidence of PTDM decreased throughout the first year posttransplant, namely, 44%, 24%, and 13% at 1, 6, and 12 months, respectively. The incidence of MS increased to 33%, 48% and 50% at 1, 6, and 12 months, respectively. Age, body mass index, plasma fasting glucose levels at 1 month posttransplant, and pretransplant fasting triglyceridemia predicted PTDM. Rejection and in-patient hyperglycemia predicted MS. PTDM and MS were closely correlated (P=.004). The HOMA index was higher among patients with MS than other subjects at 1 year posttransplant: 3.2 (1.2) versus 2.3 (0.9; P=.035). Neither PTDM nor MS was associated with impaired plasma creatinine levels at 1 year after kidney transplantation. There was an high incidence of PTDM and MS among kidney transplant recipients treated with tacrolimus as the main immunosuppressive agent. The HOMA index was a good test of insulin resistance in this population. Screening and treatment of risk factors may avoid the development of

Effect of interventions on children's blood lead levels.

PubMed Central

Hilts, S R; Bock, S E; Oke, T L; Yates, C L; Copes, R A

1998-01-01

Trail, Canada, has been the site of an active lead/zinc smelter for nearly a century. Since 1991, the Trail Community Lead Task Force has carried out blood lead screening, case management, education programs targeted at early childhood groups and the general community, community dust abatement, exposure pathways studies, and remedial trials. From 1989 through 1996, average blood lead levels of children tested for the first time declined at an average rate of 0.6 microg/dl/year, while blood lead levels in Canadian children not living near point sources appeared to be leveling off following the phase-out of leaded gasoline. Since there was no concurrent improvement in local environmental conditions during this time, it is possible that the continuing decline in Trail blood lead levels has been at least partly due to community-wide intervention programs. One year follow-up of children whose families received in-home educational visits, as well as assistance with home-based dust control measures, found that these specific interventions produced average blood lead changes of +0.5- -4.0 microg/dl, with statistically significant declines in 3 years out of 5. Education and dust control, particularly actions targeted toward higher risk children, appear to have served as effective and appropriate interim remedial measures while major source control measures have been implemented at the smelter site. Images Figure 1 Figure 2 PMID:9435149

A search for new CYP3A4 variants as determinants of tacrolimus dose requirements in renal-transplanted patients.

PubMed

Tavira, Beatriz; Coto, Eliecer; Diaz-Corte, Carmen; Alvarez, Victoria; López-Larrea, Carlos; Ortega, Francisco

2013-08-01

The CYP3A5*3 and CYP3A4*1B alleles have been related with tacrolimus (Tac) dose requirements. The rare CYP3A4*22 variant has also been associated with a significantly lower Tac dose. We genotyped the three single-nucleotide polymorphisms in 206 kidney-transplanted patients who received Tac as the primary immunosuppressor. CYP3A5*1 and CYP3A4*1B allele carriers received a significantly higher Tac dose (P<0.01) compared with wild-type homozygotes. We did not find significant differences between the CYP3A4*22 genotypes, either nominally or according to the CYP3A5 genotype (expressers vs. nonexpressers). Sequencing of CYP3A4 coding exons in a total of 15 patients revealed only one nonreported missense change (p.P227>T) in one patient. We concluded that CYP3A5*3 and CYP3A4*1B were the main determinants of the Tac dose-adjusted blood concentration in our cohort of renal-transplanted patients.

Blood lead levels in children aged 24 to 36 months in Vancouver.

PubMed Central

Jin, A; Hertzman, C; Peck, S H; Lockitch, G

1995-01-01

OBJECTIVES: To determine the blood lead levels in children and to identify risk factors for elevated levels. DESIGN: Cross-sectional study. SETTING: Vancouver. PARTICIPANTS: Random sample of children aged 24 to 36 months, born and still resident in Vancouver. The sample was stratified proportionally by the median annual family income in the census tract where each family resided. OUTCOME MEASURES: Blood lead levels and risk factors for elevated blood lead levels, determined from a questionnaire administered to parents. RESULTS: Of the children in the sample, 42% (178/422) were ineligible or could not be located. Of the remaining children, 73% (177/244) participated and adequate blood specimens were obtained from 172. The mean blood lead level was 0.29 mumol/L (standard deviation 0.13 mumol/L). (A blood lead level of 1 mumol/L is equivalent to 20.7 micrograms/dL.) The lowest level was 0.06 mumol/L, and the highest was 0.85 mumol/L. Of children with adequate samples, 8.1% (14/172) had blood lead levels of 0.48 mumol/L or higher, and 0.6% (1/172) had a level higher than 0.72 mumol/L. The logarithms of the levels were normally distributed, with a geometric mean (GM) of 0.26 mumol/L (geometric standard deviation 1.56). Of approximately 70 possible predictors of blood lead levels analysed, those that showed a statistically significant association (p < 0.05) with increased blood lead levels were soldering performed in the home as part of an electronics hobby (GM blood lead level 0.34 mumol/L, 95% confidence interval [CI] 0.27 to 0.39 mumol/L), aboriginal heritage (GM blood lead level 0.33 mumol/L, 95% CI 0.28 to 0.39 mumol/L), dwelling built before 1921 (GM blood lead level 0.32 mumol/L, 95% CI 0.28 to 0.37 mumol/L), age of water service connection to dwelling (predicted blood lead level 0.00087 mumol/L [95% CI 0.00005 to 0.00169 mumol/L] higher per year since service connection) and decreased stature (predicted blood lead level 0.018 mumol/L [95% CI 0.0353 to 0

Toward an Inexpensive Test for Vitamin D Levels in Blood

DTIC Science & Technology

2014-12-01

Vitamin D is crucial for the human body due to its role in calcium and bone metabolism. In addition, low blood levels of vitamin D levels have been...Award Number: W81XWH-12-1-0624 TITLE: Toward an Inexpensive Test for Vitamin D levels in Blood PRINCIPAL INVESTIGATOR: Alan C. West...AND SUBTITLE Toward an Inexpensive Test for Vitamin D levels in Blood 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-12-1-0624 5c. PROGRAM ELEMENT

Factors Associated With Elevated Blood Lead Levels in Children.

PubMed

Chaudhary, Sakshi; Firdaus, Uzma; Ali, Syed Manazir; Mahdi, Abbas Ali

2018-01-15

To determine the prevalence and correlates of elevated blood lead level in children (6-144 months) of Aligarh. A hospital-based cross-sectional study was conducted. Venous blood was obtained for lead estimation and a structured questionnaire was filled. A total of 260 children were enrolled. The prevalence of elevated blood lead level was 44.2%, seen mostly in children below 5 years of age. Old and deteriorating wall paints at home was found to be significantly associated with elevated levels. Lead-based house paints are potential source of lead exposure. Meticulous renovation and painting of the walls with safe paints is desirable.

A survey of blood lead levels among young Johannesburg school children.

PubMed

Mathee, A; von Schirnding, Y E R; Levin, J; Ismail, A; Huntley, R; Cantrell, A

2002-11-01

Studies conducted around the world have established beyond doubt that elevated childhood blood lead levels may lead to detrimental health effects. Research has shown that certain groups of South African children are at particular risk of elevated blood lead levels. Johannesburg is the largest urban complex in southern Africa, with a population of around 3 million and extensive industrial and manufacturing activity. Among the challenges posed in the city are rapid urbanization, extensive poverty, and inequity. Little information on the blood lead distribution of Johannesburg children is available. This study was undertaken to determine blood lead levels among children living in three areas of Johannesburg: inner city suburbs and the low-income townships of Alexandra and Westbury to the north and west of the city center, respectively. The results indicated that blood lead levels ranged from 6 to 26 micro g/dL, with a mean level of 11.9 micro g /dL. The blood lead levels of 78% of children equaled or exceeded 10 micro g/dL, the current international action level. Maternal educational status, the presence of smokers in the home, and living in an informal dwelling were among the factors associated with elevated blood lead levels.

Granulosis rubra nasi: a rare condition treated successfully with topical tacrolimus.

PubMed

Kumar, Piyush; Gosai, Anubhav; Mondal, Ashim Kumar; Lal, Niharika Ranjan; Gharami, Ramesh Chandra

2012-01-02

A 20 years-old girl presented with multiple asymptomatic reddish vesicles on face for four years. It used to get worse in summer and was associated with localized hyperhidrosis. The lesions were notable for disappearance on diascopy. Histopathology from the vesicle showed mononuclear cell infiltration in the upper dermis, especially around eccrine sweat apparatus, along with dilatation of superficial capillaries and lymphatics. Based on clinical presentation and histopathology, diagnosis of Granulosis rubra nasi (GRN) was made. GRN usually resolves at puberty; however, rarely it may persist in adulthood. We here report a case of GRN having lesions persisting in adulthood. Moreover, she showed excellent response to topical tacrolimus, a finding not observed in literature.

Associations between cadmium levels in blood and urine, blood pressure and hypertension among Canadian adults.

PubMed

Garner, Rochelle E; Levallois, Patrick

2017-05-01

Cadmium has been inconsistently related to blood pressure and hypertension. The present study seeks to clarify the relationship between cadmium levels found in blood and urine, blood pressure and hypertension in a large sample of adults. The study sample included participants ages 20 through 79 from multiple cycles of the Canadian Health Measures Survey (2007 through 2013) with measured blood cadmium (n=10,099) and urinary cadmium (n=6988). Linear regression models examined the association between natural logarithm transformed cadmium levels and blood pressure (separate models for systolic and diastolic blood pressure) after controlling for known covariates. Logistic regression models were used to examine the association between cadmium and hypertension. Models were run separately by sex, smoking status, and body mass index category. Men had higher mean systolic (114.8 vs. 110.8mmHg, p<0.01) and diastolic (74.0 vs. 69.6mmHg, p<0.01) blood pressure compared to women. Although, geometric mean blood (0.46 vs. 0.38µg/L, p<0.01) and creatinine-adjusted standardized urinary cadmium levels (0.48 vs. 0.38µg/L, p<0.01) were higher among those with hypertension, these differences were no longer significant after adjustment for age, sex and smoking status. In overall regression models, increases in blood cadmium were associated with increased systolic (0.70mmHg, 95% confidence interval [CI]=0.25-1.16, p<0.01) and diastolic blood pressure (0.74mmHg, 95% CI=0.30-1.19, p<0.01). The associations between urinary cadmium, blood pressure and hypertension were not significant in overall models. Model stratification revealed significant and negative associations between urinary cadmium and hypertension among current smokers (OR=0.61, 95% CI=0.44-0.85, p<0.01), particularly female current smokers (OR=0.52, 95% CI=0.32-0.85, p=0.01). This study provides evidence of a significant association between cadmium levels, blood pressure and hypertension. However, the significance and

Traumatic Brain Injury Causes a Tacrolimus-Sensitive Increase in Non-Convulsive Seizures in a Rat Model of Post-Traumatic Epilepsy.

PubMed

Campbell, John N; Gandhi, Anandh; Singh, Baljinderjit; Churn, Severn B

2014-01-01

Epilepsy is a significant but potentially preventable complication of traumatic brain injury (TBI). Previous research in animal models of acquired epilepsy has implicated the calcium-sensitive phosphatase, calcineurin. In addition, our lab recently found that calcineurin activity in the rat hippocampus increases acutely after lateral TBI. Here we use a calcineurin inhibitor test whether an acute increase in calcineurin activity is necessary for the development of late post-traumatic seizures. Adult rats were administered the calcineurin inhibitor Tacrolimus (5mg/kg; i.p.) 1 hour after lateral fluid percussion TBI and then monitored by video-electrocorticography (video-ECoG) for spontaneous seizure activity 5 weeks or 33 weeks later. At 5 weeks post-TBI, we observed epileptiform activity on the video-ECoG of brain injured rats but no seizures. By 33 weeks post-TBI though, nearly all injured rats exhibited spontaneous seizures, including convulsive seizures which were infrequent but lasted minutes (18% of injured rats), and non-convulsive seizures which were frequent but lasted tens of seconds (94% of injured rats). We also identified non-convulsive seizures in a smaller subset of control and sham TBI rats (56%), reminiscent of idiopathic seizures described in other rats strains. Non-convulsive seizures in the brain injured rats, however, were four-times more frequent and two-times longer lasting than in their uninjured littermates. Interestingly, rats administered Tacrolimus acutely after TBI showed significantly fewer non-convulsive seizures than untreated rats, but a similar degree of cortical atrophy. The data thus indicate that administration of Tacrolimus acutely after TBI suppressed non-convulsive seizures months later.

Low zinc serum levels and high blood lead levels among school-age children in coastal area

NASA Astrophysics Data System (ADS)

Pramono, Adriyan; Panunggal, Binar; Rahfiludin, M. Zen; Swastawati, Fronthea

2017-02-01

The coverage of environmental lead toxicant was quiet wide. Lead exposure recently has been expected to be associated with zinc deficiency and blood indices disturbance. Emphasizing on children, which could absorb more than 50 % of lead that enters the body. Lead became the issue on the coastal area due to it has polluted the environment and waters as the source of fisheries products. This was a cross sectional study to determined nutritional status, blood lead levels, zinc serum levels, blood indices levels, fish intake among school children in coastal region of Semarang. This study was carried out on the school children aged between 8 and 12 years old in coastal region of Semarang. Nutritional status was figured out using anthropometry measurement. Blood lead and zinc serum levels were analyzed using the Atomic Absorbent Spectrophotometry (AAS) at a wavelength of 213.9 nm for zinc serum and 283.3 nm for blood lead. Blood indices was measured using auto blood hematology analyzer. Fish intake was assessed using 3-non consecutive days 24-hours food recall. The children had high lead levels (median 34.86 μg/dl, range 11.46 - 58.86 μg/dl) compared to WHO cut off. Zinc serum levels was low (median 18.10 μg/dl, range 10.25 - 41.39 μg/dl) compared to the Joint WHO/UNICEF/IAEA/IZiNCG cut off. Approximately 26.4% of children were anemic. This study concluded that all school children had high blood lead levels, low zinc serum, and presented microcytic hypochromic anemia. This phenomenon should be considered as public health concern.

Ghrelin administered spinally increases the blood glucose level in mice.

PubMed

Sim, Yun-Beom; Park, Soo-Hyun; Kim, Sung-Su; Kim, Chea-Ha; Kim, Su-Jin; Lim, Su-Min; Jung, Jun-Sub; Suh, Hong-Won

2014-04-01

Ghrelin is known as a regulator of the blood glucose homeostasis and food intake. In the present study, the possible roles of ghrelin located in the spinal cord in the regulation of the blood glucose level were investigated in ICR mice. We found that intrathecal (i.t.) injection with ghrelin (from 1 to 10 μg) caused an elevation of the blood glucose level. In addition, i.t. pretreatment with YIL781 (ghrelin receptor antagonist; from 0.1 to 5 μg) markedly attenuated ghrelin-induced hyperglycemic effect. The plasma insulin level was increased by ghrelin. The enhanced plasma insulin level by ghrelin was reduced by i.t. pretreatment with YIL781. However, i.t. pretreatment with glucagon-like peptide-1 (GLP-1; 5 μg) did not affect the ghrelin-induced hyperglycemia. Furthermore, i.t. administration with ghrelin also elevated the blood glucose level, but in an additive manner, in d-glucose-fed model. Our results suggest that the activation of ghrelin receptors located in the spinal cord plays important roles for the elevation of the blood glucose level. Copyright © 2014 Elsevier Inc. All rights reserved.

Influence of blood donation on levels of water-soluble vitamins.

PubMed

Kalus, U; Pruss, A; Wodarra, J; Kiesewetter, H; Salama, A; Radtke, H

2008-12-01

Iron depletion is a well-known side effect of blood donation. Research evidence also suggests an increasing prevalence of vitamin deficiency in apparently healthy subjects, but there is little information regarding the relationship between blood donation and vitamin status. A total of 217 volunteers (80 first-time and 137 repeat blood donors) were consecutively enrolled in the study. All subjects completed self-administered medical history and food intake forms, which included questions regarding alcohol consumption and smoking as well as on vitamin supplement, iron and contraceptive use (females). Vitamin B6, folic acid, vitamin B12 and biotin levels were measured using standard techniques. The mean vitamin levels of first-time and repeat blood donors did not significantly differ. Vitamin deficiencies occurred in both first-time and repeat blood donors but not on vitamin supplements. Vitamin status was affected by alcohol, nicotine and contraceptives. Blood donation does not decrease the level of water-soluble vitamins. Vitamin deficiencies occur in apparently healthy first-time as well as in repeat blood donors and can be prevented by vitamin supplementation.

Post-transplant soluble CD30 levels are associated with early subclinical rejection in kidney transplantation.

PubMed

Grenzi, Patricia C; Campos, Érika F; Silva, Hélio T; Felipe, Claudia R; Franco, Marcelo F; Soares, Maria F; Medina-Pestana, José O; Gerbase-DeLima, Maria

2015-03-01

Several studies have shown association of high pre- or post-transplant levels of soluble CD30 (sCD30) with acute rejection and poor late kidney transplant outcome. Our goal was to investigate whether sCD30 levels at month-3 post-transplant are associated with subclinical rejection, presence of CD30(+) cells within the graft, and expression of immune response genes in peripheral blood mononuclear cells. The study comprised 118 adult first kidney graft recipients, transplanted at a single center, receiving tacrolimus in low concentration. All were submitted to a protocol biopsy at month-3. Subclinical rejection was identified in 10 biopsies and sCD30 levels ≥ 61.88 ng/mL (P = 0.004), younger recipient age (P = 0.030) and non-Caucasian ethnicity (P = 0.011) were independently associated with this outcome. Rare CD30(+) cells were present in only two biopsies. There was a correlation between sCD30 levels and CD30 gene expression in peripheral blood mononuclear cells (r = 0.385, P = 0.043). These results show that high sCD30 levels are independent predictors of graft dysfunction and may contribute to patient selection protocols by indicating those who could benefit from a more thorough evaluation. Copyright © 2015 Elsevier B.V. All rights reserved.

Association between blood cholesterol level with periodontal status of coronary heart disease patients

NASA Astrophysics Data System (ADS)

Valensia, Rosy; Masulili, Sri Lelyati C.; Lessang, Robert; Radi, Basuni

2017-02-01

Coronary heart disease (CHD) is an abnormal narrowing of heart arteries associated with local accumulation of lipids, in the form of cholesterol and triglycerides. Periodontal disease is a chronic inflammatory that suggests link to the development of CHD. In periodontitis have been reported changes in lipid profile, include increased of cholesterol levels of blood. Objective: to analyse correlation between blood cholesterol level with periodontal status of CHD and non CHD subjects. Methods: Periodontal status and blood cholesterol level of 60 CHD and 40 non CHD subjects was measured. Result: Blood cholesterol level in CHD subjects differs from non CHD subjects (p=0.032). Blood cholesterol level correlates with pocket depth (p=0.003) and clinical attachment loss (CAL) (p=0.000) in CHD subjects. Blood cholesterol level correlates with pocket depth (p=0.010) in non CHD subjects. There is no significant correlation between blood cholesterol level and bleeding on probing (BOP) in CHD subjects. There is no significant correlation between blood cholesterol level with BOP and CAL in non CHD subjects. Conclusion: Blood cholesterol level in control group is higher than CHD patients. Blood cholesterol level positively associated with pocket depth (r=0.375) and CAL (r=0.450) in CHD patients. Blood cholesterol level is positively associated with pocket depth (r=0.404) in control group.

Parsimonious model for blood glucose level monitoring in type 2 diabetes patients.

PubMed

Zhao, Fang; Ma, Yan Fen; Wen, Jing Xiao; DU, Yan Fang; Li, Chun Lin; Li, Guang Wei

2014-07-01

To establish the parsimonious model for blood glucose monitoring in patients with type 2 diabetes receiving oral hypoglycemic agent treatment. One hundred and fifty-nine adult Chinese type 2 diabetes patients were randomized to receive rapid-acting or sustained-release gliclazide therapy for 12 weeks. Their blood glucose levels were measured at 10 time points in a 24 h period before and after treatment, and the 24 h mean blood glucose levels were measured. Contribution of blood glucose levels to the mean blood glucose level and HbA1c was assessed by multiple regression analysis. The correlation coefficients of blood glucose level measured at 10 time points to the daily MBG were 0.58-0.74 and 0.59-0.79, respectively, before and after treatment (P<0.0001). The multiple stepwise regression analysis showed that the blood glucose levels measured at 6 of the 10 time points could explain 95% and 97% of the changes in MBG before and after treatment. The three blood glucose levels, which were measured at fasting, 2 h after breakfast and before dinner, of the 10 time points could explain 84% and 86% of the changes in MBG before and after treatment, but could only explain 36% and 26% of the changes in HbA1c before and after treatment, and they had a poorer correlation with the HbA1c than with the 24 h MBG. The blood glucose levels measured at fasting, 2 h after breakfast and before dinner truly reflected the change 24 h blood glucose level, suggesting that they are appropriate for the self-monitoring of blood glucose levels in diabetes patients receiving oral anti-diabetes therapy. Copyright © 2014 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.

Quantify Glucose Level in Freshly Diabetic's Blood by Terahertz Time-Domain Spectroscopy

NASA Astrophysics Data System (ADS)

Chen, Hua; Chen, Xiaofeng; Ma, Shihua; Wu, Xiumei; Yang, Wenxing; Zhang, Weifeng; Li, Xiao

2018-04-01

We demonstrate the capability of terahertz (THz) time-domain spectroscopy (TDS) to quantify glucose level in ex vivo freshly diabetic's blood. By investigating the THz spectra of different human blood, we find out THz absorption coefficients reflect a high sensitivity to the glucose level in blood. With a quantitative analysis of 70 patients, we demonstrate that the THz absorption coefficients and the blood glucose levels perform a linear relationship. A comparative experiment between THz measurement and glucometers is also conducted with another 20 blood samples, and the results confirm that the relative error is as less as 15%. Our ex vivo human blood study indicates that THz technique has great potential application to diagnose blood glucose level in clinical practice.

Emotionally arousing pictures increase blood glucose levels and enhance recall.

PubMed

Blake, T M; Varnhagen, C K; Parent, M B

2001-05-01

Arousal enhances memory in human participants and this enhancing effect is likely due to the release of peripheral epinephrine. As epinephrine does not readily enter the brain, one way that peripheral epinephrine may enhance memory is by increasing circulating blood glucose levels. The present study investigated the possibility that emotionally arousing color pictures would improve memory and elevate blood glucose levels in human participants. Blood glucose levels were measured before, 15 min, and 30 min after male university students viewed 60 emotionally arousing or relatively neutral pictures. Participants viewed each picture for 6 s and then had 10 s to rate the arousal (emotional intensity) and valence (pleasantness) of each picture. A free-recall memory test was given 30 min after the last picture was viewed. Although the emotionally arousing and neutral picture sets were given comparable valence ratings, participants who viewed the emotionally arousing pictures rated the pictures as being more arousing, recalled more pictures, and had higher blood glucose levels after viewing the pictures than did participants who viewed the neutral pictures. These findings indicate that emotionally arousing pictures increase blood glucose levels and enhance memory, and that this effect is not due to differences in the degree of pleasantness of the stimuli. These findings support the possibility that increases in circulating blood glucose levels in response to emotional arousal may be part of the biological mechanism that allows emotional arousal to enhance memory. Copyright 2001 Academic Press.

Evaluation of blood lead level in methamphetamine users in Tehran.

PubMed

Mostafazadeh, Babak; Shadnia, Shahin; Tavakkoli, Mohammad Ali; Khoddami Vishteh, Hamid Reza

2017-02-22

Given the increasing number of lead poisoning in opioids users and since no study has been conducted so far to review lead poisoning in methamphetamine (crystal) users, this study aimed to investigate blood lead level in methamphetamine addicts. This study was conducted on 20 patients with methamphetamine poisoning and their blood lead level was measured. The subjects were selected from among patients with a history of continuous use of methamphetamine, without a history of using opiates in the past 6 months confirmed by a negative urine tests, and without a history of heavy metal poisoning. Of all, 18 patients were male and the mean age was 32 ± 10 years; 17 patients were abusing the drug via inhalation and three persons via oral administration. The mean blood lead level was 2.3 ± 1.1 μg/dL and poisoning was not observed in any of the cases. Blood lead level was not associated with age, sex, dosage, and route of administration. Although blood lead level was not at poisoning level in people who only used methamphetamine in Iran, due to the simultaneous use of other substances and because of non-specific symptoms, lead poisoning must be suspected in all cases of substances poisoning.

Elevated blood lead levels from exposure via a radiator workshop.

PubMed

Treble, R G; Thompson, T S; Morton, D N

1998-04-01

Elevated lead levels were discovered in blood samples collected from family members where both the father and the mother worked in a radiator repair workshop. The father and mother were found to have blood lead levels of 2.0 and 0.5 mumol/L (41.7 and 10.4 micrograms/dL), respectively. The father's blood lead level was just below the Canadian occupational health and safety intervention level (2.5 mumol/L or 52.1 micrograms/dL). The two children had blood lead levels of 1.0 and 0.8 mumol/L (20.8 and 16.7 micrograms/dL), both of which are in excess of the recommended guideline for intervention in the case of children (0.5 mumol/L or 10.4 micrograms/dL). The exposure of the two children was possibly due to a combination of pathways including exposure at the workshop itself during visits and also the transportation of lead-containing dust to the home environment.

Erosive pustular dermatosis of the scalp successfully treated with oral prednisone and topical tacrolimus*

PubMed Central

Zahdi, Mariana Ribas; Seidel, Gabriela Bestani; Soares, Vanessa Cristina; de Freitas, Camila Fernanda Novak Pinheiro; Mulinari-Brenner, Fabiane Andrade

2013-01-01

Erosive pustular dermatosis of the scalp is a rare inflammatory disorder of the scalp, affecting elderly patients after local trauma and leading to scarring or cicatricial alopecia. Case Report: An elderly female patient complained of painful pustules on the parietal region bilaterally with progressive enlargement and ulceration. A biopsy suggested erosive pustular dermatosis of the scalp and the patient was treated with prednisone 40 mg/day and 0.1% topical tacrolimus. After 10 weeks complete closure of the eroded areas was observed and a stable scarring alopecia developed. PMID:24173187

Traumatic Brain Injury Causes a Tacrolimus-Sensitive Increase in Non-Convulsive Seizures in a Rat Model of Post-Traumatic Epilepsy

PubMed Central

Campbell, John N.; Gandhi, Anandh; Singh, Baljinderjit; Churn, Severn B.

2014-01-01

Epilepsy is a significant but potentially preventable complication of traumatic brain injury (TBI). Previous research in animal models of acquired epilepsy has implicated the calcium-sensitive phosphatase, calcineurin. In addition, our lab recently found that calcineurin activity in the rat hippocampus increases acutely after lateral TBI. Here we use a calcineurin inhibitor test whether an acute increase in calcineurin activity is necessary for the development of late post-traumatic seizures. Adult rats were administered the calcineurin inhibitor Tacrolimus (5mg/kg; i.p.) 1 hour after lateral fluid percussion TBI and then monitored by video-electrocorticography (video-ECoG) for spontaneous seizure activity 5 weeks or 33 weeks later. At 5 weeks post-TBI, we observed epileptiform activity on the video-ECoG of brain injured rats but no seizures. By 33 weeks post-TBI though, nearly all injured rats exhibited spontaneous seizures, including convulsive seizures which were infrequent but lasted minutes (18% of injured rats), and non-convulsive seizures which were frequent but lasted tens of seconds (94% of injured rats). We also identified non-convulsive seizures in a smaller subset of control and sham TBI rats (56%), reminiscent of idiopathic seizures described in other rats strains. Non-convulsive seizures in the brain injured rats, however, were four-times more frequent and two-times longer lasting than in their uninjured littermates. Interestingly, rats administered Tacrolimus acutely after TBI showed significantly fewer non-convulsive seizures than untreated rats, but a similar degree of cortical atrophy. The data thus indicate that administration of Tacrolimus acutely after TBI suppressed non-convulsive seizures months later. PMID:25580467

Work related stress and blood glucose levels.

PubMed

Sancini, A; Ricci, S; Tomei, F; Sacco, C; Pacchiarotti, A; Nardone, N; Ricci, P; Suppi, A; De Cesare, D P; Anzelmo, V; Giubilati, R; Pimpinella, B; Rosati, M V; Tomei, G

2017-01-01

The aim of the study is to evaluate work-related subjective stress in a group of workers on a major Italian company in the field of healthcare through the administration of a valid "questionnaire-tool indicator" (HSE Indicator Tool), and to analyze any correlation between stress levels taken from questionnaire scores and blood glucose values. We studied a final sample consisting of 241 subjects with different tasks. The HSE questionnaire - made up of 35 items (divided into 7 organizational dimensions) with 5 possible answers - has been distributed to all the subjects in occasion of the health surveillance examinations provided by law. The questionnaire was then analyzed using its specific software to process the results related to the 7 dimensions. These results were compared using the Pearson correlation and multiple linear regression with the blood glucose values obtained from each subject. From the analysis of the data the following areas resulted critical, in other words linked to an intermediate (yellow area) or high (red area) condition of stress: sustain from managers, sustain from colleagues, quality of relationships and professional changes. A significant positive correlation (p <0.05) between the mean values of all critical areas and the concentrations of glucose values have been highlighted with the correlation index of Pearson. Multiple linear regression confirmed these findings, showing that the critical dimensions resulting from the questionnaire were the significant variables that can increase the levels of blood glucose. The preliminary results indicate that perceived work stress can be statistically associated with increased levels of blood glucose.

Why control blood glucose levels?

PubMed

Rossini, A A

1976-03-01

The controversy as to the relationship between the degree of control of diabetes and the progression of the complications of the disease has not been solved. However, in this review, various studies suggesting a relationship between the metabolic abnormality and the diabetic complications are examined. The disadvantages of the uncontrolled diabetes mellitus can be divided into two major categories-short-term and long-term. The short-term disadvantages of controlled diabetes mellitus include the following: (1) ketoacidosis and hyperosmolar coma; (2) intracellular dehydration; (3) electrolyte imbalance; (4) decreased phagocytosis; (5) immunologic and lymphocyte activity; (6) impairment of wound healing; and (7) abnormality of lipids. The long-term disadvantages of uncontrolled diabetes melitus include the following: (1) nephropathy; (2) neuropathy; (3) retinopathy; (4) cataract formation; (5) effect on perinatal mortality; (6) complications of vascular disease; and (7) the evaluation of various clinical studies suggesting the relationship of elevated blood glucose levels and complications of diabetes mellitus. It is suggested that until the question of control can absolutely be resolved, the recommendation is that the blood glucose levels should be controlled as close to the normal as possible.

Elevated blood lead levels among unskilled construction workers in Jimma, Ethiopia.

PubMed

Gebrie, Higemengist A; Tessema, Dejene A; Ambelu, Argaw

2014-03-19

No study has been carried out to assess the blood lead levels of workers or the contribution of common workplace practices to lead exposure in Ethiopia. This study was carried out to assess the blood lead levels of female and male laborers in the construction sector in Jimma town, Ethiopia. A cross-sectional study on the blood lead levels of 45 construction workers was carried out in the town of Jimma. The t-test, analysis of variance, the Kruskal-Wallis, Mann-Whitney and odds ratio tests were used to compare mean blood lead levels and to investigate the associations between specific job type, use of self-protection device, sex, service years and occurrence of non-specific symptoms with BLLs. The mean blood lead level of the exposed group (40.03 ± 10.41 μg/dL) was found to be significantly greater than that of the unexposed group (29.81 ± 10.21 μg/dL), p = 0.05. Among the exposed group female workers were found to have higher mean blood lead level (42.04 ± 4.11 μg/dL) than their male colleagues (33.99 ± 3.28 μg/dL). Laborers who were regularly using self-protection devices were found to have significantly lower blood lead levels than those who were not using. The blood lead levels of construction workers in Jimma town are considerably high with a range of 20.46 - 70.46 μg/dL and the workers are in danger of imminent lead toxicity. More endangered are female construction workers who are bearers of the future children of the country and the issue requires urgent attention.

Maternal blood lead level during pregnancy in South Central Los Angeles.

PubMed

Rothenberg, S J; Manalo, M; Jiang, J; Khan, F; Cuellar, R; Reyes, S; Sanchez, M; Reynoso, B; Aguilar, A; Diaz, M; Acosta, S; Jauregui, M; Johnson, C

1999-01-01

Twenty-five years of public health efforts produced a striking reduction in lead exposure; the blood lead average in the United States has decreased to less than 20% of levels measured in the 1970s. However, poor minority groups that live in large urban centers are still at high risk for elevated lead levels. In this study, our data showed that pregnant immigrants (n = 1,428) who live in South Central Los Angeles--one of the most economically depressed regions of California--have significantly higher (p < .0001) blood lead levels (geometric mean = 2.3 microg/dl [0.11 micromol/l]) than 504 pregnant nonimmigrants (geometric mean = 1.9 microg/dl [0.09 micromol/l]). The most important factors associated with lower blood lead levels in both groups were younger age; more-recent date of blood sampling (i.e., decreasing secular trend); and blood sampling in mid-autumn, instead of mid-spring (i.e., seasonal trend). Blood lead levels of immigrants were strongly dependent on time elapsed since immigration to the United States; each natural log increase in years of residence was associated with an approximately 19% decrease in blood lead levels. Although blood lead means for both groups were almost the same as the estimated national average, 25 of the 30 cases of elevated blood lead (i.e., > or = 10 microg/dl [0.48 micromol/l) occurred in the immigrant group. The odds ratio (95% confidence intervals within parentheses) for having elevated blood lead levels (a) was 9.3 (1.9, 45.8) if the immigrant engaged in pica; (b) was 3.8 (1.4, 10.5) if the immigrant had low dietary calcium intake during pregnancy; and (c) was .65 (.43, .98) for every natural log unit increase of years of residence in the United States. The control of pica and dietary calcium intake may offer a means of reducing lead exposure in immigrants.

33 CFR 95.025 - Adoption of State blood alcohol concentration levels.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 33 Navigation and Navigable Waters 1 2010-07-01 2010-07-01 false Adoption of State blood alcohol... DANGEROUS DRUG § 95.025 Adoption of State blood alcohol concentration levels. (a) This section applies to... established by statute a blood alcohol concentration level for purposes of determining whether a person is...

33 CFR 95.025 - Adoption of State blood alcohol concentration levels.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 33 Navigation and Navigable Waters 1 2011-07-01 2011-07-01 false Adoption of State blood alcohol... DANGEROUS DRUG § 95.025 Adoption of State blood alcohol concentration levels. (a) This section applies to... established by statute a blood alcohol concentration level for purposes of determining whether a person is...

33 CFR 95.025 - Adoption of State blood alcohol concentration levels.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 33 Navigation and Navigable Waters 1 2012-07-01 2012-07-01 false Adoption of State blood alcohol... DANGEROUS DRUG § 95.025 Adoption of State blood alcohol concentration levels. (a) This section applies to... established by statute a blood alcohol concentration level for purposes of determining whether a person is...

33 CFR 95.025 - Adoption of State blood alcohol concentration levels.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 33 Navigation and Navigable Waters 1 2013-07-01 2013-07-01 false Adoption of State blood alcohol... DANGEROUS DRUG § 95.025 Adoption of State blood alcohol concentration levels. (a) This section applies to... established by statute a blood alcohol concentration level for purposes of determining whether a person is...

33 CFR 95.025 - Adoption of State blood alcohol concentration levels.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 33 Navigation and Navigable Waters 1 2014-07-01 2014-07-01 false Adoption of State blood alcohol... DANGEROUS DRUG § 95.025 Adoption of State blood alcohol concentration levels. (a) This section applies to... established by statute a blood alcohol concentration level for purposes of determining whether a person is...

Effect of levulose containing sweets on blood and salivary glucose levels.

PubMed

Subramaniam, Priya; K L, Girish Babu; Gona, Harsha

2015-06-01

It is common that many diabetic patients crave for sweets which are normally prohibited. To satisfy their desire to have sweets, alternative sweeteners have been introduced to provide sweetness to some items of their diabetic diet. To (1) assess the effect of sweets containing levulose on glucose levels in blood and saliva, and (2) compare it with effect of sweets containing sucrose on blood and saliva levels of glucose. The study consisted of 20 healthy participants, aged 17-20 years. Two sweet preparations of 36 g each were selected for the study. One preparation was sweetened with levulose (diabetic sweet; Group I) and the other with sucrose (regular sweet; Group II). Blood sugar and salivary glucose levels were estimated before and after the consumption of diabetic and regular sweets. The mean increase in salivary glucose level was lower in Group I than in Group II. Similarly, increase in blood glucose levels in Group I was lower and highly significant. In comparison with regular sweets, consumption of levulose containing sweet resulted in significantly lower blood and salivary glucose levels.

24 CFR 35.1130 - Child with an environmental intervention blood lead level.

Code of Federal Regulations, 2012 CFR

2012-04-01

... intervention blood lead level. 35.1130 Section 35.1130 Housing and Urban Development Office of the Secretary... STRUCTURES Public Housing Programs § 35.1130 Child with an environmental intervention blood lead level. (a... been identified as having an environmental intervention blood lead level, the PHA shall complete a risk...

24 CFR 35.730 - Child with an environmental intervention blood lead level.

Code of Federal Regulations, 2013 CFR

2013-04-01

... intervention blood lead level. 35.730 Section 35.730 Housing and Urban Development Office of the Secretary... STRUCTURES Project-Based Assistance § 35.730 Child with an environmental intervention blood lead level. (a... subpart applies has been identified as having an environmental intervention blood lead level, the owner...

24 CFR 35.730 - Child with an environmental intervention blood lead level.

Code of Federal Regulations, 2012 CFR

2012-04-01

... intervention blood lead level. 35.730 Section 35.730 Housing and Urban Development Office of the Secretary... STRUCTURES Project-Based Assistance § 35.730 Child with an environmental intervention blood lead level. (a... subpart applies has been identified as having an environmental intervention blood lead level, the owner...

24 CFR 35.830 - Child with an environmental intervention blood lead level.

Code of Federal Regulations, 2013 CFR

2013-04-01

... intervention blood lead level. 35.830 Section 35.830 Housing and Urban Development Office of the Secretary... intervention blood lead level. (a) Risk assessment. Within 15 days after being notified by a public health... an environmental intervention blood lead level, HUD shall complete a risk assessment of the dwelling...

24 CFR 35.730 - Child with an environmental intervention blood lead level.

Code of Federal Regulations, 2011 CFR

2011-04-01

... intervention blood lead level. 35.730 Section 35.730 Housing and Urban Development Office of the Secretary... STRUCTURES Project-Based Assistance § 35.730 Child with an environmental intervention blood lead level. (a... subpart applies has been identified as having an environmental intervention blood lead level, the owner...

24 CFR 35.1225 - Child with an environmental intervention blood lead level.

Code of Federal Regulations, 2010 CFR

2010-04-01

... intervention blood lead level. 35.1225 Section 35.1225 Housing and Urban Development Office of the Secretary... STRUCTURES Tenant-Based Rental Assistance § 35.1225 Child with an environmental intervention blood lead level... as having an environmental intervention blood lead level, the designated party shall complete a risk...

24 CFR 35.830 - Child with an environmental intervention blood lead level.

Code of Federal Regulations, 2010 CFR

2010-04-01

... intervention blood lead level. 35.830 Section 35.830 Housing and Urban Development Office of the Secretary... intervention blood lead level. (a) Risk assessment. Within 15 days after being notified by a public health... an environmental intervention blood lead level, HUD shall complete a risk assessment of the dwelling...

24 CFR 35.1225 - Child with an environmental intervention blood lead level.

Code of Federal Regulations, 2012 CFR

2012-04-01

... intervention blood lead level. 35.1225 Section 35.1225 Housing and Urban Development Office of the Secretary... STRUCTURES Tenant-Based Rental Assistance § 35.1225 Child with an environmental intervention blood lead level... as having an environmental intervention blood lead level, the designated party shall complete a risk...

24 CFR 35.1130 - Child with an environmental intervention blood lead level.

Code of Federal Regulations, 2013 CFR

2013-04-01

... intervention blood lead level. 35.1130 Section 35.1130 Housing and Urban Development Office of the Secretary... STRUCTURES Public Housing Programs § 35.1130 Child with an environmental intervention blood lead level. (a... been identified as having an environmental intervention blood lead level, the PHA shall complete a risk...

24 CFR 35.830 - Child with an environmental intervention blood lead level.

Code of Federal Regulations, 2011 CFR

2011-04-01

... intervention blood lead level. 35.830 Section 35.830 Housing and Urban Development Office of the Secretary... intervention blood lead level. (a) Risk assessment. Within 15 days after being notified by a public health... an environmental intervention blood lead level, HUD shall complete a risk assessment of the dwelling...

24 CFR 35.1225 - Child with an environmental intervention blood lead level.

Code of Federal Regulations, 2011 CFR

2011-04-01

... intervention blood lead level. 35.1225 Section 35.1225 Housing and Urban Development Office of the Secretary... STRUCTURES Tenant-Based Rental Assistance § 35.1225 Child with an environmental intervention blood lead level... as having an environmental intervention blood lead level, the designated party shall complete a risk...

24 CFR 35.730 - Child with an environmental intervention blood lead level.

Code of Federal Regulations, 2010 CFR

2010-04-01

... intervention blood lead level. 35.730 Section 35.730 Housing and Urban Development Office of the Secretary... STRUCTURES Project-Based Assistance § 35.730 Child with an environmental intervention blood lead level. (a... subpart applies has been identified as having an environmental intervention blood lead level, the owner...

24 CFR 35.1130 - Child with an environmental intervention blood lead level.

Code of Federal Regulations, 2011 CFR

2011-04-01

... intervention blood lead level. 35.1130 Section 35.1130 Housing and Urban Development Office of the Secretary... STRUCTURES Public Housing Programs § 35.1130 Child with an environmental intervention blood lead level. (a... been identified as having an environmental intervention blood lead level, the PHA shall complete a risk...

24 CFR 35.830 - Child with an environmental intervention blood lead level.

Code of Federal Regulations, 2012 CFR

2012-04-01

... intervention blood lead level. 35.830 Section 35.830 Housing and Urban Development Office of the Secretary... intervention blood lead level. (a) Risk assessment. Within 15 days after being notified by a public health... an environmental intervention blood lead level, HUD shall complete a risk assessment of the dwelling...

24 CFR 35.1225 - Child with an environmental intervention blood lead level.

Code of Federal Regulations, 2014 CFR

2014-04-01

... intervention blood lead level. 35.1225 Section 35.1225 Housing and Urban Development Office of the Secretary... STRUCTURES Tenant-Based Rental Assistance § 35.1225 Child with an environmental intervention blood lead level... as having an environmental intervention blood lead level, the designated party shall complete a risk...

24 CFR 35.1225 - Child with an environmental intervention blood lead level.

Code of Federal Regulations, 2013 CFR

2013-04-01

... intervention blood lead level. 35.1225 Section 35.1225 Housing and Urban Development Office of the Secretary... STRUCTURES Tenant-Based Rental Assistance § 35.1225 Child with an environmental intervention blood lead level... as having an environmental intervention blood lead level, the designated party shall complete a risk...

24 CFR 35.830 - Child with an environmental intervention blood lead level.

Code of Federal Regulations, 2014 CFR

2014-04-01

... intervention blood lead level. 35.830 Section 35.830 Housing and Urban Development Office of the Secretary... intervention blood lead level. (a) Risk assessment. Within 15 days after being notified by a public health... an environmental intervention blood lead level, HUD shall complete a risk assessment of the dwelling...

24 CFR 35.1130 - Child with an environmental intervention blood lead level.

Code of Federal Regulations, 2010 CFR

2010-04-01

... intervention blood lead level. 35.1130 Section 35.1130 Housing and Urban Development Office of the Secretary... STRUCTURES Public Housing Programs § 35.1130 Child with an environmental intervention blood lead level. (a... been identified as having an environmental intervention blood lead level, the PHA shall complete a risk...

24 CFR 35.1130 - Child with an environmental intervention blood lead level.

Code of Federal Regulations, 2014 CFR

2014-04-01

... intervention blood lead level. 35.1130 Section 35.1130 Housing and Urban Development Office of the Secretary... STRUCTURES Public Housing Programs § 35.1130 Child with an environmental intervention blood lead level. (a... been identified as having an environmental intervention blood lead level, the PHA shall complete a risk...

24 CFR 35.730 - Child with an environmental intervention blood lead level.

Code of Federal Regulations, 2014 CFR

2014-04-01

... intervention blood lead level. 35.730 Section 35.730 Housing and Urban Development Office of the Secretary... STRUCTURES Project-Based Assistance § 35.730 Child with an environmental intervention blood lead level. (a... subpart applies has been identified as having an environmental intervention blood lead level, the owner...

The Effectiveness of Lamotrigine and Its Blood Levels for Pediatric Epilepsy.

PubMed

Iwasaki, Toshiyuki; Toki, Taira; Nonoda, Yutaka; Ishii, Masahiro

This study was conducted to evaluate the effectiveness of lamotrigine (LTG) over 2 years and the usefulness of measuring its blood levels during the follow-up of patients with epilepsy. We measured peak blood LTG levels of 32 patients with epilepsy (9.16 ± 3.34 years old; mean ± SD). The blood levels were measured at 6 months, 1 year, and 2 years after reaching the LTG maintenance dosage. The effectiveness of LTG was evaluated to determine the seizure reduction rate. The patients were classified as effective cases (mean of own seizure reduction rates >50%) and ineffective cases (≤50%). The results were that the dosage and blood level showed positive correlations in the case of combination use with sodium valproate (VPA) (r = 0.690), carbamazepine and/or phenobarbital (r = 0.940), and others (r = 0.548). In several groups, the blood levels and efficacies did not show any positive correlations. In the cases of combination use with VPA, the blood levels of effective cases and ineffective cases were significantly different (P = 0.001). The optimal range was 8-11.5 μg/mL based on the average and SD values in the effective cases. No patients had any side effects. In conclusion, no precise definition of the therapeutic range was possible because of the incomplete correlation between the blood level and seizure frequency. We recommend the optimal range of LTG as a therapeutic target without any side effects, and it was established that the range in the combination with VPA was 8-11.5 μg/mL.

24 CFR 35.325 - Child with an environmental intervention blood lead level.

Code of Federal Regulations, 2012 CFR

2012-04-01

... intervention blood lead level. 35.325 Section 35.325 Housing and Urban Development Office of the Secretary... environmental intervention blood lead level. If a child less than 6 years of age living in a federally assisted dwelling unit has an environmental intervention blood lead level, the owner shall immediately conduct a...

24 CFR 35.325 - Child with an environmental intervention blood lead level.

Code of Federal Regulations, 2013 CFR

2013-04-01

... intervention blood lead level. 35.325 Section 35.325 Housing and Urban Development Office of the Secretary... environmental intervention blood lead level. If a child less than 6 years of age living in a federally assisted dwelling unit has an environmental intervention blood lead level, the owner shall immediately conduct a...

24 CFR 35.325 - Child with an environmental intervention blood lead level.

Code of Federal Regulations, 2011 CFR

2011-04-01

... intervention blood lead level. 35.325 Section 35.325 Housing and Urban Development Office of the Secretary... environmental intervention blood lead level. If a child less than 6 years of age living in a federally assisted dwelling unit has an environmental intervention blood lead level, the owner shall immediately conduct a...

24 CFR 35.325 - Child with an environmental intervention blood lead level.

Code of Federal Regulations, 2010 CFR

2010-04-01

... intervention blood lead level. 35.325 Section 35.325 Housing and Urban Development Office of the Secretary... environmental intervention blood lead level. If a child less than 6 years of age living in a federally assisted dwelling unit has an environmental intervention blood lead level, the owner shall immediately conduct a...

24 CFR 35.325 - Child with an environmental intervention blood lead level.

Code of Federal Regulations, 2014 CFR

2014-04-01

... intervention blood lead level. 35.325 Section 35.325 Housing and Urban Development Office of the Secretary... environmental intervention blood lead level. If a child less than 6 years of age living in a federally assisted dwelling unit has an environmental intervention blood lead level, the owner shall immediately conduct a...

Effect of pertussis toxin pretreated centrally on blood glucose level induced by stress.

PubMed

Suh, Hong-Won; Sim, Yun-Beom; Park, Soo-Hyun; Sharma, Naveen; Im, Hyun-Ju; Hong, Jae-Seung

2016-09-01

In the present study, we examined the effect of pertussis toxin (PTX) administered centrally in a variety of stress-induced blood glucose level. Mice were exposed to stress after the pretreatment of PTX (0.05 or 0.1 µg) i.c.v. or i.t. once for 6 days. Blood glucose level was measured at 0, 30, 60 and 120 min after stress stimulation. The blood glucose level was increased in all stress groups. The blood glucose level reached at maximum level after 30 min of stress stimulation and returned to a normal level after 2 h of stress stimulation in restraint stress, physical, and emotional stress groups. The blood glucose level induced by cold-water swimming stress was gradually increased up to 1 h and returned to the normal level. The intracerebroventricular (i.c.v.) or intrathecal (i.t.) pretreatment with PTX, a Gi inhibitor, alone produced a hypoglycemia and almost abolished the elevation of the blood level induced by stress stimulation. The central pretreatment with PTX caused a reduction of plasma insulin level, whereas plasma corticosterone level was further up-regulated in all stress models. Our results suggest that the hyperglycemia produced by physical stress, emotional stress, restraint stress, and the cold-water swimming stress appear to be mediated by activation of centrally located PTX-sensitive G proteins. The reduction of blood glucose level by PTX appears to due to the reduction of plasma insulin level. The reduction of blood glucose level by PTX was accompanied by the reduction of plasma insulin level. Plasma corticosterone level up-regulation by PTX in stress models may be due to a blood glucose homeostatic mechanism.

Exogenous and Endogenous Determinants of Blood Trihalomethane Levels after Showering

PubMed Central

Backer, Lorraine C.; Lan, Qing; Blount, Benjamin C.; Nuckols, J.R.; Branch, Robert; Lyu, Christopher W.; Kieszak, Stephanie M.; Brinkman, Marielle C.; Gordon, Sydney M.; Flanders, W. Dana; Romkes, Marjorie; Cantor, Kenneth P.

2008-01-01

Background We previously conducted a study to assess whether household exposures to tap water increased an individual’s internal dose of trihalomethanes (THMs). Increases in blood THM levels among subjects who showered or bathed were variable, with increased levels tending to cluster in two groups. Objectives Our goal was to assess the importance of personal characteristics, previous exposures, genetic polymorphisms, and environmental exposures in determining THM concentrations in blood after showering. Methods One hundred study participants completed a health symptom questionnaire, a 48-hr food and water consumption diary, and took a 10-min shower in a controlled setting. We examined THM levels in blood samples collected at baseline and 10 and 30 min after the shower. We assessed the significance of personal characteristics, previous exposures to THMs, and specific gene polymorphisms in predicting postshower blood THM concentrations. Results We did not observe the clustering of blood THM concentrations observed in our earlier study. We found that environmental THM concentrations were important predictors of blood THM concentrations immediately after showering. For example, the chloroform concentration in the shower stall air was the most important predictor of blood chloroform levels 10 min after the shower (p < 0.001). Personal characteristics, previous exposures to THMs, and specific polymorphisms in CYP2D6 and GSTT1 genes were significant predictors of both baseline and postshowering blood THM concentrations as well as of changes in THM concentrations associated with showering. Conclusion The inclusion of information about individual physiologic characteristics and environmental measurements would be valuable in future studies to assess human health effects from exposures to THMs in tap water. PMID:18197300

Brachial blood flow under relative levels of blood flow restriction is decreased in a nonlinear fashion.

PubMed

Mouser, J Grant; Ade, Carl J; Black, Christopher D; Bemben, Debra A; Bemben, Michael G

2018-05-01

Blood flow restriction (BFR), the application of external pressure to occlude venous return and restrict arterial inflow, has been shown to increase muscular size and strength when combined with low-load resistance exercise. BFR in the research setting uses a wide range of pressures, applying a pressure based upon an individual's systolic pressure or a percentage of occlusion pressure; not a directly determined reduction in blood flow. The relationship between relative pressure and blood flow has not been established. To measure blood flow in the arm under relative levels of BFR. Forty-five people (18-40 years old) participated. Arterial occlusion pressure in the right arm was measured using a 5-cm pneumatic cuff. Blood flow in the brachial artery was measured at rest and at pressures between 10% and 90% of occlusion using ultrasound. Blood flow decreased in a nonlinear, stepped fashion. Blood flow decreased at 10% of occlusion and remained constant until decreasing again at 40%, where it remained until 90% of occlusion. The decrease in brachial blood flow is not proportional to the applied relative pressure. The prescription of blood flow restriction should take into account the stimulus provided at each relative level of blood flow. © 2017 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd.

The optimal blood glucose level for critically ill adult patients.

PubMed

Lv, Shaoning; Ross, Paul; Tori, Kathleen

2017-09-01

Glycaemic control is recognized as one of the important aspects in managing critically ill patients. Both hyperglycaemia and hypoglycaemia independently increase the risk of patient mortality. Hence, the identification of optimal glycaemic control is of paramount importance in the management of critically ill patients. The aim of this literature review is to examine the current status of glycaemic control in critically ill adult patients. This literature review will focus on randomized controlled trials comparing intensive insulin therapy to conventional insulin therapy, with an objective to identify optimal blood glucose level targets for critically ill adult patients. A literature review was conducted to identify large randomized controlled trials for the optimal targeted blood glucose level for critically ill adult patients published since 2000. A total of eight studies fulfilled the selection criteria of this review. With current human and technology resources, the results of the studies support commencing glycaemic control once the blood glucose level of critically ill patients reaches 10 mmol/L and maintaining this level between 8 mmol/L and 10 mmol/L. This literature review provides a recommendation for targeting the optimal blood glucose level for critically ill patients within moderate blood glucose level target range (8-10 mmol/L). The need for uniformed glucometrics for unbiased reporting and further research for optimal blood glucose target is required, especially in light of new technological advancements in closed-loop insulin delivery and monitoring devices. This literature review has revealed a need to call for consensus in the measurement and reporting of glycaemic control using standardized glucometrics. © 2017 British Association of Critical Care Nurses.

BK Polyomavirus Replication in Renal Tubular Epithelial Cells Is Inhibited by Sirolimus, but Activated by Tacrolimus Through a Pathway Involving FKBP-12.

PubMed

Hirsch, H H; Yakhontova, K; Lu, M; Manzetti, J

2016-03-01

BK polyomavirus (BKPyV) replication causes nephropathy and premature kidney transplant failure. Insufficient BKPyV-specific T cell control is regarded as a key mechanism, but direct effects of immunosuppressive drugs on BKPyV replication might play an additional role. We compared the effects of mammalian target of rapamycin (mTOR)- and calcineurin-inhibitors on BKPyV replication in primary human renal tubular epithelial cells. Sirolimus impaired BKPyV replication with a 90% inhibitory concentration of 4 ng/mL by interfering with mTOR-SP6-kinase activation. Sirolimus inhibition was rapid and effective up to 24 h postinfection during viral early gene expression, but not thereafter, during viral late gene expression. The mTORC-1 kinase inhibitor torin-1 showed a similar inhibition profile, supporting the notion that early steps of BKPyV replication depend on mTOR activity. Cyclosporine A also inhibited BKPyV replication, while tacrolimus activated BKPyV replication and reversed sirolimus inhibition. FK binding protein 12kda (FKBP-12) siRNA knockdown abrogated sirolimus inhibition and increased BKPyV replication similar to adding tacrolimus. Thus, sirolimus and tacrolimus exert opposite effects on BKPyV replication in renal tubular epithelial cells by a mechanism involving FKBP-12 as common target. Immunosuppressive drugs may therefore contribute directly to the risk of BKPyV replication and nephropathy besides suppressing T cell functions. The data provide rationales for clinical trials aiming at reducing the risk of BKPyV replication and disease in kidney transplantation. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

Investigating the Impact of Drug Crystallinity in Amorphous Tacrolimus Capsules on Pharmacokinetics and Bioequivalence Using Discriminatory In Vitro Dissolution Testing and Physiologically Based Pharmacokinetic Modeling and Simulation.

PubMed

Purohit, Hitesh S; Trasi, Niraj S; Sun, Dajun D; Chow, Edwin C Y; Wen, Hong; Zhang, Xinyuan; Gao, Yi; Taylor, Lynne S

2018-05-01

Delivering a drug in amorphous form in a formulated product is a strategy used to enhance the apparent solubility of a drug substance and its oral bioavailability. Drug crystallization in such products may occur during the manufacturing process or on storage, reducing the solubility advantage of the amorphous drug. However, the impact of partial drug crystallization in the drug product on the resulting bioavailability and pharmacokinetics is unknown. In this study, dissolution testing of commercial tacrolimus capsules (which are formulated to contain amorphous drug), both fresh and those containing different amounts of crystalline drug, was conducted using both United States Pharmacopeia and noncompendial dissolution tests with different dissolution media and volumes. A physiologically based pharmacokinetic (PBPK) absorption model was developed to predict the impact of crystallinity extent on the oral absorption of the products and to evaluate the discriminatory ability of the different dissolution methods. Virtual bioequivalence simulations between partially crystallized tacrolimus capsules versus fresh Prograf or generic tacrolimus capsules were performed using the PBPK model and in vitro dissolution data of the various fresh and partially crystallized capsules under United States Pharmacopeia and noncompendial dissolution conditions. The results suggest that compendial dissolution tests may not be sufficiently discriminatory with respect to the presence of crystallinity in an amorphous formulation. Nonsink dissolution tests using lower dissolution volumes generate more discriminatory profiles that predict different pharmacokinetics of tacrolimus capsules containing different extents of drug crystallinity. In conclusion, the PBPK modeling approach can be used to assess the impact of partial drug crystallinity in the formulated product and to guide the development of appropriate dissolution methods. Copyright © 2018 American Pharmacists Association®. All rights

Feeding practices and blood lead levels in infants in Nagpur, India.

PubMed

Patel, Archana Behram; Belsare, Hrishikesh; Banerjee, Anita

2011-01-01

In a hospital-based cross-sectional study of 200 infants age 4-9 months in an Indian city (Nagpur), the authors determined the prevalence of elevated blood lead level (EBLL) and mean blood lead levels with respect to feeding patterns, i.e., breastfed or fed with formula or dairy milk. The blood lead levels in this study population ranged from 0.048 microg/dl to 42.944 microg/dl; the mean blood lead level was 10.148 microg/dl (+/- 9.128); EBLL prevalence was 38.2%. EBLL risk factors included removal of house paint in the past year, odds ratio (OR), 5.6 (95% confidence interval [CI], 1.6-19.65); use of surma (eye cosmetic), OR 4.27 (95% CI, 1.39-13.08); maternal use of sindur (vermillion), OR 2.118 (95% CI, 1.07-4.44). Feeding method (breastfed or not) did not appear to have an effect on blood lead level. In non-breastfed infants, boiling of water was significantly associated with EBLL, OR 1.97 (95% CI, 1.01-3.84).

Below background levels of blood lead impact cytokine levels in male and female mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Iavicoli, I.; Carelli, G.; Stanek, E.J.

2006-01-15

A number of studies have documented that Pb exerts immunotoxic effects on T lymphocytes. In studies designed to explore this general response over a broad dose range, female Swiss mice were administered six different diets containing Pb acetate 1 day after mating. During lactation, the mothers received the same feed given during pregnancy, and the same diets were administered to the offspring for 9 months after weaning. At the end of exposure, blood Pb level in the offspring was determined, and possible changes in two type 1 cytokines (IL-2, INF-{gamma}) and one type 2 cytokine (IL-4) in the serum weremore » measured. At higher dietary Pb levels (40 and 400 ppm), a significant increase in IL-4 production was associated with a profound decrease in INF-{gamma} and IL-2 production. At the lowest Pb diet level (0.02 ppm), which resulted in a blood lead level of (0.8 {mu}g/dL), which is below background (2-3 {mu}g/dL) values in humans, increases in INF-{gamma} and IL-2 production along with a significant decrease in IL-4 production were observed. The findings provide evidence of a reversal of lead-induced cytokine skewing depending on the blood lead concentration. As blood lead concentration increases, there is a notable skewing toward Th2, while the pattern is reversed favoring Th1 development at lower blood lead values. The present findings are also notable since they indicate the potential for dietary Pb to have significant biological effects below normal background concentrations.« less

Maternal blood metal levels and fetal markers of metabolic function

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ashley-Martin, Jillian; Dodds, Linda, E-mail: l.dodds@dal.ca; Arbuckle, Tye E.

Exposure to metals commonly found in the environment has been hypothesized to be associated with measures of fetal growth but the epidemiological literature is limited. The Maternal–Infant Research on Environmental Chemicals (MIREC) study recruited 2001 women during the first trimester of pregnancy from 10 Canadian sites. Our objective was to assess the association between prenatal exposure to metals (lead, arsenic, cadmium, and mercury) and fetal metabolic function. Average maternal metal concentrations in 1st and 3rd trimester blood samples were used to represent prenatal metals exposure. Leptin and adiponectin were measured in 1363 cord blood samples and served as markers ofmore » fetal metabolic function. Polytomous logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association between metals and both high (≥90%) and low (≤10%) fetal adiponectin and leptin levels. Leptin levels were significantly higher in female infants compared to males. A significant relationship between maternal blood cadmium and odds of high leptin was observed among males but not females in adjusted models. When adjusting for birth weight z-score, lead was associated with an increased odd of high leptin. No other significant associations were found at the top or bottom 10th percentile in either leptin or adiponectin models. This study supports the proposition that maternal levels of cadmium influence cord blood adipokine levels in a sex-dependent manner. Further investigation is required to confirm these findings and to determine how such findings at birth will translate into childhood anthropometric measures. - Highlights: • We determined relationships between maternal metal levels and cord blood adipokines. • Cord blood leptin levels were higher among female than male infants. • Maternal cadmium was associated with elevated leptin in male, not female infants. • No significant associations were observed between

Association between blood glucose level derived using the oral glucose tolerance test and glycated hemoglobin level.

PubMed

Kim, Hyoung Joo; Kim, Young Geon; Park, Jin Soo; Ahn, Young Hwan; Ha, Kyoung Hwa; Kim, Dae Jung

2016-05-01

Glycated hemoglobin (HbA1c) is widely used as a marker of glycemic control. Translation of the HbA1c level to an average blood glucose level is useful because the latter figure is easily understood by patients. We studied the association between blood glucose levels revealed by the oral glucose tolerance test (OGTT) and HbA1c levels in a Korean population. A total of 1,000 subjects aged 30 to 64 years from the Cardiovascular and Metabolic Diseases Etiology Research Center cohort were included. Fasting glucose levels, post-load glucose levels at 30, 60, and 120 minutes into the OGTT, and HbA1c levels were measured. Linear regression of HbA1c with mean blood glucose levels derived using the OGTT revealed a significant correlation between these measures (predicted mean glucose [mg/dL] = 49.4 × HbA1c [%] - 149.6; R (2) = 0.54, p < 0.001). Our linear regression equation was quite different from that of the Alc-Derived Average Glucose (ADAG) study and Diabetes Control and Complications Trial (DCCT) cohort. Discrepancies between our results and those of the ADAG study and DCCT cohort may be attributable to differences in the test methods used and the extent of insulin secretion. More studies are needed to evaluate the association between HbA1c and self monitoring blood glucose levels.

Measurement Challenges at Low Blood Lead Levels.

PubMed

Caldwell, Kathleen L; Cheng, Po-Yung; Jarrett, Jeffery M; Makhmudov, Amir; Vance, Kathryn; Ward, Cynthia D; Jones, Robert L; Mortensen, Mary E

2017-08-01

In 2012, the Centers for Disease Control and Prevention (CDC) adopted its Advisory Committee on Childhood Lead Poisoning Prevention recommendation to use a population-based reference value to identify children and environments associated with lead hazards. The current reference value of 5 μg/dL is calculated as the 97.5th percentile of the distribution of blood lead levels (BLLs) in children 1 to 5 years old from 2007 to 2010 NHANES data. We calculated and updated selected percentiles, including the 97.5th percentile, by using NHANES 2011 to 2014 blood lead data and examined demographic characteristics of children whose blood lead was ≥90th percentile value. The 97.5th percentile BLL of 3.48 µg/dL highlighted analytical laboratory and clinical interpretation challenges of blood lead measurements ≤5 μg/dL. Review of 5 years of results for target blood lead values <11 µg/dL for US clinical laboratories participating in the CDC's voluntary Lead and Multi-Element Proficiency quality assurance program showed 40% unable to quantify and reported a nondetectable result at a target blood lead value of 1.48 µg/dL, compared with 5.5% at a target BLL of 4.60 µg/dL. We describe actions taken at the CDC's Environmental Health Laboratory in the National Center for Environmental Health, which measures blood lead for NHANES, to improve analytical accuracy and precision and to reduce external lead contamination during blood collection and analysis. Copyright © 2017 by the American Academy of Pediatrics.

Sphingosine Kinase 2 Inhibition and Blood Sphingosine 1-Phosphate Levels.

PubMed

Kharel, Yugesh; Morris, Emily A; Congdon, Molly D; Thorpe, Steven B; Tomsig, Jose L; Santos, Webster L; Lynch, Kevin R

2015-10-01

Sphingosine 1-phosphate (S1P) levels are significantly higher in blood and lymph than in tissues. This S1P concentration difference is necessary for proper lymphocyte egress from secondary lymphoid tissue and to maintain endothelial barrier integrity. Studies with mice lacking either sphingosine kinase (SphK) type 1 and 2 indicate that these enzymes are the sole biosynthetic source of S1P, but they play different roles in setting S1P blood levels. We have developed a set of drug-like SphK inhibitors, with differing selectivity for the two isoforms of this enzyme. Although all SphK inhibitors tested decrease S1P when applied to cultured U937 cells, only those inhibitors with a bias for SphK2 drove a substantial increase in blood S1P in mice and this rise was detectable within minutes of administration of the inhibitor. Blood S1P also increased in response to SphK2 inhibitors in rats. Mass-labeled S1P was cleared more slowly after intravenous injection into SphK2 inhibitor-treated mice or mice lacking a functional SphK2 gene; thus, the increased accumulation of S1P in the blood appears to result from the decreased clearance of S1P from the blood. Therefore, SphK2 appears to have a function independent of generating S1P in cells. Our results suggest that differential SphK inhibition with a drug might afford a method to manipulate blood S1P levels in either direction while lowering tissue S1P levels. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Blood lead levels and cumulative blood lead index (CBLI) as predictors of late neurodevelopment in lead poisoned children

PubMed Central

Nie, Linda H.; Wright, Robert O.; Bellinger, David C.; Hussain, Javed; Amarasiriwardena, Chitra; Chettle, David R.; Pejović-Milić, Ana; woolf, Alan; Shannon, Michael

2011-01-01

Objective To find the best lead exposure assessment marker for children. Methods We recruited 11 children, calculated a cumulative blood lead index (CBLI) for the children, measured their concurrent BLL, assessed their development, and measured their bone lead level. Results Nine of 11 children had clinically significant neurodevelopment problems. CBLI and current blood lead level, but not the peak lead level, were significantly or marginally negatively associated with the full-scale IQ score. Conclusion Lead exposure at younger age significantly impacts a child’s later neurodevelopment. CBLI may be a better predictor of neurodevelopment than are current or peak blood lead levels. PMID:21827276

Analysis of pediatric blood lead levels in New York City for 1970-1976.

PubMed Central

Billick, I H; Curran, A S; Shier, D R

1979-01-01

A study was completed of more than 170,000 records of pediatric venous blood levels and supporting demographic information collected in New York City during 1970-1976. The geometric mean (GM) blood lead level shows a consistent cyclical variation superimposed on an overall decreasing trend with time for all ages and ethnic groups studied. The GM blood lead levels for blacks are significantly greater than those for either Hispanics or whites. Regression analysis indicates a significant statistical association between GM blood lead level and ambient air lead level, after appropriate adjustments are made for age and ethnic group. These highly significant statistical relationships provide extremely strong incentives and directions for research into casual factors related to blood lead levels in children. PMID:499123

High prevalence of elevated blood lead levels in both rural and urban Iowa newborns: Spatial patterns and area-level covariates

PubMed Central

Zahrieh, David; Young, Sean G.; Oleson, Jacob; Ryckman, Kelli K.; Wels, Brian; Simmons, Donald L.; Saftlas, Audrey

2017-01-01

Lead in maternal blood can cross the placenta and result in elevated blood lead levels in newborns, potentially producing negative effects on neurocognitive function, particularly if combined with childhood lead exposure. Little research exists, however, into the burden of elevated blood lead levels in newborns, or the places and populations in which elevated lead levels are observed in newborns, particularly in rural settings. Using ~2300 dried bloods spots collected within 1–3 days of birth among Iowa newborns, linked with the area of mother’s residence at the time of birth, we examine the spatial patterns of elevated (>5 μg/dL) blood lead levels and the ecological-level predictors of elevated blood lead levels. We find that one in five newborns exceed the 5 μg/dL action level set by the US Centers for Disease Control & Prevention (CDC). Bayesian spatial zero inflated regression indicates that elevated blood lead in newborns is associated with areas of increased pre-1940s housing and childbearing-age women with low educational status in both rural and urban settings. No differences in blood lead levels or the proportion of children exceeding 5 μg/dL are observed between urban and rural maternal residence, though a spatial cluster of elevated blood lead is observed in rural counties. These characteristics can guide the recommendation for testing of infants at well-baby appointments in places where risk factors are present, potentially leading to earlier initiation of case management. The findings also suggest that rural populations are at as great of risk of elevated blood lead levels as are urban populations. Analysis of newborn dried blood spots is an important tool for lead poisoning surveillance in newborns and can direct public health efforts towards specific places and populations where lead testing and case management will have the greatest impact. PMID:28520816

A Pilot Study of Children's Blood Lead Levels in Mount Isa, Queensland.

PubMed

Green, Donna; Sullivan, Marianne; Cooper, Nathan; Dean, Annika; Marquez, Cielo

2017-12-13

Mount Isa, Queensland, is one of three Australian cities with significant lead emissions due to nonferrous mining and smelting. Unlike the two other cities with lead mines or smelters, Mount Isa currently has no system of annual, systematic, community-wide blood lead level testing; and testing rates among Indigenous children are low. In previous screenings, this group of children has been shown to have higher average blood lead levels than non-Indigenous children. The first aim of this study was to assess whether parents and children would participate in less invasive, rapid point-of-care capillary testing. The second aim was to measure blood lead levels among a range of children that roughly reflected the percentage of the Indigenous/non-Indigenous population. This pilot study is based on a convenience sample of children between the ages of 12 and 83 months who were recruited to participate by staff at a Children and Family Centre. Over three half-days, 30 children were tested using capillary blood samples and the LeadCare II Point-of-Care testing system. Rapid point-of-care capillary testing was well tolerated by the children. Of 30 children tested, 40% ( n = 12) had blood lead levels ≥5 µg/dL and 10% had levels ≥10 µg/dL. The highest blood lead level measured was 17.3 µg/dL. The percentage of children with blood lead levels ≥5 µg/dL was higher among Indigenous children compared to non-Indigenous (64.2% compared to 18.8%) as was the geometric mean level (6.5 (95% CI, 4.7, 9.2) versus 2.4 (95% CI, 1.8, 3.1)), a statistically significant difference. Though based on a small convenience sample, this study identified 12 children (40%) of the sample with blood lead levels ≥5 µg/dL. Due to historical and ongoing heavy metal emissions from mining and smelting in Mount Isa, we recommend a multi-component program of universal blood lead level testing, culturally appropriate follow-up and intervention for children who are identified with blood lead levels ≥5

Cord blood lead level in an urban inner-city hospital.

PubMed

Chawla, S; Elbakoush, F; Natarajan, G; Dwaihy, M; Berry, A; Ravindranath, Y; Bhambhani, K; Narayan, S B

2016-09-16

Lead levels were measured by inductively coupled plasma mass spectrometry (ICP-MS) in umbilical cord blood samples of 150 neonates in an urban inner-city hospital. The mean (SD) gestation and birth weight of our cohort were 38.8 (1.7) weeks and 3,217 (519) grams. There were 89% African-Americans, 53% males and 79% were born via vaginal delivery. Mean (SD) maternal age was 24.5 (5.8) years. History of drug abuse and smoking was reported in 8.7% and 10.7% respectively, with only 1 mother reporting a history of high lead level in childhood. Prenatal vitamin intake was reported in 99.3%. Cord blood lead level was available in 144 patients, with lead level of <1μg/dL seen in 141 (97.9%) and>1 in 3 (2.1%) patients. No patient had cord blood lead level of >2μg/dL. High lead levels during childhood in high-risk urban population, however, suggest the need for intensive efforts for prevention of environmental exposure to lead in early childhood.

A Study on the Correlation between Cord Blood Glucose Level and the Apgar Score.

PubMed

Khan, Kalyan; Saha, Ashis Ranjan

2013-02-01

The study of the biochemical parameters of cord blood acts as a mirror, which usually reflects the neonatal status. The widely used system for the evaluation of a neonate is the Apgar score. There is no comprehensive published data which has established the association between the cord blood glucose level and the Apgar score. Similarly, there is also no well accepted reference range of the cord blood glucose level. The main objectives of the present study was to ascertain any adverse effects of an abnormal cord blood glucose level on the neonatal status and to find out a standard reference level of glucose in cord blood. The cord blood glucose estimation was done by using the glucose oxidase peroxidase method and the statistical analysis was performed by using the SPSS, version 16 software. In the present study, the cord blood glucose level was found to have no correlation with the Apgar scores which were calculated at both one minute and five minutes after birth. It was also found that for the foetus to be free from any obvious complication, the cord blood glucose level had to be around 87 mg/dl. The fluctuations in the maternal glucose levels are weakly associated with the glucose level in the cord blood.

Evaluation of the Crystallization Tendency of Commercially Available Amorphous Tacrolimus Formulations Exposed to Different Stress Conditions.

PubMed

Trasi, Niraj S; Purohit, Hitesh S; Taylor, Lynne S

2017-10-01

Tacrolimus, an immunosuppressant, is a poorly water soluble compound whereby the commercially available capsule formulations contain the drug in amorphous form. The goal of this study was to evaluate the robustness of the innovator product and five generic formulations to crystallization following storage at stress conditions. Products were purchased from a pharmacy and stored at 40°C/75% relative humidity (RH), open dish conditions. Crystallinity was determined using X-ray diffraction. The quantity of the ingredients in the formulations were determined using different approaches and the various factors that might cause instability in the formulations were studied. After 4 weeks of open dish storage at 40°C/75% RH, one of the generic formulations showed evidence of tacrolimus crystallization. Further investigations revealed batch-to-batch variations in crystallization tendency with the extent of crystallinity varying between 50 and 100% for different batches. Crystallization was also observed at lower storage temperatures (30°C) when the RH was maintained at 75%. It was found that crystallization could be induced in a model formulation by wet granulating an ethanolic solution of the drug with lactose and drying at 60-70°C followed by exposure to stress conditions. It seems probable that the generic that was susceptible to crystallization contains amorphous drug physically mixed with polymeric excipients, rather than as an amorphous solid dispersion. This study highlights the importance of considering the manufacturing process on the stability of the resultant amorphous product.

Effect of intrapleural oxytocin injection on blood glucose level in rat (rattus norvegicous).

PubMed

Dezhkam, Y; Dezhkam, N

2014-01-01

The effect of Oxytocin on energy metabolism is still question. The aim of the present study was to investigate the effect of exogenous oxytocin injection in different dose and timetable on blood glucose level in rat. In this study 16 adult female rats were divided into 2 groups (Treatment 1(T1) and Treatment 2(T2)). T1 with 8 adult female rats received 0.2 IU/Kg oxytocin via intrapleural (IP) and blood glucose level was tested at 0th, 20th, 40th and 60th min after injection by collecting the blood from jugular vein. In T2 eight female rats received 0.4 IU/kg oxytocin via IP taking blood glucose measure at the same minutes as T1. The experiment tested in three replicates. Blood glucose meter (Model: 3TMSO1G) was used with glucose smart blood glucose monitoring system to the measurement of blood glucose level in rats. Data were analyzed using the GLM procedure of SAS (SAS, version 9) PDIFF was used to compare least square means among treatments adjusting by tukey test. There were hypoglycemic tendency in the changes of the blood glucose level in both T1 and T2, 20th min after injection (88.79 ± 3.28, 68.58 ± 3.63, respectively), while in the remaining subjects (4th and 60th min) blood glucose level increased (115.54 ± 4, 79.7 ± 2.09 and 136.33 ± 5.8, 123.54 ± 0.9, respectively). These results showed that blood glucose level in T1 significantly higher than T2 (p < 0.0001). These in vivo results showed that exogenous oxytocin can be good choice to decrease the blood glucose level very fast.

Occupational and Lifestyle Determinants of Blood Lead Levels among Men in Madras, India.

PubMed

Potula; Hu

1996-01-01

The objective of this epidemiologic study was to assess the relationship of blood lead levels to occupational exposure to the combustion products of leaded gasoline and to several lifestyle factors (smoking, alcohol consumption, and diet) among men from four occupational groups in Madras, India. Blood lead was measured using graphite-furnace atomic-absorption spectrophotometry. The mean (SD) blood lead levels in 129 blood samples collected from traffic police, bus drivers, and auto-shop workers were 11.2 (8.8), 12 (11.1), and 17.5 (8.4) µg/dL, respectively; the corresponding value for urban controls (office workers) was 4.1 (2.1) µg/dL. In a final multivariate regression model, a non-vegetarian diet and job category remained the strongest predictors of blood lead level (p < 0.05), while smoking, alcohol consumption, and duration of employment were not significantly correlated with blood lead levels. The authors conclude that continued use of leaded gasoline probably plays a dominant role in determining blood lead levels in Madras.

Effects of end-stage renal disease and dialysis modalities on blood ammonia level

PubMed Central

VAZIRI, Nosratola D.; KHAZAELI, Mahyar; NUNES, Ane C. F.; HARLEY, Kevin T.; SAID, Hyder; ALIPOUR, Omeed; LAU, Wei Ling; PAHL, Madeleine V.

2018-01-01

Introduction Uremia results in a characteristic breath odor (uremic fetor) which is largely due to its high ammonia content. Earlier studies have shown a strong correlation between breath ammonia and blood urea levels and a 1 0-fold reduction in breath ammonia after hemodialysis in patients with chronic kidney disease. Potential sources of breath ammonia include: (i) local ammonia production from hydrolysis of urea in the oropharyngeal and respiratory tracts by bacterial flora, and (ii) release of circulating blood ammonia by the lungs. While the effects of uremia and hemodialysis on breath ammonia are well known their effects on blood ammonia are unknown and were explored here. Methods Blood samples were obtained from 23 hemodialysis patients (immediately before and after dialysis), 14 peritoneal dialysis patients, and 10 healthy controls. Blood levels of ammonia, creatinine, urea, and electrolytes were measured. Findings No significant difference was found in baseline blood ammonia between hemodialysis, peritoneal dialysis and control groups. Hemodialysis procedure led to a significant reduction in urea concentration (P<0.001) which was paradoxically accompanied by a modest but significant (P<0.05) rise in blood ammonia level in 10 of the 23 patients studied. Change in blood ammonia pre- and post-hemodialysis correlated with change in serum bicarbonate levels (r=0.61, P<0.01). On subgroup analysis of patients who had a rise in blood ammonia levels after dialysis, there was a strong correlation with drop in mean arterial pressure (r=0.88, P<0.01). The nadir intradialytic systolic blood pressure trended lower in the hemodialysis patients who had a rise in blood ammonia compared to the patients who manifested a fall in blood ammonia (124±8vs.136±6mmHg respectively, P=0.27). Discussion Fall in blood urea following hemodialysis in ESRD patients was paradoxically accompanied by a modest rise in blood ammonia levels in 43% of the patients studied, contrasting prior

Effects of end-stage renal disease and dialysis modalities on blood ammonia level.

PubMed

Vaziri, Nosratola D; Khazaeli, Mahyar; Nunes, Ane C F; Harley, Kevin T; Said, Hyder; Alipour, Omeed; Lau, Wei Ling; Pahl, Madeleine V

2017-07-01

Uremia results in a characteristic breath odor (uremic fetor) which is largely due to its high ammonia content. Earlier studies have shown a strong correlation between breath ammonia and blood urea levels and a 10-fold reduction in breath ammonia after hemodialysis in patients with chronic kidney disease. Potential sources of breath ammonia include: (i) local ammonia production from hydrolysis of urea in the oropharyngeal and respiratory tracts by bacterial flora, and (ii) release of circulating blood ammonia by the lungs. While the effects of uremia and hemodialysis on breath ammonia are well known their effects on blood ammonia are unknown and were explored here. Blood samples were obtained from 23 hemodialysis patients (immediately before and after dialysis), 14 peritoneal dialysis patients, and 10 healthy controls. Blood levels of ammonia, creatinine, urea, and electrolytes were measured. No significant difference was found in baseline blood ammonia between hemodialysis, peritoneal dialysis and control groups. Hemodialysis procedure led to a significant reduction in urea concentration (P < 0.001) which was paradoxically accompanied by a modest but significant (P < 0.05) rise in blood ammonia level in 10 of the 23 patients studied. Change in blood ammonia pre- and post-hemodialysis correlated with change in serum bicarbonate levels (r = 0.61, P < 0.01). On subgroup analysis of patients who had a rise in blood ammonia levels after dialysis, there was a strong correlation with drop in mean arterial pressure (r = 0.88, P < 0.01). The nadir intradialytic systolic blood pressure trended lower in the hemodialysis patients who had a rise in blood ammonia compared to the patients who manifested a fall in blood ammonia (124 ± 8 vs. 136 ± 6 mmHg respectively, P = 0.27). Fall in blood urea following hemodialysis in ESRD patients was paradoxically accompanied by a modest rise in blood ammonia levels in 43% of the patients studied, contrasting

Environmental lead and childhood blood lead levels in US children: NHANES, 1999-2006.

PubMed

Benson, Stacey M; Talbott, Evelyn O; Brink, LuAnn L; Wu, Candace; Sharma, Ravi K; Marsh, Gary M

2017-03-04

Although blood lead levels in the United States have fallen dramatically since 1980, there remain subgroups of children with high blood lead levels. We assessed the relationship between environmental lead sources and blood lead levels in children ages 1 to 5 years from the National Health and Nutrition Examination Survey (NHANES), 1999-2006. Modeled ambient air lead levels and industrial lead releases at the census-tract level were assigned to each child's residence with adjustment for confounding factors. Of 3,223 children, 272 (8.4%) had blood lead levels ≥ 5 ug/dL. Industrial releases (2,252 vs 1,696 lbs/mi 2 ) and ambient air lead levels (2.28 vs 1.75 ng/m 3 ) were greater in exposed versus unexposed children. For every 10,000 lb/mi 2 increase in inverse distance squared weighted exposure, there was a 1.13% increase (95% CI: 0.45%, 1.81%) in blood lead (p = .001).

Focal metatarsal fistulae syndrome affecting a greyhound dog successfully treated with topical 0.1% tacrolimus ointment.

PubMed

Scholz, Fiona M; Muse, Russell; Burrows, Amanda K

2015-12-01

Metatarsal fistulation is an uncommon cutaneous condition reported almost exclusively in German shepherd dogs and their cross-breeds. To the best of the authors' knowledge this is the first reported case of focal metatarsal fistulae syndrome affecting a greyhound. Remission was obtained within 6 weeks of commencing treatment using compounded 0.1% tacrolimus ointment twice daily and the dog remained stable for another 6 months with twice weekly application before treatment was discontinued. The dog remained in remission at the time of writing, which is 1 year after treatment withdrawal. © 2015 ESVD and ACVD.

Blood lead levels following consumption of game meat in Italy.

PubMed

Fustinoni, Silvia; Sucato, Sabrina; Consonni, Dario; Mannucci, Pier Mannuccio; Moretto, Angelo

2017-05-01

The aim of this study was to measure lead (Pb) levels in blood (Pb-blood) in consumers of game meat, taking into account other possible sources of lead exposure. A spot blood sample was obtained from 95 subjects, and a questionnaire was used to collect general information and data on game meat consumption, hunting, wine drinking and other possible sources of lead exposure. Pb-blood was measured by inductively coupled plasma-mass spectrometry. Pb-blood was not influenced by age, sex, residence in an urban or rural area, consumption of game meat, tobacco smoking or hobbies associated with potential exposure to lead, and median Pb-blood was 1.7 (5th-95th percentile 1.0-5.3)µg/dL and 3.4 (0.9-6.1)µg/dL for game meat non-eaters and eater, respectively. A multiple linear regression analysis (containing the covariates sex, age, hunting, wine drinking, game meat consumption, tobacco smoking, shooting range, and occupational exposure) found an association with hunting (Pb-blood almost double in hunters) and wine drinking (40% higher in drinkers) but not with consumption of game meat or other parameters. Whether the higher Pb-blood level was due to inhalation of lead fumes while shooting with lead ammunition, to handling lead ammunition or both could not be ascertained. Copyright © 2017 Elsevier Inc. All rights reserved.

Predictors of blood lead levels in agricultural villages practicing wastewater irrigation in Central Mexico.

PubMed

Cifuentes, E; Villanueva, J; Sanin, L H

2000-01-01

To investigate whether the agricultural use of untreated wastewater (i.e. crop irrigation) was associated with elevated blood lead levels in a farming population in the Mezquital Valley and which risk factors, other than exposure to untreated wastewater, were associated with elevated blood lead levels, lead levels were measured in venous blood obtained from 735 individuals. Blood samples were analyzed by atomic absorption spectrophotometry. Food habits and dietary intake were gathered by interview, using a semi-quantitative food-frequency questionnaire. The average blood lead level was 7.8 microg/dL (SD 4.66 microg/dL; range 1.2-36.7 microg/dL). 23% of the study population had blood lead levels exceeding 10 microg/dL. The use of lead-glazed ceramics (LGC) was significantly associated with elevated lead levels (p = < 0.001). Other significant variables included age, gender (males), and non-farming-related occupations (e.g., technicians, factory workers). p = 0.005, 0.08, and 0.001, respectively. When the analysis was stratified by the use of LGC for food preparation, an inverse relationship between higher daily calcium intake and blood lead level was detected (beta = - 0.040, p = < 0.05). Thus, blood lead levels were positively associated with the use of LGC. Calcium intake showed a protective effect, maybe by decreasing absorption of lead in the gastrointestinal tract. No association between occupational exposure to untreated wastewater or crop consumption and blood lead levels was detected. Further environmental and health surveillance is recommended.

Blood vitamin C levels of motorized tricycle drivers in Parañaque, Philippines.

PubMed

Sia Su, Glenn L; Kayali, Sara

2008-08-01

Vitamin C is an essential micronutrient maintaining the state of well being of individuals. This study examined factors affecting and the blood vitamin C levels of motorized tricycle drivers in Parañaque City, Philippines. Consenting drivers (N=49) were included in the study and were assessed through self-administered questionnaires, 24-h food recalls, and anthropometric measurements and on the analysis of their blood vitamin C levels. Factors related to the blood vitamin C levels of the motorized tricycle drivers were determined by correlation analysis. Majority (79.6%) of drivers had low blood vitamin C levels. Workplace and vitamin C supplementations (p<0.05) were significantly related to the blood vitamin C levels of the motorized tricycle drivers. Further studies are recommended to understand the problem and the determinants of vitamin C deficiency among the general population.

Assessing anxiety levels and empathic tendency in blood and platelet donors.

PubMed

Kılıç, Suar Çakı; Doğan, Erdoğan; Sevimligül, Gülgün; Yücel, Birsen; Bolat, Fatih; Kavakçı, Onder; Sencan, Mehmet

2013-06-01

In spite of a constantly-increasing requirement for blood transfusion in the world, blood donation does not exhibit an increase at the same rate. In Turkey with a population of 74 million, only 15 per 10,000 people donate blood regularly and rate of voluntary blood donation is very low compared to developed countries. The aim of this study is to determine empathic level of donors and anxiety levels of blood and platelet donors and also to enable comfort and motivation of donors by taking precautions for reducing their anxieties. This prospective and descriptive study was conducted with 100 voluntary donors (50 blood donors, 50 platelet donors) who admitted to Blood Centre of Cumhuriyet University Hospital between 15 March 2012 and 30 April 2012. Average age of these donors was 27 (19-48)years. The mean scores of donors from Empathic Tendency Scale (ETS), State Anxiety Invertory (SAI) and Trait Anxiety Inventory (TAI) were 70 (49-83), 40 (33-45) and 34 (30-44), respectively. ETS score of those donating blood/platelet for the first time was low, >1 is higher in those who donated previously. SAI and TAI scores of blood donors were higher than those of platelet donors (p<0.001) and TAI score was higher in those who donate for the first time (p<0.007) compared to previously donated precipitants. In conclusion, this study underscores that the request of the donor to help others is the most important factor for donation. People frequently donate blood to unfamiliar people and recurring blood donations increase the level of empathy. Donation made during the continuous disclosure is an important factor for being a donor. Copyright © 2013 Elsevier Ltd. All rights reserved.

Factors associated with the seasonality of blood lead levels among preschool Wisconsin children.

PubMed

Havlena, Jeff; Kanarek, Marty S; Coons, Margie

2009-05-01

Aggregate blood lead testing data for Wisconsin children younger than age 6 exhibit seasonal trends in both average blood lead levels and in the percent of those tested and found to have blood lead levels in excess of the 10 mcg/dL threshold for poisoning. Blood lead levels and poisoning rates typically peak during the late summer and early fall months, and are at their minimum during the late winter. Blood test data was analyzed to determine variations by month and age. Seasonal variations are evident even among the very young: infants younger than 10 months who likely have limited opportunity to encounter lead hazards within their home or in the outdoor soil. Seasonal periodicity is most evident among infants who reside in very urban and very rural communities. The observed seasonal periodicity might be associated with the seasonal availability of lead within the children's environment. Particulate matter data measured at several ambient air quality monitoring stations exhibit a similar periodic seasonality, suggesting a possible relationship between blood lead levels and the availability of dust and airborne particulates during the summer months. Clinicians should consider the seasonality of blood lead levels when scheduling tests and interpreting test results.

Effect of sulfonylureas administered centrally on the blood glucose level in immobilization stress model.

PubMed

Sharma, Naveen; Sim, Yun-Beom; Park, Soo-Hyun; Lim, Su-Min; Kim, Sung-Su; Jung, Jun-Sub; Hong, Jae-Seung; Suh, Hong-Won

2015-05-01

Sulfonylureas are widely used as an antidiabetic drug. In the present study, the effects of sulfonylurea administered supraspinally on immobilization stress-induced blood glucose level were studied in ICR mice. Mice were once enforced into immobilization stress for 30 min and returned to the cage. The blood glucose level was measured 30, 60, and 120 min after immobilization stress initiation. We found that intracerebroventricular (i.c.v.) injection with 30 µg of glyburide, glipizide, glimepiride or tolazamide attenuated the increased blood glucose level induced by immobilization stress. Immobilization stress causes an elevation of the blood corticosterone and insulin levels. Sulfonylureas pretreated i.c.v. caused a further elevation of the blood corticosterone level when mice were forced into the stress. In addition, sulfonylureas pretreated i.c.v. alone caused an elevation of the plasma insulin level. Furthermore, immobilization stress-induced insulin level was reduced by i.c.v. pretreated sulfonylureas. Our results suggest that lowering effect of sulfonylureas administered supraspinally against immobilization stress-induced increase of the blood glucose level appears to be primarily mediated via elevation of the plasma insulin level.

An artificial pancreas provided a novel model of blood glucose level variability in beagles.

PubMed

Munekage, Masaya; Yatabe, Tomoaki; Kitagawa, Hiroyuki; Takezaki, Yuka; Tamura, Takahiko; Namikawa, Tsutomu; Hanazaki, Kazuhiro

2015-12-01

Although the effects on prognosis of blood glucose level variability have gained increasing attention, it is unclear whether blood glucose level variability itself or the manifestation of pathological conditions that worsen prognosis. Then, previous reports have not been published on variability models of perioperative blood glucose levels. The aim of this study is to establish a novel variability model of blood glucose concentration using an artificial pancreas. We maintained six healthy, male beagles. After anesthesia induction, a 20-G venous catheter was inserted in the right femoral vein and an artificial pancreas (STG-22, Nikkiso Co. Ltd., Tokyo, Japan) was connected for continuous blood glucose monitoring and glucose management. After achieving muscle relaxation, total pancreatectomy was performed. After 1 h of stabilization, automatic blood glucose control was initiated using the artificial pancreas. Blood glucose level varied for 8 h, alternating between the target blood glucose values of 170 and 70 mg/dL. Eight hours later, the experiment was concluded. Total pancreatectomy was performed for 62 ± 13 min. Blood glucose swings were achieved 9.8 ± 2.3 times. The average blood glucose level was 128.1 ± 5.1 mg/dL with an SD of 44.6 ± 3.9 mg/dL. The potassium levels after stabilization and at the end of the experiment were 3.5 ± 0.3 and 3.1 ± 0.5 mmol/L, respectively. In conclusion, the results of the present study demonstrated that an artificial pancreas contributed to the establishment of a novel variability model of blood glucose levels in beagles.

Efficacy and safety of everolimus with reduced tacrolimus in living-donor liver transplant recipients: 12-month results of a randomized multicenter study.

PubMed

Jeng, Long-Bin; Lee, Sung Gyu; Soin, Arvinder Singh; Lee, Wei-Chen; Suh, Kyung-Suk; Joo, Dong Jin; Uemoto, Shinji; Joh, Jaewon; Yoshizumi, Tomoharu; Yang, Horng-Ren; Song, Gi-Won; Lopez, Patricia; Kochuparampil, Jossy; Sips, Carole; Kaneko, Shuhei; Levy, Gary

2018-06-01

In a multicenter, open-label, study, 284 living-donor liver transplant patients were randomized at 30 ± 5 days posttransplant to start everolimus+reduced tacrolimus (EVR+rTAC) or continue standard tacrolimus (TAC Control). EVR+rTAC was non-inferior to TAC Control for the primary efficacy endpoint of treated BPAR, graft loss or death at 12 months posttransplant: difference -0.7% (90% CI -5.2%, 3.7%); P < .001 for non-inferiority. Treated BPAR occurred in 2.2% and 3.6% of patients, respectively. The key secondary endpoint, change in estimated glomerular filtration rate (eGFR) from randomization to month 12, achieved non-inferiority (P < .001 for non-inferiority), but not superiority and was similar between groups overall (mean -8.0 vs. -12.1 mL/min/1.73 m 2 , P = .108), and in patients continuing randomized treatment (-8.0 vs. -13.3 mL/min/1.73 m 2 , P = .046). In the EVR+rTAC and TAC control groups, study drug was discontinued in 15.5% and 17.6% of patients, adverse events with suspected relation to study drug occurred in 57.0% and 40.4%, and proteinuria ≥1 g/24 h in 9.3% and 0%, respectively. Everolimus did not negatively affect liver regeneration. At 12 months, hepatocellular recurrence was only seen in the standard TAC-treated patients (5/62; 8.1%). In conclusion, early introduction of EVR+rTAC was non-inferior to standard tacrolimus in terms of efficacy and renal function at 12 months, with hepatocellular carcinoma recurrence only in TAC Control patients. ClinicalTrials.gov Identifier: NCT01888432. © 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.

Breakthrough infection of Geotrichum capitatum during empirical caspofungin therapy after umbilical cord blood transplantation.

PubMed

Oya, Shuki; Muta, Tsuyoshi

2018-06-20

We experienced a breakthrough fungal infection caused by Geotrichum capitatum during empirical therapy with caspofungin. A 68-year-old male patient with refractory acute lymphoblastic leukemia had received umbilical cord blood transplantation after two courses of induction therapy. Empirical therapy with caspofungin was initiated 5 days before transplantation. Tacrolimus was continuously infused to prevent graft-versus-host disease. A minidose of methotrexate was intravenously administered on days 1 and 3 post-transplantation, which was changed to prednisolone from day 7 due to severe mucositis. During a recurrence of fever on day 11, blood cultures were found to be positive for a yeast-like organism, which was later confirmed by mass spectrometry to be G. capitatum. The serum levels of beta-D-glucan were elevated to 747 pg/mL. Caspofungin was switched to liposomal amphotericin B; however, radiological findings revealed pulmonary, splenic, and central nervous system involvement. Progressive renal and hepatic dysfunction subsequently developed. The patient died on day 25 post-transplantation secondary to the development of hemophagocytic syndrome and respiratory failure. We emphasize that recurrent febrile episodes, prolonged neutropenia, and underlying gastrointestinal mucosal damage require extreme caution due to the possibility of breakthrough infection caused by new fungal pathogens during empirical therapy with caspofungin.

Blood lead levels in children with neurological disorders: a single centre preliminary study.

PubMed

Mahmoudian, Touran; Modaresi, Mohamadreza; Zarei, Ali; Poursafa, Parinaz; Kelishadi, Roya

2009-11-01

Lead poisoning is a potentially devastating problem among young children. Chronic low level lead exposure can lead to learning disabilities and behavior changes such as colic, insomnia, hyperactivity, impaired growth, hearing loss and upper extremity weakness. The purpose of this cross sectional study was to determine the blood lead level in children with neurological disorders in comparison with healthy controls. Blood lead concentrations were measured by flame atomic absorption spectrometry in 100 children aged 1-10 years and suffering from various neurological disorders. One hundred age and sex-matched healthy children served as controls. The mean blood lead concentration was higher in children with neurological disorders than in controls (113.2 + or - 47.5 microg/L vs 84.7 + or - 38.0 microg/L; p<0.01). Overall, 44% of children with neurological disorders and 19% of controls were found to have increased blood lead levels, i.e.>100 microg/L. An increase in blood lead level in children might be related to neurological disorders. The measurement of blood lead level might be included in diagnostic eveluation of children with neurological disorders.

Elevated blood pressure, race/ethnicity, and C-reactive protein levels in children and adolescents.

PubMed

Lande, Marc B; Pearson, Thomas A; Vermilion, Roger P; Auinger, Peggy; Fernandez, Isabel D

2008-12-01

Adult hypertension is independently associated with elevated C-reactive protein levels, after controlling for obesity and other cardiovascular risk factors. The objective of this study was to determine, with a nationally representative sample of children, whether the relationship between elevated blood pressure and C-reactive protein levels may be evident before adulthood. Cross-sectional data for children 8 to 17 years of age who participated in the National Health and Nutrition Examination Survey between 1999 and 2004 were analyzed. Bivariate analyses compared children with C-reactive protein levels of >3 mg/L versus blood pressure and other cardiovascular risk factors. Multivariate linear regression was used to evaluate the relationship between elevated blood pressure and C-reactive protein levels. Among 6112 children, 3% had systolic blood pressure of >or=95th percentile and 1.3% had diastolic blood pressure of >or=95th percentile. Children with C-reactive protein levels of >3 mg/L had higher systolic blood pressure, compared with children with C-reactive protein levels of levels of <40 mg/dL, and Hispanic ethnicity were independent predictors of elevated C-reactive protein levels. Diastolic blood pressure did not differ between groups. Linear regression analyses showed that systolic blood pressure of >or=95th percentile was independently associated with C-reactive protein levels in boys but not girls. Subset analyses according to race/ethnicity demonstrated that the independent association of elevated systolic blood pressure with C-reactive protein levels was largely limited to black boys. These data indicate that there is interplay between race/ethnicity, elevated systolic blood pressure, obesity, and inflammation in children, a finding that has potential implications for disparities in cardiovascular disease later in life.

Blood zinc levels in nursing women from different regions of the West Bank of Palestine.

PubMed

Shawahna, Ramzi; Zyoud, Ahed; Jallad, Donia; Hadwan, Labebah; Ihssan, Neeran; Hilal, Hikmat

2017-07-06

Pregnant and nursing women are at higher risk of zinc deficiency which can have detrimental consequences on health. We assessed blood zinc levels in 72 nursing women from the West Bank of Palestine and investigated the association between sociodemographic variables and blood zinc levels. Blood samples were analyzed for their zinc contents using graphite furnace atomic absorption spectrophotometry. Blood and data collection were performed between July and December 2016. The median blood zinc level was 4.53 mg/L (interquartile range of 0.38 mg/L). In unadjusted analyses, blood zinc levels were higher in nursing women who lived in cities (p-value <.001), had higher household income (p-value <.001), whose husbands had a white collar job (p-value <.05), were nonsmokers (p-value <.05), did not use hair dyes (p-value <.05), and consumed energy beverages (p-value <.001). Multiple linear analysis showed that living in cities and consuming energy beverages remained significantly associated with higher blood zinc levels (p-value <.05). Blood zinc levels were in the range previously reported for similar non-malnourished populations. Nursing women living in cities and those consuming energy beverages tended to have higher blood zinc levels. Urbanized lifestyle might have enhanced blood zinc levels in nursing women.

Prenatal exposure to lead in Spain: cord blood levels and associated factors.

PubMed

Llop, Sabrina; Aguinagalde, Xabier; Vioque, Jesus; Ibarluzea, Jesús; Guxens, Mònica; Casas, Maribel; Murcia, Mario; Ruiz, María; Amurrio, Ascensión; Rebagliato, Marisa; Marina, Loreto Santa; Fernandez-Somoano, Ana; Tardon, Adonina; Ballester, Ferran

2011-05-01

Lead is a known neurotoxic. Fetuses and infants are very vulnerable to lead exposure, since their blood-brain barrier is not completely formed. Hence, there is an importance for monitoring of blood lead levels prenatally and during early infancy. The aim of this study is to evaluate the prenatal exposure to lead and its association with maternal factors in four population based mother-child cohorts in Spain. The present research was carried out within the framework of the INMA project INfancia y Medio Ambiente (Environment and Childhood). A total of 1462 pregnant women were recruited between 2004 and 2008. Lead was analyzed in a sample of cord blood by thermal decomposition, amalgation, and Atomic Absorption Spectrometry. Maternal sociodemographic, lifestyle and dietary factors were obtained by questionnaires during pregnancy. A multivariate logistic regression model was constructed. The dependent variable was a dichotomous lead level variable (detected vs no detected, i.e. ≥ vs < 2μg/dL). A low percentage of cord blood samples with lead levels ≥ 2μg/dL were found (5.9%). Geometric mean and maximum were 1.06μg/dL and 19μg/dL, respectively. Smoking at the beginning of pregnancy, age, social class, weight gain during pregnancy, gravidity, and place of residence were the maternal factors associated with detectable cord blood lead levels. Mother's diet does not appear to be a determining factor of lead exposure. Nevertheless, daily intake of iron and zinc may act as a protective factor against having cord blood lead levels ≥ 2μg/dL. In the different regions of Spain taking part in this study, lead levels to which newborns are exposed are low. Mobilization of lead from bones may be the main contributor to the cord blood levels. Copyright © 2011 Elsevier B.V. All rights reserved.

Declining blood lead levels and cognitive changes in moderately lead-poisoned children.

PubMed

Ruff, H A; Bijur, P E; Markowitz, M; Ma, Y C; Rosen, J F

1993-04-07

To determine whether chelation therapy or biochemical changes during a lead-lowering intervention was associated with changes in cognitive functioning of moderately lead-poisoned children. It was hypothesized that cognitive performance would improve as blood lead level declined over time. Short-term intervention study with measures obtained before and after intervention. Hospital specialty clinic and university research center. A total of 154 previously untreated children referred to clinic with blood lead levels between 1.21 and 2.66 mumol/L (25 and 55 micrograms/dL) at time of enrollment. Ages ranged from 13 to 87 months. Enrolled children were treated with edetate calcium disodium (EDTA) if eligible and/or with orally administered iron supplement if iron deficient. For all children, housing inspections and abatement procedures were performed as necessary. Score on Bayley Mental Development Scale or Stanford-Binet Intelligence Scale (4th edition). There was no effect of edetate calcium disodium treatment per se. In the short term (7 weeks), changes in blood lead levels were not related to changes in cognitive scores. In the long term (6 months), however, changes in performance were significantly related to changes in blood lead level, even after controlling for confounding variables. The standardized score increased 1 point for every decrease of 0.14 mumol/L (3 micrograms/dL) in blood lead level. The results suggest an association between decreases in blood lead level and cognitive improvements in moderately lead-poisoned children.

Blood glucose level prediction based on support vector regression using mobile platforms.

PubMed

Reymann, Maximilian P; Dorschky, Eva; Groh, Benjamin H; Martindale, Christine; Blank, Peter; Eskofier, Bjoern M

2016-08-01

The correct treatment of diabetes is vital to a patient's health: Staying within defined blood glucose levels prevents dangerous short- and long-term effects on the body. Mobile devices informing patients about their future blood glucose levels could enable them to take counter-measures to prevent hypo or hyper periods. Previous work addressed this challenge by predicting the blood glucose levels using regression models. However, these approaches required a physiological model, representing the human body's response to insulin and glucose intake, or are not directly applicable to mobile platforms (smart phones, tablets). In this paper, we propose an algorithm for mobile platforms to predict blood glucose levels without the need for a physiological model. Using an online software simulator program, we trained a Support Vector Regression (SVR) model and exported the parameter settings to our mobile platform. The prediction accuracy of our mobile platform was evaluated with pre-recorded data of a type 1 diabetes patient. The blood glucose level was predicted with an error of 19 % compared to the true value. Considering the permitted error of commercially used devices of 15 %, our algorithm is the basis for further development of mobile prediction algorithms.

A pilot comparative study of topical latanoprost and tacrolimus in combination with narrow-band ultraviolet B phototherapy and microneedling for the treatment of nonsegmental vitiligo.

PubMed

Korobko, Igor V; Lomonosov, Konstantin M

2016-11-01

Prostaglandins and their analogues are beneficial as topical agents in vitiligo treatment, yet neither of the previous study addressed their comparative efficiency with conventional topical agents used in vitiligo treatment. In this pilot (24 patients) left-right comparative study we addressed efficiency of prostaglandin F2α analogue latanoprost versus tacrolimus when combined with narrow-band ultraviolet B and microneedling in repigmentation of nonsegmental vitiligo lesions. Our results confirm potency of prostaglandins, in particular, that of latanoprost, in inducing repigmentation, with the efficiency being at least comparable to that of tacrolimus, while contribution of microneedling remains unclear. In summary, results of our study provide further evidences for justified use of prostaglandins, in particular, latanoprost, in vitiligo treatment. In turn, this warrants future studies on the topic aiming to conclusively introduce prostaglandin-based formulations as conventional agents for vitiligo management. © 2016 Wiley Periodicals, Inc.

Blood pressure and blood lipid levels among vegetarian, semi-vegetarian, and non-vegetarian native Africans.

PubMed

Famodu, A A; Osilesi, O; Makinde, Y O; Osonuga, O A

1998-10-01

Several epidemiological studies have implicated hypercholesterolemia and hypertriglyceridaemia as a dietary risk factor in the etiology of vascular disease. To date, there are virtually no blood lipid data available for Negroid Black African Seventh-Day Adventist vegetarians. This study was undertaken to gain a preliminary and better understanding of the relationships between BP, blood lipids, and diets in adults at the Seventh-Day Adventist Seminary of West Africa, Ilisan-Remo, Nigeria. Three randomly selected groups of the Nigerian populace with different dietary habits were investigated. The Seventh-Day Adventist Seminary of West Africa was the study area. Anthropometric measurements, blood pressure, serum cholesterol, triglycerides, and serum glucose were estimated using standard methods. The vegetarians (VEGs) had significantly lower body weight 75.0 +/- 1.9 kg than the semi-vegetarians (SEMI-VEGs) 77.3 +/- 1.8 kg (p < 0.05). There was no significant difference between the blood pressure (BP) of the three groups studied, although the VEGs exhibited lower systolic BP. The VEGs had significantly lower serum total cholesterol and triglycerides (p < 0.05), than non-vegetarians (NON-VEGs). The SEMI-VEGs had blood triglycerides values in between NON-VEGs and VEGs levels but these were not significant. There were no differences in blood glucose in the three groups. The vegetarian diet as well as the African natural diet are associated with lower levels of important cardiovascular disease risk factors. The significantly lower cardiovascular disease risk factors in vegetarian African Adventists could be a protective measure against the development of premature IHD and CVD incidence.

Noninvasive measurement of blood glucose level using mid-infrared quantum cascade lasers

NASA Astrophysics Data System (ADS)

Yoshioka, Kiriko; Kino, Saiko; Matsuura, Yuji

2017-04-01

For non-invasive measurement of blood glucose level, attenuated total reflection (ATR) absorption spectroscopy system using a QCL as a light source was developed. The results of measurement of glucose solutions showed that the system had a sensitivity that was enough for blood glucose measurement. In-vivo measurement using the proposed system based on QCL showed that there was a correlation between absorptions measured with human lips and blood glucose level.

DNA damage in blood cells exposed to low-level lasers.

PubMed

Sergio, Luiz Philippe da Silva; Silva, Ana Paula Almeida da; Amorim, Philipi Freitas; Campos, Vera Maria Araújo; Magalhães, Luis Alexandre Gonçalves; de Paoli, Flavia; de Souza da Fonseca, Adenilson

2015-04-01

In regenerative medicine, there are increasing applications of low-level lasers in therapeutic protocols for treatment of diseases in soft and in bone tissues. However, there are doubts about effects on DNA, and an adequate dosimetry could improve the safety of clinical applications of these lasers. This work aimed to evaluate DNA damage in peripheral blood cells of Wistar rats induced by low-level red and infrared lasers at different fluences, powers, and emission modes according to therapeutic protocols. Peripheral blood samples were exposed to lasers and DNA damage was accessed by comet assay. In other experiments, DNA damage was accessed in blood cells by modified comet assay using formamidopyrimidine DNA glycosylase (Fpg) and endonuclease III enzymes. Data show that exposure to low-level red and infrared lasers induce DNA damage depending on fluence, power and emission mode, which are targeted by Fpg and endonuclease III. Oxidative DNA damage should be considered for therapeutic efficacy and patient safety in clinical applications based on low-level red and infrared lasers. © 2015 Wiley Periodicals, Inc.

Correlation between high blood IL-6 level, hyperglycemia, and glucose control in septic patients.

PubMed

Nakamura, Masataka; Oda, Shigeto; Sadahiro, Tomohito; Watanabe, Eizo; Abe, Ryuzo; Nakada, Taka-Aki; Morita, Yasumasa; Hirasawa, Hiroyuki

2012-12-12

The aim of the present study was to investigate the relationship between the blood IL-6 level, the blood glucose level, and glucose control in septic patients. This retrospective observational study in a general ICU of a university hospital included a total of 153 patients with sepsis, severe sepsis, or septic shock who were admitted to the ICU between 2005 and 2010, stayed in the ICU for 7 days or longer, and did not receive steroid therapy prior to or after ICU admission. The severity of stress hyperglycemia, status of glucose control, and correlation between those two factors in these patients were investigated using the blood IL-6 level as an index of hypercytokinemia. A significant positive correlation between blood IL-6 level and blood glucose level on ICU admission was observed in the overall study population (n = 153; r = 0.24, P = 0.01), and was stronger in the nondiabetic subgroup (n = 112; r = 0.42, P < 0.01). The rate of successful glucose control (blood glucose level < 150 mg/dl maintained for 6 days or longer) decreased with increase in blood IL-6 level on ICU admission (P < 0.01). The blood IL-6 level after ICU admission remained significantly higher and the 60-day survival rate was significantly lower in the failed glucose control group than in the successful glucose control group (P < 0.01 and P < 0.01, respectively). High blood IL-6 level was correlated with hyperglycemia and with difficulties in glucose control in septic patients. These results suggest the possibility that hypercytokinemia might be involved in the development of hyperglycemia in sepsis, and thereby might affect the success of glucose control.

High Intrapatient Variability of Tacrolimus Exposure in the Early Period After Liver Transplantation Is Associated With Poorer Outcomes.

PubMed

Rayar, Michel; Tron, Camille; Jézéquel, Caroline; Beaurepaire, Jean Marie; Petitcollin, Antoine; Houssel-Debry, Pauline; Camus, Christophe; Verdier, Marie Clémence; Dehlawi, Ammar; Lakéhal, Mohamed; Desfourneaux, Véronique; Meunier, Bernard; Sulpice, Laurent; Bellissant, Eric; Boudjema, Karim; Lemaitre, Florian

2018-03-01

Tacrolimus (TAC) is the cornerstone of immunosuppressive regimen in liver transplantation (LT). Its pharmacokinetics is characterized by a high interpatient and intrapatient variability (IPV) leading to an unpredictable dose-response relationship. The aim of our study was to evaluate the impact of TAC IPV (IPV) on graft and patient outcomes after LT. We retrospectively analyzed 812 LT recipients treated with TAC. The IPV of TAC concentrations was estimated by calculating the coefficient of variation (CV) of whole blood trough concentrations. Patients were categorized in 2 groups: low IPV (CV < 40%) and high IPV (CV ≥ 40%). There were significantly more neurologic complications (31.2% vs 16.6%, P < 0.001), cardiovascular complications (19.7% vs 9.7%, P < 0.001), and acute renal failure requiring dialysis (8.5% vs 2.2%, P < 0.001) in the high CV group than in the low CV group. Moreover, graft survival was significantly poorer in the high CV group (hazard ratio, 1.42; 95% confidence interval, 1.04-1.95; P = 0.03). A pretransplantation elevated Model for End-Stage Liver Disease score (P < 0.001) and Child-Pugh grade (P < 0.001) were identified as risk factors for presenting a high CV. A high CV of TAC concentrations was found to be predictive of TAC-related toxicity and poorer survival.

Baseline blood levels of manganese, lead, cadmium, copper, and zinc in residents of Beijing suburb

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Long-Lian, E-mail: Longlian57@163.com; Lu, Ling; Pan, Ya-Juan

Baseline blood concentrations of metals are important references for monitoring metal exposure in environmental and occupational settings. The purpose of this study was to determine the blood levels of manganese (Mn), copper (Cu), zinc (Zn), lead (Pb), and cadmium (Cd) among the residents (aged 12–60 years old) living in the suburb southwest of Beijing in China and to compare the outcomes with reported values in various developed countries. Blood samples were collected from 648 subjects from March 2009 to February 2010. Metal concentrations in the whole blood were determined by ICP-MS. The geometric means of blood levels of Mn, Cu,more » Zn, Pb and Cd were 11.4, 802.4, 4665, 42.6, and 0.68 µg/L, respectively. Male subjects had higher blood Pb than the females, while the females had higher blood Mn and Cu than the males. There was no gender difference for blood Cd and Zn. Smokers had higher blood Cu, Zn, and Cd than nonsmokers. There were significant age-related differences in blood levels of all metals studied; subjects in the 17–30 age group had higher blood levels of Mn, Pb, Cu, and Zn, while those in the 46–60 age group had higher Cd than the other age groups. A remarkably lower blood level of Cu and Zn in this population as compared with residents of other developed countries was noticed. Based on the current study, the normal reference ranges for the blood Mn were estimated to be 5.80–25.2 μg/L; for blood Cu, 541–1475 μg/L; for blood Zn, 2349–9492 μg/L; for blood Pb, <100 μg/L; and for blood Cd, <5.30 μg/L in the general population living in Beijing suburbs. - Highlights: • Baseline blood levels of metals in residents of Beijing suburb are investigated. • BMn and BPb in this cohort are higher than those in other developed countries. • Remarkably lower blood levels of Cu and Zn in this Chinese cohort are noticed. • The reference values for blood levels of Mn, Cu, Zn, Pb, and Cd are established.« less

Gingival crevicular blood for screening of blood glucose level in patients with & without diabetes: a chair-side test.

PubMed

Bhavsar, M V; Brahmbhatt, N A; Sahayata, V; Bhavsar, N V

2016-05-01

Diabetes is a pandemic disease with increasing prevalence and serious complications. Periodontitis being one of its presentation and is its sixth recognized complication. This study compares blood glucose levels in gingival crevicular blood of patients with and without diabetes elicited during routine periodontal probing and venous blood sample. Seventy patients with moderate gingivitis and periodontitis positive for bleeding on probing were chosen. All the subjects were divided in two groups, group I consisted of 35 diabetic and group II of 35 non-diabetic subjects. Blood from the gingiva of the most inflamed site was collected with the test strip of a glucose self-monitoring device, and the blood glucose levels were measured. At the same time, intravenous blood was collected for measurement in a laboratory glucose analyzer. Gingival index and probing pocket depth were evaluated for each subject at same time. The mean GCB levels and VB derived from all samples were 156.07 ± 49.23 mg dl(-1) and 156 ± 49.89 mg dl(-1) , respectively, for diabetic group and 90.80 ± 11.07 and 93.41 ± 9.30 for non-diabetic group. In both the groups, the difference between GCB and VB glucose levels was non-significant (P > 0.005). Highly significant correlation between GCB and VB (r = 0.972 for diabetic and r = 0.721 for non-diabetic) in both the groups was found. The data from this study show that GCB collected during diagnostic periodontal examination can be an excellent source for estimation of blood sugar or glucometric analysis. This technique is also suitable for routine screening of diabetic and early diagnosis of unknown diabetic cases. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Hydroxychloroquine Blood Levels in SLE: Clarifying dosing controversies and improving adherence

PubMed Central

Durcan, Laura; Clarke, William A; Magder, Laurence S.; Petri, Michelle

2015-01-01

OBJECTIVES Hydroxychloroquine is used for its effect on systemic lupus erythematosus (SLE) disease activity and long-term benefits. This can be limited by adherence. One way to assess adherence is to measure blood levels. Conflicting data exist regarding blood levels and disease activity. There is dosing controversy; rheumatologists recommend weight-based, while ophthalmologists advocate height-based ‘ideal body weight’ dosing. METHODS Patients were prescribed hydroxychloroquine not to exceed 6.5mg/kg (max400mg/day). In hemodialysis, the dose was 200mg after each session, in renal insufficiency it was 200mg/day. Levels were measured at each visit with a therapeutic range of 500-2000 ng/ml. Patients were divided according to baseline blood level. To assess the impact of measurement and counseling on adherence, we compared the proportion of patients with a level of 500ng/ml or higher based on how many prior assessments the patient had. RESULTS The proportion of patients with hydroxychloroquine levels in the therapeutic range differed significantly by age, gender and vitamin D level. There was a trend toward lower levels with renal failure. Blood levels were similar regardless of height and ideal body weight. Comparing those with undetectable, sub-therapeutic and therapeutic levels, disease activity decreased (SLEDAI 2.92, 2.36 and 2.20)(P=0.04, for trend). At first, 56% were therapeutic and by the third measurement this increased to 80% (p =<0.0001). CONCLUSION There was a trend towards higher disease activity with lower hydroxychloroquine levels. Renal failure dosing led to sub-optimum levels. We show that weight-based dosing (max 400mg daily) is appropriate and that height does not appear to influence levels. Measurement, counseling and repeated testing can increase adherences rates. PMID:26428205

Effect of LED phototherapy on blood lactate level in Taekwondo contest

NASA Astrophysics Data System (ADS)

Park, H. C.; Lee, B. K.; Lee, S. J.; Lim, S.

2017-02-01

The effect of LED phototherapy on blood lactate level in the muscle was studied. A 450cm2 large red and near infrared LED pad with its irradiance of 10mW/cm2 was applied for 10 minutes to brachial muscle and quadriceps muscle of thigh to the participants before and after the Taekwondo contest. Blood samples from the participants were taken at 5 minutes after the competition and 10 minutes after the recovery. The test results showed that the LED therapy (LEDT) before and after the competition had a significant effect on the decrease of blood lactate level of the participants.

Uric Acid Level and Elevated Blood Pressure in U.S. Adolescents

PubMed Central

Loeffler, Lauren F.; Navas-Acien, Ana; Brady, Tammy M.; Miller, Edgar R.; Fadrowski, Jeffrey J.

2012-01-01

Uric acid is associated with cardiovascular disease (CVD) and CVD risk factors in adults, including chronic kidney disease, coronary artery disease, stroke, diabetes, preeclampsia, and hypertension. We examined the association between uric acid and elevated blood pressure in a large, nationally representative cohort of U.S. adolescents, a population with a relatively low prevalence of CVD and CVD risk factors. Among 6,036 adolescents 12-17 years of age examined in the 1999-2006 National Health and Nutrition Examination Survey (NHANES) the mean age was 14.5 years, 17% were obese (body mass index [BMI] ≥95th percentile), and 3.3% had elevated blood pressure. Mean serum uric acid level was 5.0 mg/dL and 34% had a uric acid level ≥5.5 mg/dL. In analyses adjusted for age, sex, race/ethnicity and BMI percentile, the odds ratio of elevated blood pressure, defined as a systolic or diastolic blood pressure ≥95th percentile for age, sex and height, for each 0.1 mg/dL increase in uric acid level was 1.38 (95% confidence interval [CI], 1.16 to 1.65). Compared to <5.5 mg/dL, participants with a uric acid level ≥5.5 mg/dL had a 2.03 times higher odds of having elevated blood pressure (95% CI, 1.38 to 3.00). In conclusion, increasing levels of serum uric acid are associated with elevated blood pressure in healthy U.S. adolescents. Additional prospective studies and clinical trials are needed to determine if uric acid is merely a marker in a complex metabolic pathway, or causal of hypertension and thus a potential screening and therapeutic target. PMID:22353609

Immunosuppressant therapeutic drug monitoring by LC-MS/MS: workflow optimization through automated processing of whole blood samples.

PubMed

Marinova, Mariela; Artusi, Carlo; Brugnolo, Laura; Antonelli, Giorgia; Zaninotto, Martina; Plebani, Mario

2013-11-01

Although, due to its high specificity and sensitivity, LC-MS/MS is an efficient technique for the routine determination of immunosuppressants in whole blood, it involves time-consuming manual sample preparation. The aim of the present study was therefore to develop an automated sample-preparation protocol for the quantification of sirolimus, everolimus and tacrolimus by LC-MS/MS using a liquid handling platform. Six-level commercially available blood calibrators were used for assay development, while four quality control materials and three blood samples from patients under immunosuppressant treatment were employed for the evaluation of imprecision. Barcode reading, sample re-suspension, transfer of whole blood samples into 96-well plates, addition of internal standard solution, mixing, and protein precipitation were performed with a liquid handling platform. After plate filtration, the deproteinised supernatants were submitted for SPE on-line. The only manual steps in the entire process were de-capping of the tubes, and transfer of the well plates to the HPLC autosampler. Calibration curves were linear throughout the selected ranges. The imprecision and accuracy data for all analytes were highly satisfactory. The agreement between the results obtained with manual and those obtained with automated sample preparation was optimal (n=390, r=0.96). In daily routine (100 patient samples) the typical overall total turnaround time was less than 6h. Our findings indicate that the proposed analytical system is suitable for routine analysis, since it is straightforward and precise. Furthermore, it incurs less manual workload and less risk of error in the quantification of whole blood immunosuppressant concentrations than conventional methods. © 2013.

Iron deficiency in young Lebanese children: association with elevated blood lead levels.

PubMed

Muwakkit, Samar; Nuwayhid, Iman; Nabulsi, Mona; al Hajj, Rima; Khoury, Ruby; Mikati, Mohamad; Abboud, Miguel R

2008-05-01

To measure the prevalence of transferrin saturation (TS) <12%, and iron-deficiency anemia (IDA) in Lebanese children, and their association with dietary habits, sociodemographic characteristics, and blood lead levels. A cross-sectional study was performed over a period of 2 years. Of 268 children studied, 142 (53%) were boys and 126 (47%) were girls with an age range of 11 to 75 months. Information collected included nutritional status, blood counts, TS, and blood lead levels. The total prevalence of TS<12% and IDA were 33.6% and 20.5%, respectively, and were associated with not having received iron supplements. IDA was more prevalent among males (P=0.04). TS<12% and IDA were significantly associated with elevated blood lead levels in the first age group (11 to 23 mo) (P=0.04, odds ratio=3.19) and (P=0.006, odds ratio=4.59), respectively. IDA is common in Lebanese children and is associated with increased blood lead levels, lack of iron supplementation, and cultural dietary habits. Remedial measures such as iron fortification of commonly consumed food are needed on the national level. Lead exposure must be controlled and awareness must be raised about the potentially devastating consequences of combined iron deficiency and lead poisoning on young children.

Association between serum osteocalcin level and blood pressure in a Chinese population.

PubMed

Xu, Yiting; Ma, Xiaojing; Xiong, Qin; Hu, Xiang; Zhang, Xueli; Yuan, Yeqing; Bao, Yuqian

2018-04-01

This observational study investigated the association between serum osteocalcin level and blood pressure in a Chinese population. A total of 2241 subjects (909 men and 1,332 women; age, 24-78 years) from Shanghai communities were recruited. Subjects were divided into non-hypertensive and hypertensive groups according to diagnosis of hypertension based on the 1999 World Health Organization-International Society of Hypertension Guidelines. Serum osteocalcin levels were measured using an electrochemiluminescence immunoassay. Men in the hypertensive group showed lower serum osteocalcin level compared with those in the non-hypertensive group, [16.37 (13.34-20.11) ng/mL versus 17.01 (14.23-20.79) ng/mL, p = .039]. No difference in serum osteocalcin level was found between the two groups of women (p = .675). An inverse association was observed between serum osteocalcin level and systolic blood pressure (SBP) in men (p = .004), but serum osteocalcin level was not associated with diastolic blood pressure (DBP) in men (p = .472). No associations were detected between serum osteocalcin level and SBP or DBP in women (SBP: p = .108; DBP: p = .575). A multiple stepwise regression analysis showed an inverse association between serum osteocalcin level and SBP in men after adjusting for age, smoking status, family history of hypertension, and lipid and C-reactive protein levels (standardized β = -0.074, p = .023), but the association disappeared after adjustment for body mass index, waist circumference, blood glucose, and homeostasis model assessment of insulin resistance (p = .327). Serum osteocalcin level was not independently associated with blood pressure in a Chinese population.

Blood lactate accumulation in top level swimmers following competition.

PubMed

Bonifazi, M; Martelli, G; Marugo, L; Sardella, F; Carli, G

1993-03-01

The purposes of this study were to evaluate the significance of blood lactate values after competitions and the blood lactate-swimming speed relationship to swimming performances. Auricular blood samples (N = 421) were collected in 203 top level Italian swimmers (116 males and 87 females) at the end of competitions performed in a 25 m swimming pool. The distribution of all lactate values differed between males and females. The lowest lactate values occurred in swimmers performing the longest distances both in males (1500 m) and females (800 m). In swimmers performing freestyle events a relationship between V-4 mM (swimming speed at 4 mmol/l blood lactate value) and competition velocities was observed, in males, at 200, 400 and 1500 m and, in females, at 400 and 800 m. The predicted velocity corresponding to the competition lactate value assessed by the individual blood lactate-swimming speed relationship was found to be highly related to the actual competition velocity. Results suggest that blood lactate values in swimmers are a useful indication of individual aptitudes.

A randomized trial of the effect of dust control on children's blood lead levels.

PubMed

Lanphear, B P; Winter, N L; Apetz, L; Eberly, S; Weitzman, M

1996-07-01

Dust control is recommended as one of the cornerstones of controlling childhood lead exposure; however, the effectiveness of dust control has not been demonstrated for children who have low to mild elevations in blood lead (ie, less than 25 micrograms/dL). The objective of this study was to determine whether dust control, as performed by families, had an effect on children's blood lead levels and dust lead levels in children's homes. Randomized, controlled trial. Community-based trial in Rochester, NY. One hundred four children, 12 to 31 months of age at baseline. Families and children were randomized to one of two groups. Families of children in the intervention group received cleaning supplies, information about cleaning areas that are often contaminated with lead, and a cleaning demonstration. Families in the control group received only a brochure about lead poisoning prevention. Baseline measurements of lead in blood, house dust, soil, water, and paint were taken from both groups. Seven months after enrollment, a second blood lead assay was obtained, and lead levels in household dust were measured. The main outcome measures were change in blood lead levels and dust lead levels by treatment group. The median blood lead level of children enrolled in the study was 6.7 micrograms/dL (range, 1.7 to 30.6 micrograms/dL). There was no significant difference in the change of children's blood lead levels or dust lead levels by treatment group. The median change in blood lead levels among children in the intervention group was -0.05 micrograms/dL compared with -0.60 micrograms/dL among those in the control group. There also was no significant difference in the change of dust lead by group assignment, although there was a trend toward a significant difference in the percentage of change in dust lead levels on noncarpeted floors, which was greater among houses in the intervention group. These data suggest that an intervention that consists only of providing cleaning

Association between blood lead level and blood pressure in aborigines and others in central Taiwan.

PubMed

Kuo, Hsien-Wen; Lai, Li-Hsing; Chou, Sze-Yuan; Wu, Fang-Yang

2006-01-01

To investigate the relationship between the blood lead level (BLL) and blood pressure among aborigines and non-aborigines in central Taiwan, a community-based survey that included demographic data, medical history, and blood chemistry analyses was conducted among 2,565 adults during an annual health examination. BLLs were analyzed using a graphite furnace atomic absorption spectrometer (AAS). There was a dose response among the non-aborigines (high BLL odds ratio = 2.97, compared with low BLL) but not among aborigines. Based on multiple linear regression models, BLLs were positively correlated with both systolic (an increase of 0.85 mm Hg/microg/dL) and diastolic (an increase of 0.48 mm Hg/microg/dL) blood pressures after adjusting for age, gender, ethnic group, alcohol consumption, and body mass index. BLLs were higher among aborigines than non-aborigines and were significantly correlated with blood pressure, particularly systolic pressure. The association should be considered causal.

Blood lactate levels in 31 female dogs with pyometra

PubMed Central

Hagman, Ragnvi; Reezigt, Bert Jan; Bergström Ledin, Hanna; Karlstam, Erika

2009-01-01

Background Canine pyometra is a life-threatening disease common in countries where spaying of dogs is not routinely performed. The disease is associated with endotoxemia, sepsis, systemic inflammatory response syndrome (SIRS) and a 3–4% mortality rate. Blood lactate analysis is clinically valuable in predicting prognosis and survival, evaluating tissue perfusion and treatment response in human and veterinary critical care settings. The aims of the present study were to investigate 1) the blood lactate levels of female dogs with pyometra by a hand-held analyser and 2) if these levels are related with the clinical status or other biochemical or hematological disorders. Methods In total 31 female dogs with pyometra admitted for surgical ovariohysterectomy and 16 healthy female control dogs were included in the present study. A complete physical examination including SIRS-status determination was performed. Blood samples for lactate concentrations, hematological and biochemical parameters, acid-base and blood gas analysis and other laboratory parameters were collected and subsequently analysed. The diagnosis pyometra was verified with histopathological examination of the uterus and ovaries. Increased hospitalisation length and presence of SIRS were used as indicators of outcome. Results In the pyometra group the median blood lactate level was 1,6 mmol l-1 (range <0.8–2.7 mmol l-1). In the control group the median lactate level was 1,2 mmol l-1 (range <0.8–2.1 mmol l-1). Of the 31 bitches 19 (61%) fulfilled 2 or more criteria for SIRS at inclusion, 10 bitches (32%) fulfilled 3 of the SIRS criteria whereas none accomplished more than 3 criteria. Lactate levels did not differ significantly between the pyometra and control group, or between the SIRS positive and SIRS negative dogs with pyometra. Increased lactate concentration (>2.5 mmol l-1) was demonstrated in one female dog with pyometra (3%), and was not associated with longer hospitalisation or presence of SIRS

Dietary nutrient levels regulate protein and carbohydrate intake, gluconeogenic/glycolytic flux and blood trehalose level in the insect Manduca sexta L.

PubMed

Thompson, S N; Borchardt, D B; Wang, L-W

2003-03-01

This study examined the effects of dietary casein and sucrose levels on nutrient intake, and distinguished the effects of carbohydrate and protein consumption on growth, fat content, pyruvate metabolism and blood trehalose level of 5th instar Manduca sexta larvae. Growth increased with increasing casein consumption but was unaffected by carbohydrate intake. Fat content also increased with carbohydrate consumption, but on carbohydrate-free diets fat content increased with increased protein consumption. Blood trehalose level and pyruvate metabolism were examined by nuclear magnetic resonance spectroscopy analysis of blood following administration of (3-(13)C)pyruvate. On diets containing sucrose, blood trehalose increased with increasing carbohydrate intake, and on most diets trehalose was synthesized entirely from dietary sucrose. Pyruvate cycling, indicated by the alanine C2/C3 (13)C enrichment ratio, increased with carbohydrate consumption reflecting increased glycolysis, and pyruvate decarboxylation exceeded carboxylation on all sucrose diets. Larvae that consumed <75 mg/day sucrose were gluconeogenic, based on the [2 (trehalose C6)(Glx C3/C2)]/alanine C2] (13)C enrichment ratio. On carbohydrate-free diets, blood trehalose levels were low and maintained entirely by gluconeogenesis. Blood trehalose level increased with increasing protein intake. Pyruvate cycling was very low, although many insects displayed higher levels of pyruvate decarboxylation than carboxylation. All gluconeogenic larvae displayed alanine (13)C enrichment ratios <0.35 and had blood trehalose levels <50 mM.

Patient blood transfusion management: discharge hemoglobin level as a surrogate marker for red blood cell utilization appropriateness.

PubMed

Edwards, Jason; Morrison, Chris; Mohiuddin, Maleeha; Tchatalbachev, Vladislav; Patel, Charmi; Schwickerath, Vicki L; Menitove, Jay E; Singh, Gurmukh

2012-11-01

Blood transfusion management strategies minimize transfusion-associated risks, enhance outcomes, and reduce costs. We explored an association of discharge hemoglobin (Hb) with pretransfusion Hb, transfusion indications, and red blood cell (RBC) transfusions. We stipulate that patients with discharge Hb concentrations greater than 10.0 g/dL, or even 9.0 g/dL, received excessive RBC transfusions. We examined aggregate data from five hospitals and for one of the hospitals, the focus hospital, we reviewed patient records for a period of 6 months. Data analyses included number of RBC units transfused and Hb values before transfusion, after transfusion, and at discharge. In aggregate, 27% to 47% patients had discharge Hb levels greater than 10.0 g/dL. At the focus hospital, 27% had a discharge Hb level greater than 10 g/dL and 50.3% had a discharge Hb level greater than 9.0 g/dL. At the focus hospital, the mean Hb trigger for transfusion was a Hb level of 7.3 g/dL; the mean posttransfusion Hb level was 9.3 g/dL and mean discharge Hb level was 9.2 g/dL. Overall, 76% of the transfusions were of an even number of RBC units. In aggregate, overutilization exceeded 20%. At the focus hospital, approximately one-quarter of patients receiving transfusions had a Hb concentration greater than 10.0 g/dL at discharge. Transfused patients' discharge Hb concentration represents an effective indicator for retrospective monitoring of transfusion appropriateness. In light of the large number of patients receiving even number transfusions, reviewing Hb levels after transfusion of each RBC unit could reduce unnecessary transfusions. Retrospective review of discharge Hb data focuses providers on transfusion outcomes and affords an educational opportunity for blood utilization management. © 2012 American Association of Blood Banks.

Rapid evaluation of fibrinogen levels using the CG02N whole blood coagulation analyzer.

PubMed

Hayakawa, Mineji; Gando, Satoshi; Ono, Yuichi; Mizugaki, Asumi; Katabami, Kenichi; Maekawa, Kunihiko; Miyamoto, Daisuke; Wada, Takeshi; Yanagida, Yuichiro; Sawamura, Atsushi

2015-04-01

Rapid evaluation of fibrinogen (Fbg) levels is essential for maintaining homeostasis in patients with massive bleeding during severe trauma and major surgery. This study evaluated the accuracy of fibrinogen levels measured by the CG02N whole blood coagulation analyzer (A&T Corporation, Kanagawa, Japan) using heparinized blood drawn for blood gas analysis (whole blood-Fbg). A total of 100 matched pairs of heparinized blood samples and citrated blood samples were simultaneously collected from patients in the intensive care unit. Whole blood-Fbg results were compared with those of citrated plasma (standard-Fbg). The whole blood coagulation analyzer measured fibrinogen levels within 2 minutes. Strong correlations between standard-Fbg and whole blood-Fbg were observed (ρ = 0.91, p < 0.001). Error grid analysis showed that 88% of the values were clinically acceptable, and 12% were in a range with possible effects on clinical decision-making; none were in a clinically dangerous range without appropriate treatment. Using a fibrinogen cutoff value of 1.5 g/L for standard-Fbg, the area under the receiver operating characteristic curve of whole blood-Fbg was 0.980 (95% confidence interval 0.951-1.000, p < 0.001). The whole blood coagulation analyzer can rapidly measure fibrinogen levels in heparinized blood and could be useful in critical care settings where excessive bleeding is a concern. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

SMN blood levels in a Porcine Model of Spinal Muscular Atrophy

PubMed Central

Iyer, Chitra; Wang, Xueqian; Renusch, Samantha R.; Duque, Sandra I.; Wehr, Allison M.; Mo, Xiaokui-Molly; McGovern, Vicki L.; Arnold, W. David; Burghes, Arthur H.M.; Kolb, Stephen J.

2017-01-01

Spinal Muscular Atrophy (SMA) is an autosomal recessive motor neuron disease that results in loss of spinal motor neurons, muscular weakness and, in severe cases, respiratory failure and death. SMA is caused by a deletion or mutation of the SMN1 gene and retention of the SMN2 gene that leads to low SMN expression levels. The measurement of SMN mRNA levels in peripheral blood samples has been used in SMA clinical studies as a pharmacodynamic biomarker for response to therapies designed to increase SMN levels. We recently developed a postnatal porcine model of SMA by the viral delivery of a short-hairpin RNA (shRNA) targeting porcine pSMN. scAAV9-mediated knockdown of pSMN mRNA at postnatal day 5 reliably resulted in denervation, weakness and motor neuron and ventral root axon loss that began 3–4 weeks after viral delivery, and this phenotype could be ameliorated by subsequent viral delivery of human SMN (hSMN). To determine if the effect of modulating SMN levels using gene therapy can be measured in blood, we measured expression of pSMN mRNA and hSMN mRNA by quantitative droplet digital PCR (ddPCR). We found that the endogenous expression of pSMN mRNA in blood increases in the first month of life. However, there were no significant differences in blood levels of pSMN mRNA after knock-down or of human SMN mRNA after gene therapy. Our results, obtained in a large animal model of SMA that is similar in size and anatomy to human infants, suggest that measurement of SMN mRNA levels in blood may not be informative in SMA clinical trials involving intrathecal delivery of SMN-modulating therapies. PMID:28269795

Association between individual-level and community-level socio-economic status and blood pressure among Inuit in Greenland.

PubMed

Riva, Mylène; Larsen, Christina Viskum Lytken; Bjerregaard, Peter

2016-01-01

Despite abundant evidence that socio-economic status (SES) is a fundamental determinant of health, there is a dearth of research examining association between SES, measured at the individual and community levels, and cardiovascular risk factors and morbidity among indigenous populations. To examine the influence of individual-level and community-level SES on systolic and diastolic blood pressure among Greenlandic Inuit. Multilevel analysis of cross-sectional data from the Inuit Health in Transition - Greenland Survey, to which 3,108 Greenlandic Inuit aged 18 years and older participated. Blood pressure is measured using an automatic device, according to standardized protocol. Individual SES is measured by education. Community socio-economic conditions are measured using combined information on average disposable household income and settlement type. Education was not significantly associated with blood pressure. There was an inverse U-shape association between community socio-economic conditions and blood pressure with significantly lower SBP and DBP among participants living in remote traditional villages characterized by lower average disposable household income and in affluent more urbanized towns. Sex-stratified analyses demonstrate the salience of community conditions for men. The association observed between blood pressure and community-level socio-economic conditions suggests that public health and social policies, programmes and interventions aiming to improve living conditions might improve cardiovascular health in Greenland. Studies are required to further examine social gradients in cardiovascular risk factors and morbidity among indigenous populations using different measures of SES.

Relationships of diet-related blood parameters and blood lead levels with psychopathology and aggression in forensic psychiatric inpatients.

PubMed

Zaalberg, Ap; Wielders, Jos; Bulten, Erik; van der Staak, Cees; Wouters, Anouk; Nijman, Henk

2016-07-01

Earlier studies have suggested associations between diet-related blood parameters and both aggression and psychopathological symptoms, but little is known about this in forensic psychiatric inpatients. This article aims to explore the levels of diet-related blood parameters and their relationship to aggressive behaviour and/or psychopathology among Dutch forensic psychiatric inpatients. Minerals, vitamins, lead and fatty acid levels were measured in blood samples from 51 inpatients, well enough to consent and participate in the study, from a possible total of 99. Levels of aggression and psychopathology were assessed using questionnaires, observation instruments and clinical data. Associations between blood parameters and behavioural measures were calculated. Low average levels of vitamin D3 and omega (ω)-3 fatty acids were found, with nearly two-thirds of the patients having below recommended levels of D3 , while vitamin B6 levels were high. Magnesium, iron, zinc, copper and lead were overall within reference values, but copper/zinc ratios were high. Several significant associations between levels of fatty acid measures and both aggression and psychopathology were observed. In our sample of forensic psychiatric inpatients, fatty acids - but not mineral or vitamin levels - were associated with aggression and psychopathology. A potentially causal link between fatty acids and aggression could be tested in a randomised, placebo-controlled trial of fish oil supplements. General health of such patients might be improved by better vitamin D status (increased sun exposure and/or supplement use) and better ω-3 fatty acid status (oily fish or fish oil consumption), but discouraging unnecessary self-prescription of B vitamins where necessary. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

Influence of mental stress on the plasma homocysteine level and blood pressure change in young men.

PubMed

Sawai, Asuka; Ohshige, Kenji; Kura, Naoki; Tochikubo, Osamu

2008-04-01

Objective. This study aimed to determine whether mental stress influences the plasma total homocysteine level or blood pressure in young men. Method. Twenty-seven male university students were assigned to a normal blood pressure group (24-h systolic blood pressure <125 mmHg and diastolic blood pressure <75 mmHg; 13 subjects) or a high blood pressure group (24-h systolic blood pressure > or =125 mmHg, or 24-h diastolic blood pressure > or =75 mmHg; 14 subjects). Wearing an ambulatory blood pressure monitoring device, subjects rested for 30 minutes, underwent an arithmetic test for 15 minutes, and rested again for 15 minutes. Blood samples were taken before and after the test. Plasma total homocysteine levels were measured. Heart rate, blood pressure, and sympathovagal balance were determined during the test. Results. The mean total homocysteine level at rest in the high blood pressure group was slightly, but not significantly, higher than that in the normal blood pressure group. The resting total homocysteine level was significantly higher in subjects with parental history of hypertension than in those without (p < 0.01). Blood pressure, heart rate, and the plasma total homocysteine level were increased significantly by mental stress (p < 0.05). The change in total homocysteine correlated significantly with the changes in systolic blood pressure and sympathovagal balance (p < 0.05). Conclusion. Resting total homocysteine level was significantly higher in male students with a parental history of hypertension than in those without. It was shown that mental stress elevates heart rate, blood pressure, sympathovagal activity, and the plasma total homocysteine level in young men.

Successful treatment with 308-nm monochromatic excimer light and subsequent tacrolimus 0.03% ointment in refractory plasma cell cheilitis.

PubMed

Yoshimura, Kazuhiro; Nakano, Shunji; Tsuruta, Daisuke; Ohata, Chika; Hashimoto, Takashi

2013-06-01

Plasma cell cheilitis is a chronic inflammatory disease that presents with erythema, erosions, ulcers and occasional nodules within the mucosa, including the lips. It is histopathologically characterized by dense plasma cell infiltration in the lamina propria of the mucous membranes. Several treatments for plasma cell cheilitis have been reported, including topical steroids, topical antibiotics or topical tacrolimus. However, 308-nm monochromatic excimer light (MEL) has never been reported as a treatment option, while it was reported to be very effective in treating erosive oral lichen planus. We report a 62-year-old man who had chronic plasma cell cheilitis on the lower lip, which was refractory to topical and systemic corticosteroid. The lesion and severe pain were significantly improved by the treatment with nine sessions of 308-nm MEL twice per week with a total dose of 1120 mJ/cm(2). However, the lesion gradually worsened after treatment frequency was reduced to once per month. Subsequent tacrolimus 0.03% ointment cleared the lesion completely in a month and no recurrence was observed a year later. Refractory plasma cell cheilitis and concomitant severe pain quickly responded to 308-nm MEL when administrated twice per week. Because the long interval between each MEL treatment seemed ineffective to improve the lesion, appropriate frequency and adequate total dose of MEL treatment may be necessary for a successful treatment. © 2013 Japanese Dermatological Association.

Effect of Short-term 900 MHz low level electromagnetic radiation exposure on blood serotonin and glutamate levels.

PubMed

Eris, A H; Kiziltan, H S; Meral, I; Genc, H; Trabzon, M; Seyithanoglu, H; Yagci, B; Uysal, O

2015-01-01

Long term exposure to low level electromagnetic radiation (LLER) by using cellular phones causes serious health problems. Ten male Wistar Albino rats were anesthetized 30 min before the LLER exposure, 0.5 ml blood was taken from the tail vein of rats in order to determine control values. Rats were grouped by three and placed on a plexi-glass flat. A fixed equivalent frequency emitter device was used. A sign to be an electromagnetic field 15.14 V/m (608 mW/m(2)) in strength in the head region with 100 kHz FM modulation at 900 MHz was applied to the animals. After calculating the ideal position for the device, electromagnetic LLER energy was applied for 45 minutes from a distance to be equal with energy transmitted by a mobile phone from a 0.5-1 cm distance to their head regions. After 1.5 hours and before the rats awoke, 0.5 ml of blood was taken from the tail veins in order to determine the treatment values. Plasma 5-HT and glutamate levels were measured by enzyme immunoassay (EIA) using commercial kits. It was found that a single 45 min of LLER exposure increased the blood 5-HT level significantly, but did not change the glutamate level of rats. It was concluded that even a single 45 min of LLER exposure may produce an increase in 5-HT level without changing the blood glutamate level. Increased 5-HT level may lead to a retarded learning and a deficit in spatial memory (Tab. 2, Fig. 2, Ref. 24).

Plasma apelin levels, blood pressure and cardiovascular risk factors in a coastal Chinese population.

PubMed

Zhu, Pengli; Huang, Feng; Lin, Fan; Yuan, Yin; Chen, Falin; Li, Qiaowei

2013-11-01

To describe the relationship of plasma apelin levels with blood pressure in a coastal Chinese population. This cross-sectional study included a total of 1031 subjects from the coastal areas of China. One-way analysis of variance (ANOVA) and linear trend test, Pearson's correlation analysis, as well as multivariate linear regression analysis were used to evaluate the association between plasma apelin levels and blood pressure. Plasma apelin levels dropped with increasing quartiles of systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial blood pressure (MABP) (all P<0.001). SBP, DBP, and MABP values decreased as the apelin levels increased within the quartiles. After adjusting for age and gender, the significant differences in SBP, DBP, and MABP between the groups within the apelin quartiles remained (all P<0.05). A significant negative correlation between SBP, DBP, as well as MABP and apelin levels was observed (all P<0.01); even after adjusting for cardiovascular confounding factors, this negative correlation remained (all P<0.001). A negative correlation between plasma apelin levels and blood pressure was found in this 1000-population-based epidemiological study. Apelin may become a potential therapeutic target of anti-hypertensive treatment.

Blood lead levels in NASCAR Nextel Cup teams.

PubMed

O'Neil, Joseph; Steele, Gregory; McNair, C Scott; Matusiak, Matthew M; Madlem, Jyl

2006-02-01

This pilot study determines whether NASCAR racing teams demonstrate exposure to lead from exhaust by evaluation of blood lead levels (BLL). Participants were stratified by proximity to fuel exhaust or whether they worked on an engine. Each participant completed a self-reported survey recording demographics, lead exposure (occupational or in-home environment), and any physical symptoms of lead toxicity. Blood lead levels were then measured. BLL of 47 individuals ranged from 1-22 microg/dL with a median of 9.4 microg/dL. Nineteen of 47 (40.4%) had BLL > or = 10 microg/dL. Participants exposed to exhaust gas had the highest relative risks (RR) for elevated lead, followed by working on brakes and radiator repair. The RR of having an elevated BLL and self-reported adverse health outcomes or symptoms was increased. This study of NASCAR racing teams demonstrates lead exposure.

Vitamins and iron blood biomarkers are associated with blood pressure levels in European adolescents. The HELENA study.

PubMed

de Moraes, Augusto César Ferreira; Gracia-Marco, Luis; Iglesia, Iris; González-Gross, Marcela; Breidenassel, Christina; Ferrari, Marika; Molnar, Dénes; Gómez-Martínez, Sonia; Androutsos, Odysseas; Kafatos, Anthony; Cuenca-García, Magdalena; Sjöström, Michael; Gottrand, Frederic; Widhalm, Kurt; Carvalho, Heráclito Barbosa; Moreno, Luis A

2014-01-01

Previous research showed that low concentration of biomarkers in the blood during adolescence (i.e., iron status; retinol; and vitamins B6, B12, C, and D) may be involved in the early stages of development of many chronic diseases, such as hypertension. The aim was to evaluate if iron biomarkers and vitamins in the blood are associated with blood pressure in European adolescents. Participants from the Healthy Lifestyle in Europe by Nutrition in Adolescence cross-sectional study (N = 1089; 12.5-17.5 y; 580 girls) were selected by complex sampling. Multilevel linear regression models examined the associations between iron biomarkers and vitamins in the blood and blood pressure; the analyses were stratified by sex and adjusted for contextual and individual potential confounders. A positive association was found in girls between RBC folate concentration and systolic blood pressure (SBP) (β = 3.19; 95% confidence interval [CI], 0.61-5.77), although no association between the vitamin serum biomarkers concentrations and diastolic blood pressure (DBP) was found. In boys, retinol was positively associated with DBP (β = 3.84; 95% CI, 0.51-7.17) and vitamin B6 was positively associated with SBP (β = 3.82; 95% CI, 1.46-6.18). In contrast, holotranscobalamin was inversely associated with SBP (β = -3.74; 95% CI, -7.28 to -0.21). Levels of RBC folate and vitamin B6 in blood may affect BP in adolescents. In this context, programs aimed at avoiding high BP levels should promote healthy eating behavior by focusing on the promotion of vegetable proteins and foods rich in vitamin B12 (i.e., white meat and eggs), which may help to achieve BP blood control in adolescents. Copyright © 2014 Elsevier Inc. All rights reserved.

Insufficient acetabular version increases blood metal ion levels after metal-on-metal hip resurfacing.

PubMed

Hart, Alister J; Skinner, John A; Henckel, Johann; Sampson, Barry; Gordon, Fabiana

2011-09-01

Many factors affect the blood metal ion levels after metal-on-metal (MOM) hip arthroplasty. The main surgically adjustable variable is the amount of coverage of the head provided by the cup which is a function of the inclination and version angles. However, most studies have used plain radiographs which have questionable precision and accuracy, particularly for version and large diameter metal heads; further, these studies do not simultaneously assess version and inclination. Thus the relationship between version and blood metal ions levels has not been resolved. We determined whether cup inclination and version influence blood metal ion levels while adjusting for age at assessment, gender, body mass index, horizontal femoral offset, head size, manufacturer hip type, and Oxford hip score. We prospectively followed 100 individuals (51 females, 49 males) with unilateral MOM hip resurfacing who underwent clinical assessment, CT scanning, and blood metal ion measurement. Multiple regression analysis was used to determine which variables were predictors of blood metal ion levels and to model the effect of these variables. Only cup inclination, version angles, and gender influenced blood cobalt or chromium levels. Cobalt and chromium levels positively correlated with inclination angle and negatively correlated with version angle. The effect of changes in version angle was less than for inclination angle. Based on our observations, we developed a formula to predict the effect of these parameters on metal ion levels. Our data suggest insufficient cup version can cause high blood metal ions after MOM hip arthroplasty. We were unable to show that excessive version caused high levels. Level II, prognostic study. See Guidelines for Authors for a complete description of levels of evidence.

Both physiology and epidemiology support zero tolerable blood lead levels.

PubMed

Shefa, Syeda T; Héroux, Paul

2017-10-05

Inorganic lead is one of the most common causes of environmental metal poisonings, and its adverse effects on multiple body systems are of great concern. The brain, along with the kidneys, are critically susceptible to lead toxicity for their hosting of high affinity lead binding proteins, and very sensitive physiology. Prolonged low-lead exposure frequently remains unrecognized, causes subtle changes in these organ systems, and manifests later at an irreversible stage. With the repeated documentation of "no safe blood lead level", the pernicious effects of lead at any measurable concentration need to be emphasized. In this review, we surveyed articles on chronic low-level lead exposures with a blood lead concentrations <10μg/dL and the development of neurobehavioral or renal disorders. The negative impacts of lead on both nervous and renal systems were obvious at a blood lead concentration of 2μg/dL, with the absence of any detectable threshold. The deleterious effect of lead on two different organ systems at such low concentrations drew our attention to the various extracellular and intracellular events that might be affected by minimal concentration of body lead, especially blood lead. Is there a true common ground between low-level lead toxicity in both the nervous system and the kidney? Copyright © 2017 Elsevier B.V. All rights reserved.

Blood Glucose Levels Following Intra-Articular Steroid Injections in Patients with Diabetes: A Systematic Review.

PubMed

Choudhry, M N; Malik, R A; Charalambous, Charalambos Panayiotou

2016-03-22

Parenterally administered steroids have been shown to affect the metabolism of glucose and to cause abnormal blood glucose levels in diabetic patients. These abnormal blood glucose levels in diabetic patients raise concerns that intra-articular steroid injections also may affect blood glucose levels. We performed a systematic review of studies examining the effect of intra-articular steroid injections on blood glucose levels in patients with diabetes mellitus. A literature search of the PubMed, EMBASE, AMED, and CINAHL databases using all relevant keywords and phrases revealed 532 manuscripts. After the application of inclusion criteria, seven studies with a total of seventy-two patients were analyzed. All studies showed a rise in blood glucose levels following intra-articular steroid injection. Four of the seven studies showed a substantial increase in blood glucose. Peak values reached as high as 500 mg/dL. The peak increase in blood glucose did not occur immediately following intra-articular steroid injection, and in some cases it took several days to occur. In many patients, post-injection hyperglycemia occurred within twenty-four to seventy-two hours. Intra-articular steroid injections may cause hyperglycemia in patients with diabetes mellitus, and patients should be warned of this complication. Diabetic patients should be advised to regularly monitor their blood glucose levels for up to a week after injection and should seek medical advice if safe thresholds are breached. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Laboratory Measurement Implications of Decreasing Childhood Blood Lead Levels

PubMed Central

Caldwell, Kathleen L.; Cheng, Po-Yung; Jarrett, Jeffery M.; Makhmudov, Amir; Vance, Kathryn; Ward, Cynthia D.; Jones, Robert L.; Mortensen, Mary E.

2017-01-01

In 2012, the Centers for Disease Control and Prevention (CDC) adopted its Advisory Committee on Childhood Lead Poisoning Prevention (ACCLPP) recommendation to use a population-based reference value to identify children and environments associated with lead hazards. The current reference value of 5 μg/dL is calculated as the 97.5th percentile of the distribution of blood lead levels (BLL) in children one to five years old from 2007–2010 National Health and Nutrition Examination Survey (NHANES) data. We calculated and updated selected percentiles, including the 97.5th percentile, using NHANES 2011–2014 blood lead data and examined demographic characteristics of children whose blood lead was ≥90th percentile value. The 97.5% percentile BLL of 3.48 μg/dL highlighted analytical laboratory and clinical interpretation challenges of blood lead measurements ≤ 5 μg/dL. Review of five years of results for target blood lead values < 11 μg/dL for U.S. clinical laboratories participating in CDC’s voluntary Lead and Multi-Element Proficiency (LAMP) quality assurance program showed 40% unable to quantify and reported a non-detectable result at a target blood lead value of 1.48 μg/dL compared 5.5 % at a target blood lead of 4.60 μg/dL. We describe actions taken at CDC’s Environmental Health Laboratory in the Division of Laboratory Sciences, which measures blood lead for NHANES, to improve analytical accuracy and precision and to reduce external lead contamination during blood collection and analysis. PMID:28771411

Effect of environmental lead pollution on blood lead levels in traffic police constables in Islamabad, Pakistan.

PubMed

Agha, Farida; Sadaruddin, Agha; Khatoon, Naz

2005-10-01

To determine the blood lead levels and trace elements (copper and manganese) in traffic police constables in Islamabad in order to assess the effects of environmental pollution on the levels of metals in body fluids. Blood samples were collected from 47 male traffic police constables, 21 to 45 years of age, posted in different areas of Islamabad and controlling traffic from 3 months to 18 years, 8 hours/day, 6 days/week. Adolescent males (13-19 years), residing in comparatively clean and very low traffic areas were included as controls. Blood lead, copper, and manganese concentrations were estimated by atomic absorption spectrophotometry. The mean blood lead level among constables (27.27 microg/dl) was significantly (p<0.0001) high as compared to controls (3.22 microg/dl). Twenty one percent constables had elevated blood lead levels (over 25 microg/dl) and 13% had levels above the safety limit (40 microg/dl). No correlation was found between blood lead levels and length of service. No significant difference was found in the mean values for copper between traffic constables (93.49 microg/dl) and controls (71.15 microg/dl). The mean blood manganese levels in traffic constables (21.94 microg/dl) were significantly (p<0.0001) higher than in controls (1.70 microg/dl). The mean blood lead levels were significantly high in traffic constables of Karachi (47.7 microg/dl) as compared to Islamabad (27.2 microg/dl), which shows direct relation of rise in blood lead levels with vehicle exhaust. Environmental lead pollution is associated with an increased blood lead concentration in those who are regularly exposed to vehicle exhaust in high traffic areas. The degree of lead pollution arising from vehicle exhaust differs in Karachi and Islamabad. Exposure to air containing dust particles rich in manganese may affect blood manganese levels.

[Blood and urine lead levels in children with attention deficit hyperactivity disorder].

PubMed

Sánchez-Villegas, M del Carmen S; Cortés-Vargas, Astrid; Hidalgo-Luna, Ricardo Gerardo; Alam-Escamilla, David Abraham; Vargas-García, Víctor Manuel; Loría-Castellanos, Jorge

2014-01-01

Attention deficit hyperactivity disorder is the most common neuropsychiatric disorder in children; symptoms can persist into adult life by 60 %. Our objective was to quantify the levels of lead in blood and urine in pediatric patients with attention deficit hyperactivity disorder. We did an observational study which included a captive population of children diagnosed with attention deficit hyperactivity disorder in the mental health service of Hospital General, from Centro Médico Nacional La Raza. Lead levels were determined in blood and urine by atomic absorption technique. We included 39 patients, 932 % male, with a mean age of 9.2 ± 2.16 years. The deficit and hyperactivity disorder combined type was the most frequent (69.2 %); 49 % of patients were found with toxic lead levels in blood (above 10 mg/dL); 17.9 % with stage III and 5.12 % with stage IV, according to the Mexican Official Standard (NOM-199-SSA-2000). Significant association was found between blood lead levels and the clinical expression of attention deficit hyperactivity disorder. Levels of lead exposure during early childhood have been shown to be inversely proportional to neurological development in the first seven years of life. Data results are insufficient to relate them with causality.

Surface dust wipes are the best predictors of blood leads in young children with elevated blood lead levels

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gulson, Brian, E-mail: brian.gulson@mq.edu.au; CSIRO Earth Science and Resource Engineering, North Ryde NSW 2113; Anderson, Phil

Background: As part of the only national survey of lead in Australian children, which was undertaken in 1996, lead isotopic and lead concentration measurements were obtained from children from 24 dwellings whose blood lead levels were ≥15 µg/dL in an attempt to determine the source(s) of their elevated blood lead. Comparisons were made with data for six children with lower blood lead levels (<10 µg/dL). Methods: Thermal ionisation and isotope dilution mass spectrometry were used to determine high precision lead isotopic ratios ({sup 208}Pb/{sup 206}Pb, {sup 207}Pb/{sup 206}Pb and {sup 206}Pb/{sup 204}Pb) and lead concentrations in blood, dust from floormore » wipes, soil, drinking water and paint (where available). Evaluation of associations between blood and the environmental samples was based on the analysis of individual cases, and Pearson correlations and multiple regression analyses based on the whole dataset. Results and discussion: The correlations showed an association for isotopic ratios in blood and wipes (r=0.52, 95% CI 0.19–0.74), blood and soil (r=0.33, 95% CI −0.05–0.62), and blood and paint (r=0.56, 95% CI 0.09–0.83). The regression analyses indicated that the only statistically significant relationship for blood isotopic ratios was with dust wipes (B=0.65, 95% CI 0.35–0.95); there were no significant associations for lead concentrations in blood and environmental samples. There is a strong isotopic correlation of soils and house dust (r=0.53, 95% CI 0.20–0.75) indicative of a common source(s) for lead in soil and house dust. In contrast, as with the regression analyses, no such association is present for bulk lead concentrations (r=−0.003, 95% CI −0.37–0.36), the most common approach employed in source investigations. In evaluation of the isotopic results on a case by case basis, the strongest associations were for dust wipes and blood. -- Highlights: • Children with elevated blood lead ≥15 µg/dL compared with a group

Effect of cholesterol and triglycerides levels on the rheological behavior of human blood

NASA Astrophysics Data System (ADS)

Moreno, Leonardo; Calderas, Fausto; Sanchez-Olivares, Guadalupe; Medina-Torres, Luis; Sanchez-Solis, Antonio; Manero, Octavio

2015-02-01

Important public health problems worldwide such as obesity, diabetes, hyperlipidemia and coronary diseases are quite common. These problems arise from numerous factors, such as hyper-caloric diets, sedentary habits and other epigenetic factors. With respect to Mexico, the population reference values of total cholesterol in plasma are around 200 mg/dL. However, a large proportion has higher levels than this reference value. In this work, we analyze the rheological properties of human blood obtained from 20 donors, as a function of cholesterol and triglyceride levels, upon a protocol previously approved by the health authorities. Samples with high and low cholesterol and triglyceride levels were selected and analyzed by simple-continuous and linear-oscillatory shear flow. Rheometric properties were measured and related to the structure and composition of human blood. In addition, rheometric data were modeled by using several constitutive equations: Bautista-Manero-Puig (BMP) and the multimodal Maxwell equations to predict the flow behavior of human blood. Finally, a comparison was made among various models, namely, the BMP, Carreau and Quemada equations for simple shear rate flow. An important relationship was found between cholesterol, triglycerides and the structure of human blood. Results show that blood with high cholesterol levels (400 mg/dL) has flow properties fully different (higher viscosity and a more pseudo-plastic behavior) than blood with lower levels of cholesterol (tendency to Newtonian behavior or viscosity plateau at low shear rates).

The child-adolescent blood pressure study: I. Distribution of blood pressure levels in Seventh-Day-Adventist (SDA) and non-SDA children.

PubMed

Harris, R D; Phillips, R L; Williams, P M; Kuzma, J W; Fraser, G E

1981-12-01

Distribution of systolic and diastolic blood pressures (measured with an automated blood pressure recorder) of two large groups of children-3,159 from Seventh-Day Adventist (SDA) schools and 4,681 from non-SDA schools-are reported. They boys and girls were from four different ethnic groups and attended grades one through 10 in 29 Southern California schools. The analysis of the data failed to show significant differences in mean blood pressure levels between the two groups of children at all ages, despite marked differences in life-style between the two groups, and despite the fact that adults from the two population groups have marked differences in mortality from diseases associated with elevated blood pressure. A comparison between boys and girls showed significantly higher trends in mean systolic blood pressure for boys after age 12. Inter-ethnic comparisons of blood pressure revealed that Black children of both sexes had slightly higher mean blood pressure levels at all ages.

The child-adolescent blood pressure study: I. Distribution of blood pressure levels in Seventh-Day-Adventist (SDA) and non-SDA children.

PubMed Central

Harris, R D; Phillips, R L; Williams, P M; Kuzma, J W; Fraser, G E

1981-01-01

Distribution of systolic and diastolic blood pressures (measured with an automated blood pressure recorder) of two large groups of children-3,159 from Seventh-Day Adventist (SDA) schools and 4,681 from non-SDA schools-are reported. They boys and girls were from four different ethnic groups and attended grades one through 10 in 29 Southern California schools. The analysis of the data failed to show significant differences in mean blood pressure levels between the two groups of children at all ages, despite marked differences in life-style between the two groups, and despite the fact that adults from the two population groups have marked differences in mortality from diseases associated with elevated blood pressure. A comparison between boys and girls showed significantly higher trends in mean systolic blood pressure for boys after age 12. Inter-ethnic comparisons of blood pressure revealed that Black children of both sexes had slightly higher mean blood pressure levels at all ages. PMID:7315999

The Effects of Blood Glucose Levels on Cognitive Performance: A Review of the Literature

NASA Technical Reports Server (NTRS)

Feldman, Jolene; Barshi, Immanuel

2007-01-01

The purpose of this review paper is to discuss the research literature on the effects of blood glucose levels on executive and non-executive functions in humans. The review begins with a brief description of blood glucose, how it has been studied, previous syntheses of prior studies, and basic results regarding the role of blood glucose on cognitive functioning. The following sections describe work that investigated the effect of blood glucose on both non-executive and executive functions (e.g., sensory processing, psychomotor functioning, attention, vigilance, memory, language and communication, judgement and decision-making, and complex task performance). Within each section, summaries of the findings and challenges to the literature are included. Measurement conversions of blood glucose levels, blood glucose values, and associated symptoms are depicted. References to the types of tests used to investigate blood glucose and cognitive performance are provided. For more detailed descriptions of references within (and in addition to) this paper, an annotated bibliography is also provided. Several moderator variables including individual differences and contextual variables related to the effects of blood glucose levels on performance (e.g., age, gender, time of day, familiarity with the task and symptom awareness, expectancy effects, dose dependent effects, time dependent effects, task specific effects, rising and falling blood glucose levels, and speed and/or accuracy trade-offs) are addressed later in the paper. Some suggestions for future experimental methodologies are also made.

Relation of pediatric blood lead levels to lead in gasoline.

PubMed Central

Billick, I H; Curran, A S; Shier, D R

1980-01-01

Analysis of a large data set of pediatric blood lead levels collected in New York City (1970-1976) shows a highly significant association between geometric mean blood lead levels and the amount of lead present in gasoline sold during the same period. This association was observed for all age and ethnic groups studied, and it suggests that possible exposure pathways other than ambient air should be considered. Even without detailed knowledge of the exact exposure pathways, sufficient information now exists for policy analysis and decisions relevant to controls and standards related to lead in gasoline and its effect on subsets of the population. PMID:7389685

Intracerebroventricular Kainic Acid-Induced Damage Affects Blood Glucose Level in d-glucose-fed Mouse Model

PubMed Central

Kim, Chea-Ha

2015-01-01

We have previously reported that the intracerebroventricular (i.c.v.) administration of kainic acid (KA) results in significant neuronal damage on the hippocampal CA3 region. In this study, we examined possible changes in the blood glucose level after i.c.v. pretreatment with KA. The blood glucose level was elevated at 30 min, began to decrease at 60 min and returned to normal at 120 min after D-glucose-feeding. We found that the blood glucose level in the KA-pretreated group was higher than in the saline-pretreated group. The up-regulation of the blood glucose level in the KA-pretreated group was still present even after 1~4 weeks. The plasma corticosterone and insulin levels were slightly higher in the KA-treated group. Corticosterone levels decreased whereas insulin levels were elevated when mice were fed with D-glucose. The i.c.v. pretreatment with KA for 24 hr caused a significant reversal of D-glucose-induced down-regulation of corticosterone level. However, the insulin level was enhanced in the KA-pretreated group compared to the vehicle-treated group when mice were fed with D-glucose. These results suggest that KA-induced alterations of the blood glucose level are related to cell death in the CA3 region whereas the up-regulation of blood glucose level in the KA-pretreated group appears to be due to a reversal of D-glucose feeding-induced down-regulation of corticosterone level. PMID:25792867

Intracerebroventricular Kainic Acid-Induced Damage Affects Blood Glucose Level in d-glucose-fed Mouse Model.

PubMed

Kim, Chea-Ha; Hong, Jae-Seung

2015-03-01

We have previously reported that the intracerebroventricular (i.c.v.) administration of kainic acid (KA) results in significant neuronal damage on the hippocampal CA3 region. In this study, we examined possible changes in the blood glucose level after i.c.v. pretreatment with KA. The blood glucose level was elevated at 30 min, began to decrease at 60 min and returned to normal at 120 min after D-glucose-feeding. We found that the blood glucose level in the KA-pretreated group was higher than in the saline-pretreated group. The up-regulation of the blood glucose level in the KA-pretreated group was still present even after 1~4 weeks. The plasma corticosterone and insulin levels were slightly higher in the KA-treated group. Corticosterone levels decreased whereas insulin levels were elevated when mice were fed with D-glucose. The i.c.v. pretreatment with KA for 24 hr caused a significant reversal of D-glucose-induced down-regulation of corticosterone level. However, the insulin level was enhanced in the KA-pretreated group compared to the vehicle-treated group when mice were fed with D-glucose. These results suggest that KA-induced alterations of the blood glucose level are related to cell death in the CA3 region whereas the up-regulation of blood glucose level in the KA-pretreated group appears to be due to a reversal of D-glucose feeding-induced down-regulation of corticosterone level.

Association of sleep duration with blood glucose level of Gujarati Indian adolescents.

PubMed

Patel, Minal C; Shaikh, Wasim A; Singh, S K

2012-01-01

Recently studies conducted in various parts of the world indicate short sleep duration as a novel risk factor for development of type 2 diabetes. However, ethnic differences exist in the etiopathogenesis of diseases, the current study was undertaken to study the effect of sleep duration on the blood glucose level of Gujarati Indian adolescents. A randomized, non-experimental, cross-sectional study was done on the voluntary participants n = 332 Gujarati adolescent boys and girls of age group 13-20 years studying at the schools and colleges in the Anand district. The participants were assessed for their sleep duration, body composition and blood glucose level. The sleep duration was reported by the subjects as the number of hours they slept on most of the nights in a week over the last one-year. The observations of the study were then analyzed after grouping them into: 1) Adequate sleep duration at night, ASDN (> or = 7 hrs) and 2) Inadequate sleep duration at night, ISDN (< 7 hrs) groups. One-way ANOVA and post hoc Tuky-Krammer test were used for finding significant differences (P < 0.05) between groups. No significant difference was found in all parameters of body composition and fasting blood glucose level between the ASDN group and ISDN group in both boys and girls. However, gender difference exists in the body composition and blood glucose level. The current study indicates that inadequate sleep duration at night (< 7 hrs) does not affect the blood glucose level of the Gujarati Indian adolescents of age group 13-20 years.